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WO2025129158A1 - Engineered arc delivery vesicles and uses thereof - Google Patents

Engineered arc delivery vesicles and uses thereof Download PDF

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WO2025129158A1
WO2025129158A1 PCT/US2024/060268 US2024060268W WO2025129158A1 WO 2025129158 A1 WO2025129158 A1 WO 2025129158A1 US 2024060268 W US2024060268 W US 2024060268W WO 2025129158 A1 WO2025129158 A1 WO 2025129158A1
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aenn
noe
revcoor
engineered
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Feng Zhang
Michael Segel
Blake Lash
Daniel STREBINGER
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Massachusetts Institute of Technology
Broad Institute Inc
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    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/01—Carboxylic ester hydrolases (3.1.1)
    • C12Y301/01004—Phospholipase A2 (3.1.1.4)

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Abstract

Provided herein are compositions, systems, and methods for delivering cargo to a cell. The compositions, systems, and methods comprise one or more engineered Arc polypeptides, engineered delivery vesicles containing the one or more engineered Arc polypeptides, and delivering a cargo to a cell using the engineered delivery vesicles.

Description

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^ 114412717 A ARR R Nannoorantaecaurset maocne snu-nose XM_1714.1 XP_1777.1 11272 A ARR Panteraaruetsr eoar X X XMMM111472724.121 X X XPPP1114127.111
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^v=c"oco"r^:^ec"^^e^"^:^^ ^ ^ ^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^noe=nn"noo__orwem ev:^cscoeoo-os urru e==m n""o-w ce:^ccccc""^"c^^caaaacaaaaaaacaacaaacc^ ^^no_revcoor:^ cc"^ ^ ^^:^^ ^ ^^ ^^^^^^^^^^^s^^^^o^^^^^^u^^^^r^^^^c^^^^e^^^^^^^^^^^^^^^a^^^e="s..ource^"^ ^^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^noe=nn"oo__rwevnccooo_ororer=v="c"ooeeraa:^"e"^a^"^ ^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^a^en=".o._rraenvsc^oaoorn=^"-"^"^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^ ^^^ ^^^ ^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^^^^^ar^ansna.o._own="c^oor"=^" "^ ^ ^ ^^ ^^ ^^^ ^^ ^^^ ^^ ^^^ ^^ ^^^ ^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^^ ^^^^^ ^^^^^ ^^^^^ ^^^^^ ^^^^^ ^^^^ ^^e ^^^^^r^ansnn=" ao .o_ ._orwnev"^ =c"co ^ooorr"==^"" cc""^^ ^ ^ ^^ ^^^^ ^^^^ ^^^^ ^^^^^^^^^^^^^^^^^^^^^aen="o_rev"c^oor=" "^ r^^^^^ a^^^^^^ n^^^^^^^^^ s^^^^^^^^^ a^^^^^^^^^^^^^^^ o^^^^^nnno_wcoor=" "^ =o"e="no_revcoor:^ "^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^a^..^ "^^^:^^ ^ ^ ^^^^^^^^^^^ r^^^^^^ a^^^^^^^^^^^^^^^^^^en="o_rev"^coor=" c"^ n^^^^^^s^^^^^^a^^^^^^^^^^o^^^^n="no_wcoor=" c"^ ^ ^^^^^^^^^m^^^^^s^^c^^_eaure^^^^..^ "^^^:^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^aenn="oo__orwzeavcc^osoeoorru==e""nce"a^aaacc""^^ ^ ^ ^ ^^ ^^^^ ^^^^ ^^^^ ^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^n^a^oee=="".."n^^o_revcoor:^aac"^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^ nnoo__rwevccoooorr=="" cc""^^ ^r^^a^^n^^^s^^^a^^^^^o^^n=" ^^^^^^^^^^^^^^^^^^^..^"^^^:^^ ^ ^ ^^ ^^^ ^^ ^^^ ^^ ^^^ ^^ ^^^ r^^ ^^^ ^^ ^^^ a^^ ^^^ ^^ ^^^ n^^ ^^^ ^^ ^^^ ^^ ^^^ s^^ ^^^ ^^ ^^^ ^^ ^^^^^^^^^^^^^^^^^^^^aenn="oo__rwevccoooo"r^r==""aaee""^^ a^^^^^^^^^^^^^^noe="no_revcoor:^ae"^ ^ ^^^^^^^^^m^^^^^s^^c^^_^^^eoanu=r"e^^^^comemen"^..^^^:^^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^aenn="oos__urmwevoc-comooorr==-r""ev"^aaaacc""^^ ^ ^no_^^r^^e^vncoooer=:"^noea:^seuence:^ccccaccacaaa^^^:^^ ^^^^^^^^^^m^^^^^s^^c^^_^^^^e^^a^uaree^^^^="s_.".^ac"^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^noe=nn"noo__orweev:^cscoeooourre==n""ce:^aaee"c"^^ ^no_revcoor:^ae"^ ccc^^^^:^^ ^ ^^ ^^ ^^^^^^^^^^^m^^^^^^^^^^s^^^^c^^^^_^^^^^^^^e^^^^a^^uaree^^^n^="o_rne..vecro"^or^="a ^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^m^ ^^^^^^^^^^s^^^^c^^^^_^^^^^^e^^^^a^^unroee^^^=n^"o_w..ncoo_roe^rv=c"oor:a^aacc""^a^ac"^ ^ ^ ^^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^ae ^^^^^nn=" .oo__rwevaccoooorr=="""^ee""^^ ^^ ^^^^ ^^^^ ^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^aenn="o. o__rrawenvsc^ coaoooorrn==^""-""^^"^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^r^ansa..on="^ "^^^:^^ ^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ae="ransaon^-"^ ^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ n ^^^^r^ansnao .o_ ._orwnev=c"co ^ooorr=="" ""^^"^^^:^^ ^ ^ ^^^^^^^^^^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^aenn="oo__rrawenvsccoaoooorrn==^""-""^^"^ ^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^r^ansa..on="^ "^^^:^^ ^ ^^^^^^^^^^^^^^^^^^^^^ae="rc^^cv-reuae^coseeon^assocae^roen^"^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^noe=nn"oo__rwevnccooo_ororer=v="c"occorcc:^c""c^^"^ ^ ^^^^r^^a^^n^^^s^^^a^^^^^o^^n=" ^^^^^^:^^^^^^^ *"^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^a^e=".."^^ ^ ^^^^^^^r^^^^a^^^^n^^^^^^^ s^^^^^^^^^ a^^^^^^^^^^^^^^^ o^^^^^ n n="noo__rwevccoooorr=="" cc""^^ ^:^^ *"^^
Figure imgf000274_0001
^ ^^^^^^^^^^^^^^n^^^^o^^_^^r^^e^vncoooer=:"^ncoec:^se"u^ence:^cccacac c^ ^^ :^ ^ ^ ^ ^^ ^^^^^^^^m^^^^^^^^^^s^^^^c^^^^_^^^^^^^^e^^^^a^^uaree^^^n^="oa_mre..an-w^"^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^noe=n"o_wvnccooo_ororer==""ee""^^ ^^^^^^^^^^^m^^^^^s^^c^^_^^^^e^^a^uaree^^^^=c"ocmermemenv-croevo"r^.:.^ e^"^ ^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^m^^^^^n^^^^ s^^^^^^^^ ^^c^^o^^^^ _^^ ^^_^^^^^^ ^^er^^^^^^ ^^e^ a^ n ^vuncarooeeoe^^^r=no ^=:"^no__orweev:c " ..a^scoeooourre==n""ce:^aaaaaeec""^c^aaaacca acca ccccaac^ ^^ :^ ^ "^e"^^
Figure imgf000275_0001
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Figure imgf000275_0002
^ ^ ^^^^^^^^^^^^^^^^ ^^^cccccaaaaaccccaaa^^c^accaaaacacacccc^^a^ccaacaaaccaca^c^^caacacaaa^^ca^cacacccaac^c^ccacaccaa^^ ^ ^^^^^^^^^^^ ^^aacaaacaccc^^ccaacacc^a^cccaccccacc^ccccca^caccca^^cacccaac^^ ^ ^ ^^ ^^^^^^^^^^ ^ca aa^accaaaa^aaca ^a^cacaaaaaacc^ca^aacaacaaa^acc^ccaacaaaacac^^ ^^^^^^^^^^^^^^^ ^ ^ ^^a ^aca ccaa ccccaa cccaccaccca^^^cc^c caccaccccccacac^^^cccccccacaaa^^ac^cccccacacccacccc^^acccc^ccaccaaaacac^aac^ac^caaccaaacccaca^a^^ ^ ^ ^^^^^^^^^^^^^^^ ^^a^acccccccacc^a^^cccacacacccc^a ca^^ca ca^cacccaaaaaccc^ ca^^cc^accacaa acccaac^^^aaaccccca ^ccacaacccacac^ aca^^acca ^aaccaac ccccc^ac^^c^ ^ . , .- .. .-, .... .. . .. .. - . . , .. . ..- . , .. , . ...- - . - -..- - . ..,.-.. , .,. , . , .. , - ,. , , ^ - ... . ..- - . - . .. ... . . . .. , , .. .., , . .. . . . . . - . . - .. . . .. - .. . ^ .-. . . . .. ,.., , , .-. . . ., .. . .. .. , - , . . aoneo.ns xermen
Figure imgf000280_0001
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Figure imgf000286_0001
, . ,- . ., , , . , , - -. . .,., , ,-. , . .,... ^ , .-. . .. . , - .-... .. . . . ., , ,. ,– - .. ..- .. --... , . .. - ., . , -. .. . .. . .. . , , - .. ^ .. ., . . .. . , , - . . .. . .- - , .. . , .–,. - .,.. ,....,..,, .,, .., . , , .. . ^^^^^^^o_o_aav-vu^^^^^^^^s-^^^^_ _ . ^^^^^.^^"creaor:roa^nsue"^"mar ^crcuar^^^^^--^ ^^^ ^^^^^more^usn^e^enan^meorr:emr.^"e^^name:^ ^^^^^^^^^^x- ^^^^^re_or^s^n^-^^^m^^^^^^^^^^c^^o^-mocsauemmoneon-aurac-..neresr^ma^_n-erma.^ ^ ^^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^aenn="o_orevc^ooror=n""^ea"^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^n^^ocoem="oe_mwenncoo_roerv=c"o..oera:^^e"a^"^ ^ ^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^aenn="oo__mrwevcco"o^oorr==""aae"^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^n^^ocoem="emenno_revco..or:^^e"^ae"^ ^ ^^^^^^^r^^^^a^^^^n^^^^^^s^^^^^^a^^^^^^^^^^^^^ o^^^^^ n n="noo__rwevccoooorr=="" cc""^^ "^^^:^^
Figure imgf000288_0001
^ ^ ^^^^^^^^^^^^r^^^m^^^^e^^r^^_^^na^e^^^=^""^.. ^ ^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ no_revcoor="aac"^ ^^^^^^^^^^^^^^m^^^^^^^^^s^^^^c^^^^_^^^^^^^^^^n^^none^^=n^^"o_w.n.coo_roer^v=c"ooara:c^a"a^c"^ ^ ^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^aenn="oo__arcwev"cc^oooorr==""cc ee""^^ ^^ ^^^^ ^^^^ ^^^^ ^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^n^a^oee=="".."n^^o_revcoor:^c e"^ ^ ^ ^^ ^^^^ ^^^^^^^^^^^^^ m^^^^^^^^^^^^^^^ s^^^^^^ c^^^^^^ _^^^^^^^^^ e^^^^^^ a^^unroee^^^=nn^c"o oo_ m_rwevnc eco mooo e_ror ner=v="c"oora .:aa .^acc""^a^^ac"^ ^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^^^^^^^^^^^^^^ae="roen-roucon--rev"^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^noe=nn"noo__orweevccoooorr==""cccc""^^ ^ ^^^^^^^^^^^^^^n^^^^^o^^^^_^^r^^e^^v^^c^^oor:^..cc:^s^e"u^ence:^cca aaaaacc a aaaca aaccccaaa^ ^^ :^ ^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^aenn="oo__rrawenvsccoaoooorrn==^"" -""^^"^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^a^en=".o._rraenvsc^oaoorn=^" e-"^"^ ^ ^ ^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ nn.oo.__rwevcc^oooorr=="" ec""^^ ^^^^r^^a^^n^^^s^^^^^^a^^^^^^^^^^o^^^^n="no_wcoor=" c"^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ .. ^ "^ ^^ :^ ^ ^ ^^^^^^^r^^^^a^^^^n^^^^^^s^^^^^^^ a^^^^^^^^^^^^^^^ o^^^^^ n n="noo__rwevccoooorr=="" cc""^^ ^ ^ "^ ^^ :^ ^ ^^ ^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^a^en=".o._rraenvsc^oaoorn=^" -ae"^"^ ^ ^ ^^ ^^^^^^^^^^^^e^^^^^x^^^^o^^^^n^^^^^^^^^^^^^^^^^^^^^^^^^^^^^a^en="o.._rawnsc^aooorn=^" -ae"^"^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ nn.oo.__rwevcc^oooorr=="" aaaacc""^^ ^ ^ ^ ^^ ^^ ^^^ ^^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^aenn="oo__xrwevscc"o^ooorr==""cc ee""^^ ^^^^^^^^^^^^^s^^^^o^^^ ^^^^^u^^^ ^^^r^^^ ^^^c^^^ ^^^e^^^ ^^^^^^^^^^^^^^^n^a^o^^ee==""s..ournceo^"^_revcoor:^c e"^ ^ ^ ^^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^ ^^^^ ^^^ n ^^^n^^oe=n"o .o__rwevnccooo_ororer=v="c"oor:^""^^"^ ^^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ransnnaoo.__orwnev=c^ "coooorr=="""^ cc""^^^^ :^ ^ ^^ ^^ ^^^ ^^^ ^^^ ^^^^ ^^^ ^^^ ^^ ^^^ ^^ ^^^ m^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^ s^ ^^^^^ ^^^ c^^ ^^^^^ ^^^ _^^ ^^^^ ^^^^ ^^ e^^ ^^^^ ^^ a^^^^^^ ^ n urraen^^s^n.o ^ao.__orwnevc^ .=."coooor ^r=="""^ cc""^^^^ :^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^aen="o_rse-mvcoo-sru=mo-w"^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^noe=n"no_owe:^sceooure=n""ce:^ccccc""c^^caaaacaaaa aaac aac aaacc^ ^^ :^ ^^ ^ ^^^^^^^n ^^^^^^^^^^o ^^^^_ ^^^^^^revcoor:^ cc"^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^a^en=".o._rraenvsc^oaoorn=^" -"^"^ ^^ ^^^^ ^^^^ ^^^^ ^^^^ ^s^^ ^^^o^^^^ ^^^^^u^^^ ^^^r^^^ ^^^c^^^ ^^^e^^^ ^^^^^^^ ^^^^^^^^^^a^^^en="os._.ouwrceco^"^or=" "^ ^ ^ ^^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^ ^^^ n ^noe=n"oo__rwevnccooo_ororer=v="c"ooeeraa:^"e"^a^"^ ^^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^ransnn. aoo.__orwnev=c^ "coooorr"==^"" cc""^^ ^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^a^e=".. "^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ nnoo__rwevccoor=" "^ ^^ ^^^^ ^^^^ ^^^^ ^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^n^^oe=n".o._revnc^ooo_oro rer =v= "c"oor:^"^ c"^"^ ^^^^r^^^a^^^^n^^^^^^s^^^^^^a^^^^^^^^^^o^^^^n="no_wcoor=" c"^ ^ ^^^^^^^^^m^^^^^s^^c^^_^^^^e^^a^uare^^^^ .. ^ "^ ^^ :^ ^ ^ ^ ^^ ^^ ^^^ ^^ ^^^ ^^ ^^^ ^^ ^^^ ^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^^^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^ e ^ n ^^^n^^oe=n=" "o .o_ ._orwzeavncc^os ^ooe _ororeru=v=e"c"nce" oora^ :a^aacc""^a^ac"^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^aen="o_revcoo"r^=" ae"^ ^ ^ ^ ^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^ ^^^ ^^^ ^^^ ^^^ ^^^ ^^^ ^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^^^^n^^oe=n n".o_wcoor=" ae"^ o._n^o_revcoor:^ ae"^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ no_rwevccoooorr=="" cc""^^ ^^^^r^arnsma^^^^ er^o^^ ^^n^^=^^^"^^comemen "^..^^^:^ ^
Figure imgf000291_0001
^ ^ ^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^naoee=n=""soxe_reenuv_ecnwoceo:_r^ca=a"cca"ca^acc"a^acccc"^ ^^ :^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ n.o._wc^oor="aac"^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^aen="o_rraenvscoaoorn=^" -"^"^ ^ ^ ^ ^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ n.o._wc^oor=" "^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^aen="o_rraenvsaon^ - "^ ^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^e^ ^^^ ^^x^^^^o^^^^n^^^^^^^^^^^^^^^^^^^^^^^^^^^n^^^oe=n"o.._wncco ^oo_ororer=v="c"oor:^aaee""^^ae"^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^ae ^^ nn="oo__rrawenvsccoaoooorrn==^"" aa-aacc""^^"^ ^ ^ ^^^^^^^^^^^ r^^^^^^ a^^^^^^ n^^^^^^^^^ s^^^^^^^^^ a^^^^^^^^^^^^^^^^^^^ n.o._revc^oor=" c"^ o^^^^ no_wcoor=" c"^ ^ ^ ^^^ n=" **"^ ^^ :^ ^ ^^ ^^ ^^^^^ ^^^^ ^^^^^^^^^^^r^^^^^^m^^^^^^^^e^^^^r^^^^^^^^^^^^^n^a^^o^^ceeo==m""seeam_uceennscee:^ne_re..v"^ac^c ca"^ ^^ :^ ^ ^^^ ^^^^^^^^^^m^^^^^^^^^^s^^^^c^^^^_^^^^^^e^^^^a^^ure^^^nn^oo__rwe.v.ccoooor^r=="" aa""^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^ae=" "^ ^^^^^^^^^^m^^^^^^^^^^s^^^^c^^^^_^^^^^^e^^^^a^^ure^^^nn^oo__rwe.v.ccoooor^r==""cc ee""^^ ^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^ae=" "^ ^^^^^^^^^^ ^^^^ ^^^ ^^^ ^^^ ^r^^ ^^^ ^^^ ^m^^ ^^^ ^^^ ^^^ ^e^^ ^^^ ^r^^ ^^^ ^^^^ ^^^ n ^^^^^^^^^conmoo__rewemveccnoooorr==""c.c. ee"^"^^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^naoee=n= n""sos oe__rweu_vrecenv cooc"eo^:r^=" ca"^ "^ ^^ :^ ^ ^ ^^ ^^^^^^^^^^^r^^^m^^^^e^^r^^^^^^^^^^a^^^^comemenor="..ca^"^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^noee=n= n""soe_arreuve_cnsoceo:_r^r=ea"v"^ae a"^aa "^ ^^ :^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^a^e=".o._xwc^oor=" e "^ ^ ^ ^^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^noe=nn"oo__rwevs ncc"o^ oo_ororer=v="c"occor:^eec""^^e"^ ^^ ^^^^ ^^^^ ^^^^ ^^^e ^^^^^^^^^x ^^^^^^o ^^^^^^n ^^^^^^^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^^^^^ ^a^en="o.._rraenvsc^oaoorn=^" c-c"^"^ ^ ^^^^^^^^^s^^o^^^u^^r^^c^^e^^^^^^^^^^^^^^^no._.wco^or=" cc"^ ^ ^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^aen="os_oruervcceo"^or=" "^ ^^^^^^^^^^^^^^e^^^^^x^^^^o^^^^ ^n^^ ^^^ ^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^^^^n^^a^oee=n ="o_w "..rannc s^oo a_ro oer nv= ^c"oor:^ "^"^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ no_revcoor=" c-a"^"^ ^^^^^^^^^^^^^^^^^^^^^^^noe=n"o_wncoo_roerv=c"oor:c^a"c^a"^ ^ ^ ^ ^^ ^^^^ ^^^^^^^^^e^^^^^^x^^^^o^^^^n^^^^^^^^^^^^^^^^^^^^^^^^^^^^^a^en="o.._rraenvsc^oaoorn=^"aac-"^"^ ^ ^ ^^ ^^^ ^^^^^ ^^^^ ^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^a^en=".o._rawnsc^aooorn=^"aa-c"^"^ ^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^ ^^^ ^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^^ ^^^^^ ^^^^^ ^^^^^ ^^^^^ ^^^^^ ^^^^^ ^^^^^^^n^^oe=nn"o .o_ ._rwevncco ^oo_ororer=v="c"oaoaarac:c^a""a^^c"^ ^ ^ ^^ ^^^^^^^^^^^^^^^^^^^^^ nnoo__rwevccoooorr=="" cc""^^ ^^^^ ^^^^ ^^^^ ^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^r^ansna.o._orne=vc"^oor=""^ c"^^^ :^ ^ ^ ^ ^^^^^^^^^^^^^^m^^^^^ ^^^ ^^^ ^^s^ ^^^ ^^c^ ^^^ ^^_^ ^^^ ^^^^e^^^^a^^urraen^^s^n^ao_own.=."coo^r=""^ c"^^^ :^ ^ ^ ^ ^^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^aenn="oo__rswe-mvccooo-osrru==m""o-w"^""^^ ^^^^^^^^^^^^^e^^^^^^x^^^^o^^ ^^^n^^^^^^^^^^^^^^^^^^^^^^^^^^^n^^a^oee==""..ranns^oa_roenv^coor:-^ "^"^ ^ ^ ^^^^^^^^^^^^^^m^^^^^^^^^^s^^^ ^^c^ ^^^ ^^_^ ^^^ ^^^ ^^e^^^^a^^ure^^^nn^oo__rwe.v.ccoooor^r==""aaaacc""^^ ^ ^ ^^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^aenn="ooa__mrwevaccono-oowrr=="""^ee""^^ ^^ ^^^^ ^^^^^ ^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^n^a^oee= n="".o._rrcn ev^c^o_r oor^evc ="co cvor:^ c-ree "^ua"^e^coseeon-assocae^roen^"^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ no_wcoor="cc "^ ^^^^^^^^^^ ^^^^^^^^^^^^n^^oe=".. n^o_revcoor:^cc "^ ^ ^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ransnnaoo__orwnev=c"co*o"o^orr=="" cc""^^ ^ ^^^^^^^e^^^x^^o^^n^^^^^^^^^^^^^^^^^^^^a^e="..rans^a ^^^^^^^^^^^^^^^^^^^^^^^^^ no_revcooorn=^"aac-"^"^ ^ ^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^a^en n=".o o._wcoor="aac"^ _rrcev^c^oor^="ccvc-re"^uae^coseeon-assocae^roen^"^
Figure imgf000293_0001
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Claims

. - ., - . , , . . . , - . . , . . , . , -. . ,, - , , . , . ,, , . ^
. , . . , . . , . . , . . , . . , . - . , . - . ,- ,- . - , . , - - . - ^
.. , . ., . , . .. , . . , .. , .. , . , . . ., . , , , , , . ^
. -. . , . . , , , . . , . ,.. , , . -. . , , , . .. , . , , , . ^
. , , , , . , . . ., . , . , . , , ,, , . , . . , .. , .. , . , . . , , . , ^
. , -, . . , , , . . , , , . , ,. , , , , , . , . , ,, . . . , . . , .. , ^
.. , . . , .. , . , . . , . . , . . , , , , . . . ., . , . ^
. , . . . , . , . . , , . , . , . , ., , - - . . , . , . , , , . ^
. , . . . . ,. . , . . , , . . , . ., , , ,, . ,.. , , ^
. , , , . . , , , -, - . . , , , . . , . . , . . , ,. . , - . ., ,, , - ,,, , - , , , , , ^ , - , , . . , , - - , - - , , . - ,,, .’ , , , , , , , -, , , , , , , - ,, ,, , , ’ ,, --. - - . , . ^
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Citations (146)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4186183A (en) 1978-03-29 1980-01-29 The United States Of America As Represented By The Secretary Of The Army Liposome carriers in chemotherapy of leishmaniasis
US4217344A (en) 1976-06-23 1980-08-12 L'oreal Compositions containing aqueous dispersions of lipid spheres
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4261975A (en) 1979-09-19 1981-04-14 Merck & Co., Inc. Viral liposome particle
US4485054A (en) 1982-10-04 1984-11-27 Lipoderm Pharmaceuticals Limited Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV)
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US4737323A (en) 1986-02-13 1988-04-12 Liposome Technology, Inc. Liposome extrusion method
EP0264166A1 (en) 1986-04-09 1988-04-20 Genzyme Corporation Transgenic animals secreting desired proteins into milk
US4774085A (en) 1985-07-09 1988-09-27 501 Board of Regents, Univ. of Texas Pharmaceutical administration systems containing a mixture of immunomodulators
US4797368A (en) 1985-03-15 1989-01-10 The United States Of America As Represented By The Department Of Health And Human Services Adeno-associated virus as eukaryotic expression vector
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US4873316A (en) 1987-06-23 1989-10-10 Biogen, Inc. Isolation of exogenous recombinant proteins from the milk of transgenic mammals
US4897355A (en) 1985-01-07 1990-01-30 Syntex (U.S.A.) Inc. N[ω,(ω-1)-dialkyloxy]- and N-[ω,(ω-1)-dialkenyloxy]-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4946787A (en) 1985-01-07 1990-08-07 Syntex (U.S.A.) Inc. N-(ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US5049386A (en) 1985-01-07 1991-09-17 Syntex (U.S.A.) Inc. N-ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)Alk-1-YL-N,N,N-tetrasubstituted ammonium lipids and uses therefor
WO1991016024A1 (en) 1990-04-19 1991-10-31 Vical, Inc. Cationic lipids for intracellular delivery of biologically active molecules
WO1991017424A1 (en) 1990-05-03 1991-11-14 Vical, Inc. Intracellular delivery of biologically active substances by means of self-assembling lipid complexes
US5173414A (en) 1990-10-30 1992-12-22 Applied Immune Sciences, Inc. Production of recombinant adeno-associated virus vectors
WO1993001294A1 (en) 1991-07-02 1993-01-21 Zeneca Limited Plant-derived enzyme and dna sequences, and uses thereof
WO1993024641A2 (en) 1992-06-02 1993-12-09 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Adeno-associated virus with inverted terminal repeat sequences as promoter
US5543158A (en) 1993-07-23 1996-08-06 Massachusetts Institute Of Technology Biodegradable injectable nanoparticles
US5580737A (en) 1990-06-11 1996-12-03 Nexstar Pharmaceuticals, Inc. High-affinity nucleic acid ligands that discriminate between theophylline and caffeine
US5660985A (en) 1990-06-11 1997-08-26 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands containing modified nucleotides
US5789156A (en) 1993-06-14 1998-08-04 Basf Ag Tetracycline-regulated transcriptional inhibitors
US5814618A (en) 1993-06-14 1998-09-29 Basf Aktiengesellschaft Methods for regulating gene expression
US5855913A (en) 1997-01-16 1999-01-05 Massachusetts Instite Of Technology Particles incorporating surfactants for pulmonary drug delivery
US5985309A (en) 1996-05-24 1999-11-16 Massachusetts Institute Of Technology Preparation of particles for inhalation
US6007845A (en) 1994-07-22 1999-12-28 Massachusetts Institute Of Technology Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers
US20020150626A1 (en) 2000-10-16 2002-10-17 Kohane Daniel S. Lipid-protein-sugar particles for delivery of nucleic acids
US6479626B1 (en) 1998-03-02 2002-11-12 Massachusetts Institute Of Technology Poly zinc finger proteins with improved linkers
US6534261B1 (en) 1999-01-12 2003-03-18 Sangamo Biosciences, Inc. Regulation of endogenous gene expression in cells using zinc finger proteins
US20040013648A1 (en) 2000-10-06 2004-01-22 Kingsman Alan John Vector system
US6740525B2 (en) 2000-02-09 2004-05-25 Genvec, Inc. Adenoviral capsid containing chimeric protein IX
US6746838B1 (en) 1997-05-23 2004-06-08 Gendaq Limited Nucleic acid binding proteins
US6750059B1 (en) 1998-07-16 2004-06-15 Whatman, Inc. Archiving of vectors
US20040171156A1 (en) 1995-06-07 2004-09-02 Invitrogen Corporation Recombinational cloning using nucleic acids having recombination sites
US6794136B1 (en) 2000-11-20 2004-09-21 Sangamo Biosciences, Inc. Iterative optimization in the design of binding proteins
US20050019923A1 (en) 2001-10-19 2005-01-27 Ijeoma Uchegbu Dendrimers for use in targeted delivery
EP1519714A1 (en) 2002-06-28 2005-04-06 Protiva Biotherapeutics Inc. Method and apparatus for producing liposomes
US6911199B2 (en) 1998-08-27 2005-06-28 Aventis Pharma S.A. Targeted adenovirus vectors for delivery of heterologous genes
WO2005105152A2 (en) 2004-05-05 2005-11-10 Atugen Ag Lipids, lipid complexes and use thereof
US7013219B2 (en) 1999-01-12 2006-03-14 Sangamo Biosciences, Inc. Regulation of endogenous gene expression in cells using zinc finger proteins
US7030215B2 (en) 1999-03-24 2006-04-18 Sangamo Biosciences, Inc. Position dependent recognition of GNN nucleotide triplets by zinc fingers
EP1664316A1 (en) 2003-09-15 2006-06-07 Protiva Biotherapeutics Inc. Polyethyleneglycol-modified lipid compounds and uses thereof
WO2006069782A2 (en) 2004-12-27 2006-07-06 Silence Therapeutics Ag. Lipid complexes coated with peg and their use
US20060281180A1 (en) 2003-10-30 2006-12-14 Philippa Radcliffe Vectors
US20070054961A1 (en) 1999-03-31 2007-03-08 Malcolm Maden Factor
EP1766035A1 (en) 2004-06-07 2007-03-28 Protiva Biotherapeutics Inc. Lipid encapsulated interfering rna
EP1781593A2 (en) 2004-06-07 2007-05-09 Protiva Biotherapeutics Inc. Cationic lipids and methods of use
US7256036B2 (en) 1997-04-02 2007-08-14 Transgene Modified adenoviral fiber and target adenoviruses
WO2007121947A1 (en) 2006-04-20 2007-11-01 Silence Therapeutics Ag. Lipoplex formulations for specific delivery to vascular endothelium
US7303910B2 (en) 1997-09-25 2007-12-04 Oxford Biomedica (Uk) Limited Retroviral vectors comprising a functional splice donor site and a functional splice acceptor site
US7344872B2 (en) 2001-06-22 2008-03-18 The Trustees Of The University Of Pennsylvania Method for rapid screening of bacterial transformants and novel simian adenovirus proteins
US7351585B2 (en) 2002-09-03 2008-04-01 Oxford Biomedica (Uk) Ltd. Retroviral vector
WO2008042973A2 (en) 2006-10-03 2008-04-10 Alnylam Pharmaceuticals, Inc. Lipid containing formulations
WO2008042156A1 (en) 2006-09-28 2008-04-10 Northwestern University Maximizing oligonucleotide loading on gold nanoparticle
US20080267903A1 (en) 2004-10-14 2008-10-30 Ijeoma Uchegbu Bioactive Polymers
US20090007284A1 (en) 2001-12-21 2009-01-01 Philippa Radcliffe Transgenic organism
US20090017543A1 (en) 2005-12-22 2009-01-15 Fraser Wilkes Viral Vectors
WO2009012418A2 (en) 2007-07-17 2009-01-22 Somalogic, Inc. Method for generating aptamers with improved off-rates
US7585849B2 (en) 1999-03-24 2009-09-08 Sangamo Biosciences, Inc. Position dependent recognition of GNN nucleotide triplets by zinc fingers
US20100129793A1 (en) 2005-08-10 2010-05-27 Northwestern University Composite particles
US20100190178A1 (en) 2000-02-18 2010-07-29 Calos Michele P Altered Recombinases for Genome Modification
US7776321B2 (en) 2001-09-26 2010-08-17 Mayo Foundation For Medical Education And Research Mutable vaccines
US7838658B2 (en) 2005-10-20 2010-11-23 Ian Maclachlan siRNA silencing of filovirus gene expression
US20110027239A1 (en) 2009-07-29 2011-02-03 Tissue Genesis, Inc. Adipose-derived stromal cells (asc) as delivery tool for treatment of cancer
WO2011028929A2 (en) 2009-09-03 2011-03-10 The Regents Of The University Of California Nitrate-responsive promoter
US7915399B2 (en) 2006-06-09 2011-03-29 Protiva Biotherapeutics, Inc. Modified siRNA molecules and uses thereof
US20110117189A1 (en) 2008-07-08 2011-05-19 S.I.F.I. Societa' Industria Farmaceutica Italiana S.P.A. Ophthalmic compositions for treating pathologies of the posterior segment of the eye
US7982027B2 (en) 2003-07-16 2011-07-19 Protiva Biotherapeutics, Inc. Lipid encapsulated interfering RNA
US20110212179A1 (en) 2008-10-30 2011-09-01 David Liu Micro-spherical porous biocompatible scaffolds and methods and apparatus for fabricating same
US8021867B2 (en) 2005-10-18 2011-09-20 Duke University Rationally-designed meganucleases with altered sequence specificity and DNA-binding affinity
US8058069B2 (en) 2008-04-15 2011-11-15 Protiva Biotherapeutics, Inc. Lipid formulations for nucleic acid delivery
US20110293571A1 (en) 2010-05-28 2011-12-01 Oxford Biomedica (Uk) Ltd. Method for vector delivery
US20110293703A1 (en) 2008-11-07 2011-12-01 Massachusetts Institute Of Technology Aminoalcohol lipidoids and uses thereof
US8071082B2 (en) 2006-07-21 2011-12-06 Massachusetts Institute Of Technology End-modified poly(beta-amino esters) and uses thereof
US8101741B2 (en) 2005-11-02 2012-01-24 Protiva Biotherapeutics, Inc. Modified siRNA molecules and uses thereof
US20120164118A1 (en) 2009-05-04 2012-06-28 Fred Hutchinson Cancer Research Center Cocal vesiculovirus envelope pseudotyped retroviral vectors
US8236943B2 (en) 2009-07-01 2012-08-07 Protiva Biotherapeutics, Inc. Compositions and methods for silencing apolipoprotein B
US8278036B2 (en) 2005-08-23 2012-10-02 The Trustees Of The University Of Pennsylvania RNA containing modified nucleosides and methods of use thereof
WO2012135025A2 (en) 2011-03-28 2012-10-04 Massachusetts Institute Of Technology Conjugated lipomers and uses thereof
US20120251618A1 (en) 2011-03-31 2012-10-04 modeRNA Therapeutics Delivery and formulation of engineered nucleic acids
US8283333B2 (en) 2009-07-01 2012-10-09 Protiva Biotherapeutics, Inc. Lipid formulations for nucleic acid delivery
US20120295960A1 (en) 2011-05-20 2012-11-22 Oxford Biomedica (Uk) Ltd. Treatment regimen for parkinson's disease
US8372951B2 (en) 2010-05-14 2013-02-12 National Tsing Hua University Cell penetrating peptides for intracellular delivery
WO2013093648A2 (en) 2011-11-04 2013-06-27 Nitto Denko Corporation Method of producing lipid nanoparticles for drug delivery
US20130185823A1 (en) 2012-01-16 2013-07-18 Academia Sinica Mesoporous silica nanoparticle-mediated delivery of dna into arabidopsis root
US20130244279A1 (en) 2011-12-16 2013-09-19 modeRNA Therapeutics Formulation and delivery of plga microspheres
US20130302401A1 (en) 2010-08-26 2013-11-14 Massachusetts Institute Of Technology Poly(beta-amino alcohols), their preparation, and uses thereof
WO2014018423A2 (en) 2012-07-25 2014-01-30 The Broad Institute, Inc. Inducible dna binding proteins and genome perturbation tools and applications thereof
US8709843B2 (en) 2006-08-24 2014-04-29 Rohm Co., Ltd. Method of manufacturing nitride semiconductor and nitride semiconductor element
WO2014093622A2 (en) 2012-12-12 2014-06-19 The Broad Institute, Inc. Delivery, engineering and optimization of systems, methods and compositions for sequence manipulation and therapeutic applications
WO2014118272A1 (en) 2013-01-30 2014-08-07 Santaris Pharma A/S Antimir-122 oligonucleotide carbohydrate conjugates
US20140301951A1 (en) 2009-01-05 2014-10-09 Juewen Liu Porous nanoparticle supported lipid nanostructures
US20140308304A1 (en) 2011-12-07 2014-10-16 Alnylam Pharmaceuticals, Inc. Lipids for the delivery of active agents
US20140328759A1 (en) 2011-10-25 2014-11-06 The University Of British Columbia Limit size lipid nanoparticles and related methods
WO2014186366A1 (en) 2013-05-13 2014-11-20 Tufts University Nanocomplexes for delivery of saporin
US20140348900A1 (en) 2013-03-15 2014-11-27 Cureport, Inc. Methods and devices for preparation of lipid nanoparticles
US20150082080A1 (en) 2013-09-11 2015-03-19 Huawei Technologies Co., Ltd. Fault Isolation Method, Computer System, and Apparatus
WO2015050959A1 (en) 2013-10-01 2015-04-09 Yale University Anti-kit antibodies and methods of use thereof
US20150105538A1 (en) 2008-01-11 2015-04-16 Lawrence Livermore National Security, Llc Nanolipoprotein particles and related methods and systems for protein capture, solubilization, and/or purification
WO2015089419A2 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for targeting disorders and diseases using particle delivery components
US20150250725A1 (en) 2010-08-30 2015-09-10 Hoffmann-La Roche Inc. Method for producing a lipid particle, the lipid particle itself and its use
US20160129120A1 (en) 2013-05-14 2016-05-12 Tufts University Nanocomplexes of modified peptides or proteins
US20160174546A1 (en) 2014-12-22 2016-06-23 Oro Agri Inc Nano particulate delivery system
WO2016106236A1 (en) 2014-12-23 2016-06-30 The Broad Institute Inc. Rna-targeting system
US9405700B2 (en) 2010-11-04 2016-08-02 Sonics, Inc. Methods and apparatus for virtualization in an integrated circuit
US9410129B2 (en) 2011-11-25 2016-08-09 Targovax Oy Recombinant serotype 5 (Ad5) adenoviral vectors
US20160244761A1 (en) 2013-11-18 2016-08-25 Arcturus Therapeutics, Inc. Lipid particles with asymmetric cationic lipids for rna delivery
WO2016176330A1 (en) 2015-04-27 2016-11-03 The Trustees Of The University Of Pennsylvania Nucleoside-modified rna for inducing an adaptive immune response
US20160367686A1 (en) 2015-06-19 2016-12-22 Massachusetts Institute Of Technology Alkenyl substituted 2,5-piperazinediones, compositions, and uses thereof
US20170079916A1 (en) 2015-09-23 2017-03-23 Massachusetts Institute Of Technology Compositions and methods for modified dendrimer nanoparticle delivery
US9868692B2 (en) 2015-09-17 2018-01-16 Modernatx, Inc. Compounds and compositions for intracellular delivery of therapeutic agents
US20180057810A1 (en) 2014-09-25 2018-03-01 The Broad Institute Inc. Functional screening with optimized functional crispr-cas systems
WO2018081638A1 (en) 2016-10-27 2018-05-03 The Trustees Of The University Of Pennsylvania Nucleoside-modified rna for inducing an adaptive immune response
US10064959B2 (en) 2010-10-01 2018-09-04 Modernatx, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
WO2018213708A1 (en) 2017-05-18 2018-11-22 The Broad Institute, Inc. Systems, methods, and compositions for targeted nucleic acid editing
WO2018213726A1 (en) 2017-05-18 2018-11-22 The Broad Institute, Inc. Systems, methods, and compositions for targeted nucleic acid editing
US20180346934A1 (en) 2005-02-02 2018-12-06 Intrexon Corporation Site-Specific Serine Recombinases and Methods of Their Use
WO2019005884A1 (en) 2017-06-26 2019-01-03 The Broad Institute, Inc. Crispr/cas-adenine deaminase based compositions, systems, and methods for targeted nucleic acid editing
WO2019005886A1 (en) 2017-06-26 2019-01-03 The Broad Institute, Inc. Crispr/cas-cytidine deaminase based compositions, systems, and methods for targeted nucleic acid editing
WO2019071048A1 (en) 2017-10-04 2019-04-11 The Broad Institute, Inc. Systems, methods, and compositions for targeted nucleic acid editing
US10272150B2 (en) 2015-10-22 2019-04-30 Modernatx, Inc. Combination PIV3/hMPV RNA vaccines
US10577403B2 (en) 2012-04-02 2020-03-03 Modernatx, Inc. Modified polynucleotides for the production of secreted proteins
WO2020061229A2 (en) * 2018-09-18 2020-03-26 Vnv Newco Inc. Arc-based capsids and uses thereof
WO2020131862A1 (en) 2018-12-17 2020-06-25 The Broad Institute, Inc. Crispr-associated transposase systems and methods of use thereof
US20200239544A1 (en) 2017-10-03 2020-07-30 Precision Biosciences, Inc. Modified epidermal growth factor receptor peptides for use in genetically-modified cells
US20200276300A1 (en) 2017-08-17 2020-09-03 The Trustees Of The University Of Pennsylvania Modified mrna vaccines encoding herpes simplex virus glycoproteins and uses thereof
US10786549B2 (en) 2015-04-23 2020-09-29 Baylor College Of Medicine CD5 chimeric antigen receptor for adoptive T cell therapy
US20200347100A1 (en) * 2019-03-15 2020-11-05 The Broad Institute, Inc. Non-naturally occurring capsids for delivery of nucleic acids and/or proteins
US10851358B2 (en) 2016-10-14 2020-12-01 Precision Biosciences, Inc. Engineered meganucleases specific for recognition sequences in the hepatitis B virus genome
WO2021087394A1 (en) 2019-11-01 2021-05-06 The Broad Institute, Inc. Type i-b crispr-associated transposase systems
WO2021102042A1 (en) 2019-11-19 2021-05-27 The Broad Institute, Inc. Retrotransposons and use thereof
WO2021138469A1 (en) 2019-12-30 2021-07-08 The Broad Institute, Inc. Genome editing using reverse transcriptase enabled and fully active crispr complexes
US20210269543A1 (en) 2016-12-26 2021-09-02 Jcr Pharmaceuticals Co., Ltd. Anti-Human Transferrin Receptor Antibody Capable of Penetrating Blood-Brain Barrier
WO2021257997A2 (en) 2020-06-18 2021-12-23 The Broad Institute, Inc. Crispr-associated transposase systems and methods of use thereof
WO2022076820A1 (en) 2020-10-08 2022-04-14 The Research Foundation For The State University Of New York Truxillic acid monoester-derivatives as selective fabp5 inhibitors and pharmaceutical compositions and uses thereof
WO2022087494A1 (en) 2020-10-23 2022-04-28 The Broad Institute, Inc. Reprogrammable iscb nucleases and uses thereof
WO2022147321A1 (en) 2020-12-30 2022-07-07 The Broad Institute, Inc. Type i-b crispr-associated transposase systems
WO2022150790A2 (en) 2021-01-11 2022-07-14 The Broad Institute, Inc. Prime editor variants, constructs, and methods for enhancing prime editing efficiency and precision
WO2022150651A1 (en) 2021-01-07 2022-07-14 The Broad Institute, Inc. Dna nuclease guided transposase compositions and methods of use thereof
WO2022159892A1 (en) 2021-01-25 2022-07-28 The Broad Institute, Inc. Reprogrammable tnpb polypeptides and use thereof
WO2022165262A1 (en) 2021-01-28 2022-08-04 The Broad Institute, Inc. Compositions and methods for delivering cargo to a target cell
WO2022173830A1 (en) 2021-02-09 2022-08-18 The Broad Institute, Inc. Nuclease-guided non-ltr retrotransposons and uses thereof
WO2023114872A2 (en) 2021-12-14 2023-06-22 The Broad Institute, Inc. Reprogrammable fanzor polynucleotides and uses thereof
EP4238990A1 (en) 2020-11-01 2023-09-06 Nanjing Iaso Biotechnology Co., Ltd. Fully human antibody targeting cd5, and fully human chimeric antigen receptor (car) and application thereof

Patent Citations (192)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4217344A (en) 1976-06-23 1980-08-12 L'oreal Compositions containing aqueous dispersions of lipid spheres
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4186183A (en) 1978-03-29 1980-01-29 The United States Of America As Represented By The Secretary Of The Army Liposome carriers in chemotherapy of leishmaniasis
US4261975A (en) 1979-09-19 1981-04-14 Merck & Co., Inc. Viral liposome particle
US4485054A (en) 1982-10-04 1984-11-27 Lipoderm Pharmaceuticals Limited Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV)
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US4897355A (en) 1985-01-07 1990-01-30 Syntex (U.S.A.) Inc. N[ω,(ω-1)-dialkyloxy]- and N-[ω,(ω-1)-dialkenyloxy]-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US5049386A (en) 1985-01-07 1991-09-17 Syntex (U.S.A.) Inc. N-ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)Alk-1-YL-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4946787A (en) 1985-01-07 1990-08-07 Syntex (U.S.A.) Inc. N-(ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4797368A (en) 1985-03-15 1989-01-10 The United States Of America As Represented By The Department Of Health And Human Services Adeno-associated virus as eukaryotic expression vector
US4774085A (en) 1985-07-09 1988-09-27 501 Board of Regents, Univ. of Texas Pharmaceutical administration systems containing a mixture of immunomodulators
US4737323A (en) 1986-02-13 1988-04-12 Liposome Technology, Inc. Liposome extrusion method
EP0264166A1 (en) 1986-04-09 1988-04-20 Genzyme Corporation Transgenic animals secreting desired proteins into milk
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US4873316A (en) 1987-06-23 1989-10-10 Biogen, Inc. Isolation of exogenous recombinant proteins from the milk of transgenic mammals
WO1991016024A1 (en) 1990-04-19 1991-10-31 Vical, Inc. Cationic lipids for intracellular delivery of biologically active molecules
WO1991017424A1 (en) 1990-05-03 1991-11-14 Vical, Inc. Intracellular delivery of biologically active substances by means of self-assembling lipid complexes
US5580737A (en) 1990-06-11 1996-12-03 Nexstar Pharmaceuticals, Inc. High-affinity nucleic acid ligands that discriminate between theophylline and caffeine
US5660985A (en) 1990-06-11 1997-08-26 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands containing modified nucleotides
US5173414A (en) 1990-10-30 1992-12-22 Applied Immune Sciences, Inc. Production of recombinant adeno-associated virus vectors
WO1993001294A1 (en) 1991-07-02 1993-01-21 Zeneca Limited Plant-derived enzyme and dna sequences, and uses thereof
WO1993024641A2 (en) 1992-06-02 1993-12-09 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Adeno-associated virus with inverted terminal repeat sequences as promoter
US5814618A (en) 1993-06-14 1998-09-29 Basf Aktiengesellschaft Methods for regulating gene expression
US5789156A (en) 1993-06-14 1998-08-04 Basf Ag Tetracycline-regulated transcriptional inhibitors
US5543158A (en) 1993-07-23 1996-08-06 Massachusetts Institute Of Technology Biodegradable injectable nanoparticles
US6007845A (en) 1994-07-22 1999-12-28 Massachusetts Institute Of Technology Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers
US20040171156A1 (en) 1995-06-07 2004-09-02 Invitrogen Corporation Recombinational cloning using nucleic acids having recombination sites
US5985309A (en) 1996-05-24 1999-11-16 Massachusetts Institute Of Technology Preparation of particles for inhalation
US5855913A (en) 1997-01-16 1999-01-05 Massachusetts Instite Of Technology Particles incorporating surfactants for pulmonary drug delivery
US7256036B2 (en) 1997-04-02 2007-08-14 Transgene Modified adenoviral fiber and target adenoviruses
US6746838B1 (en) 1997-05-23 2004-06-08 Gendaq Limited Nucleic acid binding proteins
US7241574B2 (en) 1997-05-23 2007-07-10 Gendaq Ltd. Nucleic acid binding proteins
US7241573B2 (en) 1997-05-23 2007-07-10 Gendaq Ltd. Nucleic acid binding proteins
US6866997B1 (en) 1997-05-23 2005-03-15 Gendaq Limited Nucleic acid binding proteins
US7303910B2 (en) 1997-09-25 2007-12-04 Oxford Biomedica (Uk) Limited Retroviral vectors comprising a functional splice donor site and a functional splice acceptor site
US6479626B1 (en) 1998-03-02 2002-11-12 Massachusetts Institute Of Technology Poly zinc finger proteins with improved linkers
US7595376B2 (en) 1998-03-02 2009-09-29 Massachusetts Institute Of Technology Poly zinc finger proteins with improved linkers
US6903185B2 (en) 1998-03-02 2005-06-07 Massachusetts Institute Of Technology Poly zinc finger proteins with improved linkers
US6750059B1 (en) 1998-07-16 2004-06-15 Whatman, Inc. Archiving of vectors
US6911199B2 (en) 1998-08-27 2005-06-28 Aventis Pharma S.A. Targeted adenovirus vectors for delivery of heterologous genes
US6933113B2 (en) 1999-01-12 2005-08-23 Sangamo Biosciences, Inc. Modulation of endogenous gene expression in cells
US6824978B1 (en) 1999-01-12 2004-11-30 Sangamo Biosciences, Inc. Regulation of endogenous gene expression in cells using zinc finger proteins
US6607882B1 (en) 1999-01-12 2003-08-19 Sangamo Biosciences, Inc. Regulation of endogenous gene expression in cells using zinc finger proteins
US6979539B2 (en) 1999-01-12 2005-12-27 Sangamo Biosciences, Inc. Regulation of endogenous gene expression in cells using zinc finger proteins
US7013219B2 (en) 1999-01-12 2006-03-14 Sangamo Biosciences, Inc. Regulation of endogenous gene expression in cells using zinc finger proteins
US7220719B2 (en) 1999-01-12 2007-05-22 Sangamo Biosciences, Inc. Modulation of endogenous gene expression in cells
US6534261B1 (en) 1999-01-12 2003-03-18 Sangamo Biosciences, Inc. Regulation of endogenous gene expression in cells using zinc finger proteins
US7030215B2 (en) 1999-03-24 2006-04-18 Sangamo Biosciences, Inc. Position dependent recognition of GNN nucleotide triplets by zinc fingers
US7585849B2 (en) 1999-03-24 2009-09-08 Sangamo Biosciences, Inc. Position dependent recognition of GNN nucleotide triplets by zinc fingers
US20070054961A1 (en) 1999-03-31 2007-03-08 Malcolm Maden Factor
US20100317109A1 (en) 1999-03-31 2010-12-16 Malcolm Maden Factor
US6740525B2 (en) 2000-02-09 2004-05-25 Genvec, Inc. Adenoviral capsid containing chimeric protein IX
US20100190178A1 (en) 2000-02-18 2010-07-29 Calos Michele P Altered Recombinases for Genome Modification
US20070025970A1 (en) 2000-10-06 2007-02-01 Oxford Biomedica (Uk) Limited Vector system
US20090111106A1 (en) 2000-10-06 2009-04-30 Kyri Mitrophanous Vector System
US7259015B2 (en) 2000-10-06 2007-08-21 Oxford Biomedia (Uk) Limited Vector system
US20040013648A1 (en) 2000-10-06 2004-01-22 Kingsman Alan John Vector system
US20020150626A1 (en) 2000-10-16 2002-10-17 Kohane Daniel S. Lipid-protein-sugar particles for delivery of nucleic acids
US6794136B1 (en) 2000-11-20 2004-09-21 Sangamo Biosciences, Inc. Iterative optimization in the design of binding proteins
US7344872B2 (en) 2001-06-22 2008-03-18 The Trustees Of The University Of Pennsylvania Method for rapid screening of bacterial transformants and novel simian adenovirus proteins
US7776321B2 (en) 2001-09-26 2010-08-17 Mayo Foundation For Medical Education And Research Mutable vaccines
US20050019923A1 (en) 2001-10-19 2005-01-27 Ijeoma Uchegbu Dendrimers for use in targeted delivery
US20090007284A1 (en) 2001-12-21 2009-01-01 Philippa Radcliffe Transgenic organism
US7901708B2 (en) 2002-06-28 2011-03-08 Protiva Biotherapeutics, Inc. Liposomal apparatus and manufacturing methods
EP1519714A1 (en) 2002-06-28 2005-04-06 Protiva Biotherapeutics Inc. Method and apparatus for producing liposomes
US7351585B2 (en) 2002-09-03 2008-04-01 Oxford Biomedica (Uk) Ltd. Retroviral vector
US7982027B2 (en) 2003-07-16 2011-07-19 Protiva Biotherapeutics, Inc. Lipid encapsulated interfering RNA
US7803397B2 (en) 2003-09-15 2010-09-28 Protiva Biotherapeutics, Inc. Polyethyleneglycol-modified lipid compounds and uses thereof
EP1664316A1 (en) 2003-09-15 2006-06-07 Protiva Biotherapeutics Inc. Polyethyleneglycol-modified lipid compounds and uses thereof
US20060281180A1 (en) 2003-10-30 2006-12-14 Philippa Radcliffe Vectors
WO2005105152A2 (en) 2004-05-05 2005-11-10 Atugen Ag Lipids, lipid complexes and use thereof
US7745651B2 (en) 2004-06-07 2010-06-29 Protiva Biotherapeutics, Inc. Cationic lipids and methods of use
EP1781593A2 (en) 2004-06-07 2007-05-09 Protiva Biotherapeutics Inc. Cationic lipids and methods of use
EP1766035A1 (en) 2004-06-07 2007-03-28 Protiva Biotherapeutics Inc. Lipid encapsulated interfering rna
US7799565B2 (en) 2004-06-07 2010-09-21 Protiva Biotherapeutics, Inc. Lipid encapsulated interfering RNA
US20080267903A1 (en) 2004-10-14 2008-10-30 Ijeoma Uchegbu Bioactive Polymers
WO2006069782A2 (en) 2004-12-27 2006-07-06 Silence Therapeutics Ag. Lipid complexes coated with peg and their use
US20180346934A1 (en) 2005-02-02 2018-12-06 Intrexon Corporation Site-Specific Serine Recombinases and Methods of Their Use
US20100129793A1 (en) 2005-08-10 2010-05-27 Northwestern University Composite particles
US20150038558A1 (en) 2005-08-23 2015-02-05 The Trustees Of The University Of Pennsylvania RNA Containing Modified Nucleosides and Methods of Use Thereof
US9750824B2 (en) 2005-08-23 2017-09-05 The Trustees Of The University Of Pennsylvania RNA containing modified nucleosides and methods of use thereof
US10232055B2 (en) 2005-08-23 2019-03-19 The Trustees Of The University Of Pennsylvania RNA containing modified nucleosides and methods of use thereof
US8748089B2 (en) 2005-08-23 2014-06-10 The Trustees Of The University Of Pennsylvania RNA containing modified nucleosides and methods of use thereof
US20200030460A1 (en) 2005-08-23 2020-01-30 The Trustees Of The University Of Pennsylvania RNA Containing Modified Nucleosides and Methods of Use Thereof
US8691966B2 (en) 2005-08-23 2014-04-08 The Trustees Of The University Of Pennsylvania RNA containing modified nucleosides and methods of use thereof
US20130261172A1 (en) 2005-08-23 2013-10-03 The Trustees Of The University Of Pennsylvania RNA Containing Modified Nucleosides and Methods of Use Thereof
US20130197068A1 (en) 2005-08-23 2013-08-01 The Trustees Of The University Of Pennsylvania RNA Containing Modified Nucleosides and Methods of Use Thereof
US20170043037A1 (en) 2005-08-23 2017-02-16 The Trustees Of The University Of Pennsylvania RNA Containing Modified Nucleosides and Methods of Use Thereof
US8278036B2 (en) 2005-08-23 2012-10-02 The Trustees Of The University Of Pennsylvania RNA containing modified nucleosides and methods of use thereof
US8119381B2 (en) 2005-10-18 2012-02-21 Duke University Rationally-designed meganucleases with altered sequence specificity and DNA-binding affinity
US8133697B2 (en) 2005-10-18 2012-03-13 Duke University Methods of cleaving DNA with rationally-designed meganucleases
US8163514B2 (en) 2005-10-18 2012-04-24 Duke University Methods of cleaving DNA with rationally-designed meganucleases
US8129134B2 (en) 2005-10-18 2012-03-06 Duke University Methods of cleaving DNA with rationally-designed meganucleases
US8124369B2 (en) 2005-10-18 2012-02-28 Duke University Method of cleaving DNA with rationally-designed meganucleases
US8021867B2 (en) 2005-10-18 2011-09-20 Duke University Rationally-designed meganucleases with altered sequence specificity and DNA-binding affinity
US8119361B2 (en) 2005-10-18 2012-02-21 Duke University Methods of cleaving DNA with rationally-designed meganucleases
US7838658B2 (en) 2005-10-20 2010-11-23 Ian Maclachlan siRNA silencing of filovirus gene expression
US8101741B2 (en) 2005-11-02 2012-01-24 Protiva Biotherapeutics, Inc. Modified siRNA molecules and uses thereof
US8188263B2 (en) 2005-11-02 2012-05-29 Protiva Biotherapeutics, Inc. Modified siRNA molecules and uses thereof
US20090017543A1 (en) 2005-12-22 2009-01-15 Fraser Wilkes Viral Vectors
WO2007121947A1 (en) 2006-04-20 2007-11-01 Silence Therapeutics Ag. Lipoplex formulations for specific delivery to vascular endothelium
US7915399B2 (en) 2006-06-09 2011-03-29 Protiva Biotherapeutics, Inc. Modified siRNA molecules and uses thereof
US8071082B2 (en) 2006-07-21 2011-12-06 Massachusetts Institute Of Technology End-modified poly(beta-amino esters) and uses thereof
US8709843B2 (en) 2006-08-24 2014-04-29 Rohm Co., Ltd. Method of manufacturing nitride semiconductor and nitride semiconductor element
WO2008042156A1 (en) 2006-09-28 2008-04-10 Northwestern University Maximizing oligonucleotide loading on gold nanoparticle
WO2008042973A2 (en) 2006-10-03 2008-04-10 Alnylam Pharmaceuticals, Inc. Lipid containing formulations
WO2009012418A2 (en) 2007-07-17 2009-01-22 Somalogic, Inc. Method for generating aptamers with improved off-rates
US20150105538A1 (en) 2008-01-11 2015-04-16 Lawrence Livermore National Security, Llc Nanolipoprotein particles and related methods and systems for protein capture, solubilization, and/or purification
US8058069B2 (en) 2008-04-15 2011-11-15 Protiva Biotherapeutics, Inc. Lipid formulations for nucleic acid delivery
US20110117189A1 (en) 2008-07-08 2011-05-19 S.I.F.I. Societa' Industria Farmaceutica Italiana S.P.A. Ophthalmic compositions for treating pathologies of the posterior segment of the eye
US20110212179A1 (en) 2008-10-30 2011-09-01 David Liu Micro-spherical porous biocompatible scaffolds and methods and apparatus for fabricating same
US20110293703A1 (en) 2008-11-07 2011-12-01 Massachusetts Institute Of Technology Aminoalcohol lipidoids and uses thereof
US20140301951A1 (en) 2009-01-05 2014-10-09 Juewen Liu Porous nanoparticle supported lipid nanostructures
US20120164118A1 (en) 2009-05-04 2012-06-28 Fred Hutchinson Cancer Research Center Cocal vesiculovirus envelope pseudotyped retroviral vectors
US8283333B2 (en) 2009-07-01 2012-10-09 Protiva Biotherapeutics, Inc. Lipid formulations for nucleic acid delivery
US8236943B2 (en) 2009-07-01 2012-08-07 Protiva Biotherapeutics, Inc. Compositions and methods for silencing apolipoprotein B
US20110027239A1 (en) 2009-07-29 2011-02-03 Tissue Genesis, Inc. Adipose-derived stromal cells (asc) as delivery tool for treatment of cancer
WO2011028929A2 (en) 2009-09-03 2011-03-10 The Regents Of The University Of California Nitrate-responsive promoter
US8372951B2 (en) 2010-05-14 2013-02-12 National Tsing Hua University Cell penetrating peptides for intracellular delivery
US20110293571A1 (en) 2010-05-28 2011-12-01 Oxford Biomedica (Uk) Ltd. Method for vector delivery
US20130302401A1 (en) 2010-08-26 2013-11-14 Massachusetts Institute Of Technology Poly(beta-amino alcohols), their preparation, and uses thereof
US20150250725A1 (en) 2010-08-30 2015-09-10 Hoffmann-La Roche Inc. Method for producing a lipid particle, the lipid particle itself and its use
US10064959B2 (en) 2010-10-01 2018-09-04 Modernatx, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
US9405700B2 (en) 2010-11-04 2016-08-02 Sonics, Inc. Methods and apparatus for virtualization in an integrated circuit
WO2012135025A2 (en) 2011-03-28 2012-10-04 Massachusetts Institute Of Technology Conjugated lipomers and uses thereof
US20120251618A1 (en) 2011-03-31 2012-10-04 modeRNA Therapeutics Delivery and formulation of engineered nucleic acids
US20120295960A1 (en) 2011-05-20 2012-11-22 Oxford Biomedica (Uk) Ltd. Treatment regimen for parkinson's disease
US20140328759A1 (en) 2011-10-25 2014-11-06 The University Of British Columbia Limit size lipid nanoparticles and related methods
WO2013093648A2 (en) 2011-11-04 2013-06-27 Nitto Denko Corporation Method of producing lipid nanoparticles for drug delivery
US9410129B2 (en) 2011-11-25 2016-08-09 Targovax Oy Recombinant serotype 5 (Ad5) adenoviral vectors
US20140308304A1 (en) 2011-12-07 2014-10-16 Alnylam Pharmaceuticals, Inc. Lipids for the delivery of active agents
US20130245107A1 (en) 2011-12-16 2013-09-19 modeRNA Therapeutics Dlin-mc3-dma lipid nanoparticle delivery of modified polynucleotides
US20130244279A1 (en) 2011-12-16 2013-09-19 modeRNA Therapeutics Formulation and delivery of plga microspheres
US20130252281A1 (en) 2011-12-16 2013-09-26 modeRNA Therapeutics Formulation and delivery of plga microspheres
US20130185823A1 (en) 2012-01-16 2013-07-18 Academia Sinica Mesoporous silica nanoparticle-mediated delivery of dna into arabidopsis root
US10577403B2 (en) 2012-04-02 2020-03-03 Modernatx, Inc. Modified polynucleotides for the production of secreted proteins
US10703789B2 (en) 2012-04-02 2020-07-07 Modernatx, Inc. Modified polynucleotides for the production of secreted proteins
US20150291966A1 (en) 2012-07-25 2015-10-15 The Broad Institute, Inc. Inducible dna binding proteins and genome perturbation tools and applications thereof
US20190203212A1 (en) 2012-07-25 2019-07-04 Massachusetts Institute Of Technology Inducible dna binding proteins and genome perturbation tools and applications thereof
WO2014018423A2 (en) 2012-07-25 2014-01-30 The Broad Institute, Inc. Inducible dna binding proteins and genome perturbation tools and applications thereof
US20170166903A1 (en) 2012-07-25 2017-06-15 The Broad Institute, Inc. Inducible dna binding proteins and genome perturbation tools and applications thereof
WO2014093622A2 (en) 2012-12-12 2014-06-19 The Broad Institute, Inc. Delivery, engineering and optimization of systems, methods and compositions for sequence manipulation and therapeutic applications
WO2014118272A1 (en) 2013-01-30 2014-08-07 Santaris Pharma A/S Antimir-122 oligonucleotide carbohydrate conjugates
US20140348900A1 (en) 2013-03-15 2014-11-27 Cureport, Inc. Methods and devices for preparation of lipid nanoparticles
WO2014186366A1 (en) 2013-05-13 2014-11-20 Tufts University Nanocomplexes for delivery of saporin
US20160129120A1 (en) 2013-05-14 2016-05-12 Tufts University Nanocomplexes of modified peptides or proteins
US20150082080A1 (en) 2013-09-11 2015-03-19 Huawei Technologies Co., Ltd. Fault Isolation Method, Computer System, and Apparatus
WO2015050959A1 (en) 2013-10-01 2015-04-09 Yale University Anti-kit antibodies and methods of use thereof
US20160244761A1 (en) 2013-11-18 2016-08-25 Arcturus Therapeutics, Inc. Lipid particles with asymmetric cationic lipids for rna delivery
WO2015089419A2 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for targeting disorders and diseases using particle delivery components
US20180057810A1 (en) 2014-09-25 2018-03-01 The Broad Institute Inc. Functional screening with optimized functional crispr-cas systems
US11001829B2 (en) 2014-09-25 2021-05-11 The Broad Institute, Inc. Functional screening with optimized functional CRISPR-Cas systems
US20160174546A1 (en) 2014-12-22 2016-06-23 Oro Agri Inc Nano particulate delivery system
WO2016106236A1 (en) 2014-12-23 2016-06-30 The Broad Institute Inc. Rna-targeting system
US10786549B2 (en) 2015-04-23 2020-09-29 Baylor College Of Medicine CD5 chimeric antigen receptor for adoptive T cell therapy
US20180303925A1 (en) 2015-04-27 2018-10-25 The Trustees Of The University Of Pennsylvania Nucleoside-Modified RNA For Inducing an Adaptive Immune Response
WO2016176330A1 (en) 2015-04-27 2016-11-03 The Trustees Of The University Of Pennsylvania Nucleoside-modified rna for inducing an adaptive immune response
US20160367686A1 (en) 2015-06-19 2016-12-22 Massachusetts Institute Of Technology Alkenyl substituted 2,5-piperazinediones, compositions, and uses thereof
US9868692B2 (en) 2015-09-17 2018-01-16 Modernatx, Inc. Compounds and compositions for intracellular delivery of therapeutic agents
US10442756B2 (en) 2015-09-17 2019-10-15 Modernatx, Inc. Compounds and compositions for intracellular delivery of therapeutic agents
US10266485B2 (en) 2015-09-17 2019-04-23 Modernatx, Inc. Compounds and compositions for intracellular delivery of therapeutic agents
US20170079916A1 (en) 2015-09-23 2017-03-23 Massachusetts Institute Of Technology Compositions and methods for modified dendrimer nanoparticle delivery
US10272150B2 (en) 2015-10-22 2019-04-30 Modernatx, Inc. Combination PIV3/hMPV RNA vaccines
US10702600B1 (en) 2015-10-22 2020-07-07 Modernatx, Inc. Betacoronavirus mRNA vaccine
US10851358B2 (en) 2016-10-14 2020-12-01 Precision Biosciences, Inc. Engineered meganucleases specific for recognition sequences in the hepatitis B virus genome
WO2018081638A1 (en) 2016-10-27 2018-05-03 The Trustees Of The University Of Pennsylvania Nucleoside-modified rna for inducing an adaptive immune response
US20190274968A1 (en) 2016-10-27 2019-09-12 The Trustees Of The University Of Pennsylvania Nucleoside-modified rna for inducing an adaptive immune response
US20210269543A1 (en) 2016-12-26 2021-09-02 Jcr Pharmaceuticals Co., Ltd. Anti-Human Transferrin Receptor Antibody Capable of Penetrating Blood-Brain Barrier
WO2018213726A1 (en) 2017-05-18 2018-11-22 The Broad Institute, Inc. Systems, methods, and compositions for targeted nucleic acid editing
WO2018213708A1 (en) 2017-05-18 2018-11-22 The Broad Institute, Inc. Systems, methods, and compositions for targeted nucleic acid editing
WO2019005884A1 (en) 2017-06-26 2019-01-03 The Broad Institute, Inc. Crispr/cas-adenine deaminase based compositions, systems, and methods for targeted nucleic acid editing
WO2019005886A1 (en) 2017-06-26 2019-01-03 The Broad Institute, Inc. Crispr/cas-cytidine deaminase based compositions, systems, and methods for targeted nucleic acid editing
US20200276300A1 (en) 2017-08-17 2020-09-03 The Trustees Of The University Of Pennsylvania Modified mrna vaccines encoding herpes simplex virus glycoproteins and uses thereof
US20200239544A1 (en) 2017-10-03 2020-07-30 Precision Biosciences, Inc. Modified epidermal growth factor receptor peptides for use in genetically-modified cells
WO2019071048A1 (en) 2017-10-04 2019-04-11 The Broad Institute, Inc. Systems, methods, and compositions for targeted nucleic acid editing
WO2020061229A2 (en) * 2018-09-18 2020-03-26 Vnv Newco Inc. Arc-based capsids and uses thereof
WO2020131862A1 (en) 2018-12-17 2020-06-25 The Broad Institute, Inc. Crispr-associated transposase systems and methods of use thereof
US20200347100A1 (en) * 2019-03-15 2020-11-05 The Broad Institute, Inc. Non-naturally occurring capsids for delivery of nucleic acids and/or proteins
WO2021087394A1 (en) 2019-11-01 2021-05-06 The Broad Institute, Inc. Type i-b crispr-associated transposase systems
WO2021102042A1 (en) 2019-11-19 2021-05-27 The Broad Institute, Inc. Retrotransposons and use thereof
WO2021138469A1 (en) 2019-12-30 2021-07-08 The Broad Institute, Inc. Genome editing using reverse transcriptase enabled and fully active crispr complexes
WO2021257997A2 (en) 2020-06-18 2021-12-23 The Broad Institute, Inc. Crispr-associated transposase systems and methods of use thereof
WO2022076820A1 (en) 2020-10-08 2022-04-14 The Research Foundation For The State University Of New York Truxillic acid monoester-derivatives as selective fabp5 inhibitors and pharmaceutical compositions and uses thereof
WO2022087494A1 (en) 2020-10-23 2022-04-28 The Broad Institute, Inc. Reprogrammable iscb nucleases and uses thereof
EP4238990A1 (en) 2020-11-01 2023-09-06 Nanjing Iaso Biotechnology Co., Ltd. Fully human antibody targeting cd5, and fully human chimeric antigen receptor (car) and application thereof
WO2022147321A1 (en) 2020-12-30 2022-07-07 The Broad Institute, Inc. Type i-b crispr-associated transposase systems
WO2022150651A1 (en) 2021-01-07 2022-07-14 The Broad Institute, Inc. Dna nuclease guided transposase compositions and methods of use thereof
WO2022150790A2 (en) 2021-01-11 2022-07-14 The Broad Institute, Inc. Prime editor variants, constructs, and methods for enhancing prime editing efficiency and precision
WO2022159892A1 (en) 2021-01-25 2022-07-28 The Broad Institute, Inc. Reprogrammable tnpb polypeptides and use thereof
WO2022165262A1 (en) 2021-01-28 2022-08-04 The Broad Institute, Inc. Compositions and methods for delivering cargo to a target cell
WO2022173830A1 (en) 2021-02-09 2022-08-18 The Broad Institute, Inc. Nuclease-guided non-ltr retrotransposons and uses thereof
WO2023114872A2 (en) 2021-12-14 2023-06-22 The Broad Institute, Inc. Reprogrammable fanzor polynucleotides and uses thereof

Non-Patent Citations (350)

* Cited by examiner, † Cited by third party
Title
"Methods in Enzymology", 1995, ACADEMIC PRESS, INC., article "PCR 2: A Practical Approach"
"Remington's Pharmaceutical Sciences", 1975, MACK PUBLISHING COMPANY
AHMAD ET AL., CANCER RES., vol. 52, 1992, pages 4817 - 4820
ALEKU ET AL., CANCER RES., vol. 68, no. 23, 1 December 2008 (2008-12-01), pages 9788 - 98
ALTAE-TRAN HKANNAN SDEMIRCIOGLU FE ET AL.: "The widespread IS200/IS605 transposon family encodes diverse programmable RNA-guided endonucleases", SCIENCE, vol. 374, no. 6563, 2021, pages 57 - 65, XP055901842, DOI: 10.1126/science.abj6856
ALTINOGLU ET AL., BIOMATER SCI., vol. 4, no. 12, 15 November 2016 (2016-11-15), pages 1773 - 80
ALVAREZ-ERVITI ET AL., NAT BIOTECHNOL, vol. 29, 2011, pages 341
AMALFITANO ET AL., J. VIROL., vol. 72, 1998, pages 926 - 933
ANNAMALI ET AL., J VIROL., vol. 9, no. 6, 2005, pages 3277 - 3288
ANZALONE AVGAO XDPODRACKY CJ ET AL.: "Programmable deletion, replacement, integration and inversion of large DNA sequences with twin prime editing", NAT BIOTECHNOL., vol. 40, no. 5, 2022, pages 731 - 740, XP037927032, DOI: 10.1038/s41587-021-01133-w
ANZALONE ET AL., NATURE, vol. 576, 2019, pages 149 - 157
ANZALONE ET AL., NATURE., vol. 576, 2019, pages 149 - 157
ARBABI GHAHROUDI MDESMYTER AWYNS LHAMERS RMUYLDERMANS S: "Selection and identification of single domain antibody fragments from camel heavy-chain antibodies", FEBS LETTERS., vol. 414, no. 3, September 1997 (1997-09-01), pages 521 - 6, XP004261105, DOI: 10.1016/S0014-5793(97)01062-4
ASHLEY ET AL., CELL, vol. 172, no. 1-2, 2018, pages 262 - 274
AZZOUZ ET AL., J. NERUOSCI.
BALAGAAN, J GENE MED, vol. 8, 2006, pages 275 - 285
BALAGUE ET AL., BLOOD, vol. 95, 2000, pages 820 - 828
BALDRICK P.: "Pharmaceutical excipient development: the need for preclinical guidance.", REGUL. TOXICOL PHARMACOL., vol. 32, no. 2, 2000, pages 210 - 8
BARRICK, ROBERTS. PROTEIN SCI., vol. 11, no. 11, 2002, pages 2688 - 2696
BARTLETT ET AL., PNAS, vol. 104, no. 39, 25 September 2007 (2007-09-25)
BATES K AND KOSTARELOS K., ADV DRUG DELIV REV, vol. 65, 2013, pages 2023 - 33
BAWAGE SS ET AL., SYNTHETIC MRNA EXPRESSED CAS13A MITIGATES RNA VIRUS INFECTIONS
BEERLI RRSEGAL DJDREIER BBARBAS CF.: "3rd Toward controlling gene expression at will: specific regulation of the erbB-2/HER-2 promoter by using polydactyl zinc finger proteins constructed from modular building blocks", PROC NATL ACAD SCI U S A., vol. 95, 1998, pages 14628 - 14633, XP002924795, DOI: 10.1073/pnas.95.25.14628
BENDER ET AL., PLOS PATHOG., vol. 12, 2016, pages 1005461
BENNETZENHALL, J BIOL CHEM., vol. 257, no. 6, 25 March 1982 (1982-03-25), pages 3026 - 31
BERNSTEIN DLLE LAY JERUANO EGKAESTNER KH: "TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts", J CLIN INVEST., vol. 125, 2015, pages 1998 - 2006, XP055574014, DOI: 10.1172/JCI77321
BETCHENKAPLITT, CURR. OPIN. NEUROL., vol. 16, 2003, pages 487 - 493
BINLEY ET AL., HUMAN GENE THERAPY, vol. 23, September 2012 (2012-09-01), pages 980 - 991
BINZ ET AL.: "Engineering novel binding proteins from nonimmunoglobulin domains", NAT BIOTECHNOL, vol. 23, 2005, pages 1257 - 1268, XP055023079, DOI: 10.1038/nbt1127
BLACK JBADLER AFWANG HG ET AL.: "Targeted Epigenetic Remodeling of Endogenous Loci by CRISPR/Cas9-Based Transcriptional Activators Directly Converts Fibroblasts to Neuronal Cells", CELL STEM CELL, vol. 19, no. 3, 2016, pages 406 - 414, XP029711990, DOI: 10.1016/j.stem.2016.07.001
BLAESE ET AL., CANCER GENE THER., vol. 2, 1995, pages 291 - 297
BONADIOSHIFMAN: "Computational design ad experimental optimization of protein binders with prospects for biomedical applications", PROTEIN ENG DES SEL., vol. 34, 2021
BORREBAECK CAOHLIN M: "Antibody evolution beyond Nature", NATURE BIOTECHNOLOGY, vol. 20, no. 12, December 2002 (2002-12-01), pages 1189 - 90, XP055629452, DOI: 10.1038/nbt1202-1189
BOSHART ET AL., CELL, vol. 41, 1985, pages 521 - 530
BROWN ET AL., STAR PROTOCOLS, vol. 1, 18 December 2020 (2020-12-18), pages 100152
BRUNE ET AL., FRONTIERS IN IMMUNOLOGY., vol. 9, 2018, pages 1432
BRYANTELOFSSON, COMMUNICATIONS CHEMISTRY, vol. 6, 2023
BUCHHOLZ ET AL., TRENDS BIOTECHNOL., vol. 33, 2015, pages 777 - 790
BUCHSCHER ET AL., J. VIROL., vol. 66, 1992, pages 1635 - 1640
BUCKHOLZ, R.G.GLEESON, M.A., BIOTECHNOLOGY (NY, vol. 9, no. 11, 1991, pages 1067 - 72
BUNING ET AL., CURRENT OPINION IN PHARMACOLOGY, vol. 24, 2015, pages 94 - 104
BYRNERUDDLE, PROC. NATL. ACAD. SCI. USA, vol. 86, 1989, pages 5473 - 5477
CALAMEEATON, ADV. IMMUNOL., vol. 43, 1988, pages 235 - 275
CAMPBELLGOWRI, PLANT PHYSIOL., vol. 92, no. 1, January 1990 (1990-01-01), pages 1 - 11
CAMPESTILGHMAN, GENES DEV., vol. 3, 1989, pages 537 - 546
CANO-RODRIGUEZ DGJALTEMA RAJILDERDA LJ ET AL.: "Writing of H3K4Me3 overcomes epigenetic silencing in a sustained but context-dependent manner", NAT COMMUN., vol. 7, 2016, pages 12284
CAO ET AL., NATURE, vol. 605, 2022, pages 551 - 560
CAPANA ET AL., PLANT MOL BIOL, vol. 25, 1994, pages 681 - 91
CARILLO, H.LIPMAN, D., SIAM J. APPLIED MATH., vol. 48, 1988, pages 1073
CASTELLO ET AL., MOL. CELL, vol. 63, no. 4, 2016, pages 696 - 710
CELL REPORTS., vol. 22, pages 2818 - 2826
CHAMOUN-EMANEULLI ET AL., BIOTECHNOL. BIOENG., vol. 112, 2015, pages 2611 - 2617
CHARMAN WN: "Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts.", J PHARM SCI., vol. 89, no. 8, 2000, pages 967 - 78, XP008099512
CHAVEZ A ET AL.: "Highly efficient Cas9-mediated transcriptional programming", NAT METHODS, vol. 12, 2015, pages 326 - 328, XP055694813, DOI: 10.1038/nmeth.3312
CHEN ET AL., ADV DRUG DELIV REV., vol. 65, no. 10, 15 October 2013 (2013-10-15), pages 1357 - 1369
CHEN HSHI MGILAM A ET AL.: "Hemophilia A ameliorated in mice by CRISPR-based in vivo genome editing of human Factor VIII.", SCI REP., vol. 9, no. 1, 2019, pages 16838, XP055807516, DOI: 10.1038/s41598-019-53198-y
CHOI ET AL., PROC. NATL. ACAD. SCI. USA., vol. 110, no. 19, 2013, pages 7625 - 7630
CHOI PSMEYERSON M., NAT COMMUN, vol. 5, 2014, pages 3728
CHOUDHURY ET AL., ONCOTARGET, vol. 7, no. 29, 19 July 2016 (2016-07-19), pages 46545 - 46556
CHRISTENSEN SM ET AL.: "RNA from the 5' end of the R2 retrotransposon controls R2 protein binding to and cleavage of its DNA target site", PROC NATL ACAD SCI U S A., vol. 103, no. 47, 21 November 2006 (2006-11-21), pages 17602 - 7, XP055659527, DOI: 10.1073/pnas.0605476103
CIDECIYAN ET AL., N ENGL J MED., vol. 361, 2009, pages 725 - 727
COCKRELL ET AL., MOL. BIOTECHNOL., vol. 36, 2007, pages 184 - 204
COELHO ET AL., N ENGL J MED, vol. 369, 2013, pages 819 - 29
CONG LZHOU RKUO YCCUNNIFF MZHANG F: "Comprehensive interrogation of natural TALE DNA-binding modules and transcriptional repressor domains", NAT COMMUN., vol. 3, 2012, pages 968, XP002700145, DOI: 10.1038/ncomms1962
COONEY ET AL., MOL. THER., vol. 23, no. 4, 2015, pages 667 - 674
COTTEN ET AL., NUCL. ACID RES., vol. 19, 1991, pages 2629 - 2635
COX ET AL., SCIENCE, vol. 356, no. 6335, 2017, pages 1019 - 1027
CRANE ET AL., GENE THER., vol. 19, no. 4, 2012, pages 145 - 153
CROYLE ET AL., GENE THER., vol. 12, 2005, pages 579 - 587
CRYSTAL, SCIENCE, vol. 270, 1995, pages 404 - 410
CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, 1987
CUTLER ET AL., J. AM. CHEM. SOC., vol. 133, 2011, pages 9254 - 9257
CUTLER ET AL., J. AM. CHEM. SOC., vol. 134, 2012, pages 16488 - 1691
DAI ET AL., MOL. THER., vol. 29, no. 9, 2021, pages 2707 - 2722
D'ASTOLFO DSPAGLIERO RJPRAS A ET AL., CELL, vol. 161, 2015, pages 674 - 690
DAVIS ET AL., NATURE, vol. 464, 15 April 2010 (2010-04-15)
DAWSON MAKOUZARIDES T: "Cancer epigenetics: from mechanism to therapy", CELL, vol. 150, no. 1, 2012, pages 935 - 949
DE VEYLDER ET AL., PLANT CELL PHYSIOL, vol. 38, 1997, pages 568 - 803
DONGBELL, GENE, vol. 237, no. 2, 1999, pages 421 - 428
DONGBELL. ET AL., J VIROL., vol. 92, no. 7, 2018, pages 02171 - 17
DOYLE ET AL., PLOS ONE, vol. 8, 2013, pages 67938
DOYON, Y. ET AL.: "Enhancing zinc-finger-nuclease activity with improved obligate heterodimeric architectures", NAT. METHODS, vol. 8, 2011, pages 74 - 79, XP055075068, DOI: 10.1038/nmeth.1539
D'SOUZA, BIOSENSORS AND BIOELECTRONICS, vol. 16, 2001, pages 337 - 353
DU ET AL., NUCLEIC ACIDS RESEARCH, vol. 49, 8 January 2021 (2021-01-08), pages 1122 - 1129
DU X ET AL., BIOMATERIALS, vol. 35, 2014, pages 5580 - 90
DURFEE PN ET AL., ACS NANO, vol. 10, 2016, pages 8325 - 45
EDLUND ET AL., SCIENCE, vol. 230, 1985, pages 912 - 916
EHRHARDT ET AL., MOL. THER., vol. 156, 2007, pages 1834 - 1841
EICKBUSH TH ET AL.: "Integration, Regulation, and Long-Term Stability of R2 Retrotransposons", MICROBIOL SPECTR., vol. 3, no. 2, April 2015 (2015-04-01), XP055660172, DOI: 10.1128/microbiolspec.MDNA3-0011-2014
EL-ANDALOUSSI ET AL., NATURE PROTOCOLS, vol. 7, 2012, pages 2112 - 2126
EL-ANDALOUSSI S ET AL., NAT PROTOC., vol. 7, no. 12, December 2012 (2012-12-01), pages 2112 - 26
ENKIRCH T. ET AL., GENE THER., vol. 20, 2013, pages 16 - 23
FARR ET AL., PROC. NATL. ACAD, SCI. U.SA., vol. 102, no. 47, 2005, pages 17148 - 17153
FARZADFARD FPERLI SDLU TK: "Tunable and multifunctional eukaryotic transcription factors based on CRISPR/Cas", ACS SYNTH BIOL., vol. 2, 2013, pages 604 - 613, XP055194786, DOI: 10.1021/sb400081r
FEHRING ET AL., MOL. THER., vol. 22, no. 4, 22 April 2014 (2014-04-22), pages 811 - 20
FLOTTE ET AL., HUM. GENE. THER., vol. 7, 1996, pages 1145 - 1159
FREJDKIM, EXP. MOL. MED., vol. 49, no. 3, 2017, pages 306
FRIEDRICH ET AL., MOL. THER., vol. 21, 2013, pages 849 - 859
FUNES ET AL., J. BIOL. CHEM., vol. 277, 2002, pages 6051 - 6058
FUNKE ET AL., MOLEC. THER., vol. 16, no. 8, 2008, pages 1427 - 1436
GALANIS ET AL., FEBS LETT, vol. 282, 1991, pages 425 - 430
GAO ET AL., GENE THERAPY, vol. 2, 1995, pages 710 - 722
GATZ ET AL., MOL GEN GENET, vol. 227, 1991, pages 229 - 37
GAUDELI ET AL., NATURE, vol. 551, 2017, pages 464 - 471
GEBAUERSKERRA: "Engineered protein scaffolds as next-generation antibody therapeutics", CURR OPIN CHEM BIOL., vol. 13, 2009, pages 245 - 55
GEIGENMULLER-GNIRKE ET AL., J VIROL., 1993, pages 1620 - 1626
GEISBERT ET AL., LANCET, vol. 375, 2010, pages 1896 - 905
GILBERT LA ET AL.: "CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes", CELL, vol. 154, 2013, pages 442 - 451, XP055115843, DOI: 10.1016/j.cell.2013.06.044
GILLDAMLE: "Biopharmaceutical drug discovery using novel protein scaffolds", CURR OPIN BIOTECHNOL, vol. 17, 2006, pages 653 - 658
GIRARD-GAGNEPAIN ET AL., BLOOD, vol. 124, 2014, pages 1221 - 1231
GORLEKU ET AL., J. BIOL. CHEM., vol. 286, 2011, pages 39573 - 39584
GORSUCH ET AL.: "Targeting the hepatitis B cccdna with a sequence-specific arcus nuclease to eliminate hepatitis B virus in vivo", MOLECULAR THERAPY, vol. 30, no. 9, 2022, pages 2909 - 2922, XP093237393, DOI: 10.1016/j.ymthe.2022.05.013
GREGORY DJZHANG YKOBZIK LFEDULOV AV: "Specific transcriptional enhancement of inducible nitric oxide synthase by targeted promoter demethylation", EPIGENETICS, vol. 8, 2013, pages 1205 - 1212
GRIMM, D. ET AL., J. VIROL., vol. 82, 2008, pages 5887 - 5911
GROTH AC ET AL., PROC. NATL. ACAD. SCI. USA, vol. 97, 2000, pages 5995 - 6000
GROTH, A. C.CALOS, M. P., J. MOL. BIOL., vol. 335, 2004, pages 667 - 678
GUPTA ET AL., NUCLEIC ACIDS RES., vol. 35, May 2007 (2007-05-01), pages 3407 - 3419
HAN JS: "Non-long terminal repeat (non-LTR) retrotransposons: mechanisms, recent developments, and unanswered questions", MOB DNA, vol. 1, no. 1, 12 May 2010 (2010-05-12), pages 15, XP021084898, DOI: 10.1186/1759-8753-1-15
HANA SPETERSON MMCLAUGHLIN H ET AL.: "Highly efficient neuronal gene knockout in vivo by CRISPR-Cas9 via neonatal intracerebroventricular injection of AAV in mice", GENE THER., vol. 28, no. 10-11, 2021, pages 646 - 658, XP037621324, DOI: 10.1038/s41434-021-00224-2
HANAWA ET AL., MOLEC. THER., vol. 5, no. 3, 2002, pages 242 - 251
HAO ET AL., SMALL, vol. 7, 2011, pages 3158 - 3162
HARDEE ET AL., GENES, vol. 8, no. 2, 2017, pages 65
HENTZE ET AL., NATURE REVIEWS MOLECULAR CELL BIOLOGY, vol. 19, 2018, pages 327 - 341
HERMONATMUZYCZKA, PNAS, vol. 81, 1984, pages 6466 - 6470
HILTON IB ET AL.: "Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers", NAT BIOTECHNOL., 2015
HINDI ET AL., CELL, vol. 186, no. 10, 2023, pages 2062 - 2077
HIRE ET AL., PLANT MOL BIOL, vol. 20, 1992, pages 207 - 18
HOBBS ET AL., BIOCHEMISTRY, vol. 12, 1973, pages 5138 - 5145
HOLT LJHERRING CJESPERS LSWOOLVEN BPTOMLINSON IM: "Domain antibodies: proteins for therapy", TRENDS IN BIOTECHNOLOGY, vol. 21, no. 11, November 2003 (2003-11-01), pages 484 - 90, XP004467495, DOI: 10.1016/j.tibtech.2003.08.007
HOWARD ET AL., J. NEUROSURG., vol. 71, 1989, pages 105
IVICS ET AL., CELL, vol. 91, no. 4, 1997, pages 501 - 510
JAMES E. DAHLMANCARMEN BARNES ET AL., NATURE NANOTECHNOLOGY, 11 May 2014 (2014-05-11)
JAYARAMAN, ANGEW. CHEM. INT. ED., vol. 51, 2012, pages 8529 - 8533
JENSEN ET AL., SCI. TRANSL. MED., vol. 5, 2013
JI Q ET AL.: "Engineered zinc-finger transcription factors activate OCT4 (POUSF1), SOX2, KLF4, c-MYC (MYC) and miR302/367", NUCLEIC ACIDS RES., vol. 42, 2014, pages 6158 - 6167, XP055378599, DOI: 10.1093/nar/gku243
JONKERS ET AL., AM. J. VET. RES., vol. 25, 1964, pages 236 - 242
JUDGE, J. CLIN. INVEST., vol. 119, 2009, pages 661 - 673
K. MATSUO ET AL., ANGEW. CHEM. INT. ED., vol. 57, 2018, pages 659
KAFRI T., MOL. BIOL., vol. 246, 2004, pages 367 - 390
KANG JGPARK JSKO JHKIM YS: "Regulation of gene expression by altered promoter methylation using a CRISPR/Cas9-mediated epigenetic editing system", SCI REP., vol. 9, no. 1, 2019, pages 11960, XP055688645, DOI: 10.1038/s41598-019-48130-3
KAPITONOV VV ET AL.: "ISC, a Novel Group of Bacterial and Archaeal DNA Transposons That Encode Cas9 Homologs", J BACTERIOL., vol. 198, no. 5, 28 December 2015 (2015-12-28), pages 797 - 807, XP055393473, DOI: 10.1128/JB.00783-15
KASARANENI ET AL., SCI. REPORTS, no. 10990, 2018, pages 8
KAUFMAN ET AL., EMBO J., vol. 6, 1987, pages 187 - 195
KAY ET AL., NAT. GENET., vol. 24, 2000, pages 257 - 261
KEARNS NAPHAM HTABAK B ET AL.: "Functional annotation of native enhancers with a Cas9-histone demethylase fusion", NAT METHODS., vol. 12, no. 5, 2015, pages 401 - 403, XP055931429, DOI: 10.1038/nmeth.3325
KESSELGRUSS, SCIENCE, vol. 249, 1990, pages 374 - 379
KIM ET AL., J BIOL. CHEM., vol. 284, no. 45, 2009, pages 31028 - 31037
KIM, Y. G. ET AL.: "Chimeric restriction endonuclease", PROC. NATL. ACAD. SCI. U.S.A., vol. 91, 1994, pages 883 - 887, XP002020280, DOI: 10.1073/pnas.91.3.883
KIM, Y. G. ET AL.: "Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain", PROC. NATL. ACAD. SCI. U.S.A., vol. 93, 1996, pages 1156 - 1160, XP002116423, DOI: 10.1073/pnas.93.3.1156
KOGURE K ET AL., J CONTROL RELEASE, vol. 98, 2004, pages 317 - 23
KOIDEKOIDE: "Monobodies: antibody mimics based on the scaffold of the fibronectin type III domain", METHODS MOL BIOL, vol. 352, 2007, pages 95 - 109, XP009102789
KOIRALA ET AL., ADV. EXP. MED. BIOL., vol. 801, 2014, pages 703 - 709
KOLMAR: "Alternative binding proteins: biological activity and therapeutic potential of cystine-knot miniproteins", FEBS J, vol. 275, 2008, pages 2684 - 2690, XP055417456, DOI: 10.1111/j.1742-4658.2008.06440.x
KOMOR ET AL., NATURE, vol. 533, 2016, pages 420 - 424
KONERMANN ET AL.: "Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex", NATURE, 10 December 2014 (2014-12-10)
KONERMANN ET AL.: "Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex", NATURE., 10 December 2014 (2014-12-10)
KONERMANN S ET AL.: "Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex", NATURE, vol. 517, 2015, pages 583 - 588, XP093213286, DOI: 10.1038/nature14136
KONERMANN S ET AL.: "Optical control of mammalian endogenous transcription and epigenetic states", NATURE, vol. 500, 2013, pages 472 - 476, XP055696669, DOI: 10.1038/nature12466
KOONIN EVMAKAROVA KS, PHIL. TRANS. R. SOC. B, vol. 374, 2019, pages 20180087
KORMAN ET AL., NAT. BIOTECH., vol. 29, 2011, pages 154 - 157
KOTIN, HUMAN GENE THERAPY, vol. 5, 1994, pages 793 - 801
KUBOMITANI, J. VIROL., vol. 77, no. 5, 2003, pages 2964 - 2971
KUIJANHERSKOWITZ, CELL, vol. 30, 1982, pages 933 - 943
KUSTER ET AL., PLANT MOL BIOL, vol. 29, 1995, pages 759 - 72
LAI ET AL., DNA CELL. BIOL., vol. 21, 2002, pages 895 - 913
LAWRENCE ET AL., JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 129, 2007, pages 10110 - 10112
LEE K ET AL., NAT BIOMED ENG, vol. 1, 2017, pages 889 - 901
LEI ET AL., FEBS LETT., vol. 592, no. 8, April 2018 (2018-04-01), pages 1389 - 1399
LEIKINA ET AL., DEV. CELL, vol. 46, no. 6, 2018, pages 767 - 780
LEVY ET AL., NATURE BIOMEDICAL ENGINEERING, 2019
LI ET AL., CELL, vol. 152, no. 5, 2013, pages 1173 - 1183
LI ET AL., NAT. BIOTECH., vol. 36, pages 324 - 327
LI JMAHATA BESCOBAR M ET AL.: "Programmable human histone phosphorylation and gene activation using a CRISPR/Cas9-based chromatin kinase", NAT COMMUN., vol. 12, no. 1, 2021, pages 896
LIANG ET AL., NAT. PROTOCOL., vol. 13, 2018, pages 413 - 430
LIM, F.M. SPINGOLAD. S.: "Peabody. ''Altering the RNA binding specificity of a translational ''repressor.", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 269, no. 12, 1994, pages 9006 - 9010, XP002109137
LINGER ET AL., RNA, vol. 10, 2004, pages 128 - 138
LIU ET AL., MOL. BIOL. CELL., vol. 18, no. 3, 2007, pages 1073 - 1082
LIU PQ ET AL.: "Regulation of an endogenous locus using a panel of designed zinc finger proteins targeted to accessible chromatin regions. Activation of vascular endothelial growth factor A", J BIOL CHEM., vol. 276, 2001, pages 11323 - 11334
LIU XSWU HJI X ET AL.: "Editing DNA Methylation in the Mammalian Genome", CELL, vol. 167, no. 1, 2016, pages 233 - 247, XP029748854, DOI: 10.1016/j.cell.2016.08.056
LOFBLOM J ET AL., FEBS LETT., vol. 584, no. 12, 18 June 2010 (2010-06-18), pages 2670 - 80
LUCKLOWSUMMERS, VIROLOGY, vol. 170, 1989, pages 31 - 39
LUO DSALTZMAN WM., NAT BIOTECHNOL, vol. 18, 2000, pages 893 - 5
LUO GF ET AL., SCI REP, vol. 4, 2014, pages 6064
MAEDER NILLINDER SJCASCIO VMFU YHO QHJOUNG JK: "CRISPR RNA-guided activation of endogenous human genes", NAT METHODS., vol. 10, no. 10, 2013, pages 977 - 979, XP055291599, DOI: 10.1038/nmeth.2598
MAKAROVA ET AL., CRISPR-CAS SYSTEMS ARE DIVIDED INTO 3 SUBTYPES, 2020
MAKAROVA ET AL., NAT. REV., vol. 18, 2020, pages 67 - 83
MAKAROVA ET AL., SYSTEMS ALSO INCLUDE CRISPR-CAS VARIANTS, 2020
MAKAROVA ET AL., THE CRISPR JOURNAL, vol. 1, no. 5, 2018
MAKAROVA ET AL., TYPE I CRISPR-CAS SYSTEMS CAN CONTAIN A CAS3 PROTEIN THAT CAN HAVE HELICASE ACTIVITY, 2020
MAKAROVA ET AL.: "Evolutionary classification of CRISPR-Cas systems: a burst of class 2 and derived variants", NATURE REVIEWS MICROBIOLOGY, vol. 18, February 2020 (2020-02-01), pages 67 - 81
MALIK HS ET AL.: "The age and evolution of non-LTR retrotransposable elements", MOL BIOL EVOL., vol. 16, no. 6, June 1999 (1999-06-01), pages 793 - 805
MARCHAND ET AL.: "Computational design of novel protein-protein interactions - An overview on methodological approaches and applications", CURR OPIN STRUCT BIOL., vol. 74, 2022, pages 102370, XP087089517, DOI: 10.1016/j.sbi.2022.102370
MATOUSCHEK ET AL., PNAS USA, vol. 85, 1997, pages 2091 - 2095
MATTHEWS: "Capsid-Incorporation of Antigens into Adenovirus Capsid Proteins for a Vaccine Approach", MOL PHARM, vol. 8, no. 1, 2011, pages 3 - 11, XP055945109, DOI: 10.1021/mp100214b
MILLAY ET AL., GENS, vol. 28, no. 15, 2014, pages 1641 - 1646
MILLER ET AL., J. VIROL., vol. 65, 1991, pages 2220 - 2224
MIRKIN ET AL., SMALL, vol. 10, pages 186 - 192
MIRKIN, NANOMEDICINE, vol. 7, 2012, pages 635 - 638
MIRKOVITCH ET AL., CELL, vol. 39, 1984, pages 223 - 232
MISKEY ET AL., NUCLEIC ACID RES., vol. 31, no. 23, 2003, pages 6873 - 6881
MOL. CELL. BIOL., vol. 8, no. 1, 1988, pages 466 - 472
MORIZONO ET AL., J. GENE MED., vol. 11, 2009, pages 549 - 558
MORIZONO ET AL., J. GENE MED., vol. 11, pages 655 - 663
MORIZONO ET AL., J. VIROL., vol. 75, 2001, pages 8016 - 8020
MORIZONO ET AL., J. VIROL., vol. 84, no. 14, 2010, pages 6923 - 6934
MORIZONO ET AL., NAT. MED., vol. 11, 2005, pages 346 - 352
MORIZONO ET AL., VIROLOGY, vol. 355, 2006, pages 71 - 81
MORRAL ET AL., HUM. GENE THER., vol. 9, 1998, pages 2709 - 2716
MORRAL ET AL., PNAS, vol. 96, 1999, pages 12816 - 12821
MORRISSEY ET AL., NATURE BIOTECHNOLOGY, vol. 23, no. 8, August 2005 (2005-08-01)
MORTON BR, J MOL EVOL., vol. 46, no. 4, April 1998 (1998-04-01), pages 449 - 59
MOSCOU ET AL., SCIENCE, vol. 326, 2009, pages 1509 - 1512
MOUT R ET AL., ACS NANO, vol. 11, 2017, pages 2452 - 8
MURRAY ET AL., NUCLEIC ACIDS RES., vol. 17, no. 2, 25 January 1989 (1989-01-25), pages 477 - 98
MUZYCZKA, J. CLIN. INVEST., vol. 94, 1994, pages 1351
NAIR, JK ET AL., JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 136, no. 49, 2014, pages 16958 - 16961
NAKAMURA T ET AL., ACC CHEM RES, vol. 45, 2012, pages 1113 - 21
NAKAMURA, Y. ET AL.: "Codon usage tabulated from the international DNA sequence databases: status for the year 2000", NUCL. ACIDS RES., vol. 28, 2000, pages 292, XP002941557, DOI: 10.1093/nar/28.1.292
NAT COMMUN, vol. 9, 2018, pages 1870
NEEDELMANWUNSCH, J. MOL. BIOL., vol. 48, 1970, pages 443 - 453
NEHLSEN ET AL., GENE THER. MOL. BIOL., vol. 10, 2006, pages 233 - 244
NISHIDA ET AL., SCIENCE, 2016, pages 353
NIXONWOOD: "Engineered protein inhibitors of proteases", CURR OPIN DRUG DISCOV DEV, vol. 9, 2006, pages 261 - 268
NORD ET AL., NAT. BIOTECHNOL., vol. 15, no. 8, 1997, pages 772 - 777
NORSTRND ET AL., NATURE, vol. 583, 2020, pages 711 - 719
NOVOBRANTSEVA, MOLECULAR THERAPY-NUCLEIC ACIDS, vol. 1, 2012, pages 4
NWE, K.BRECHBIEL, M. W.: "Growing Applications of ''Click Chemistry'' for Bioconjugation in Contemporary Biomedical Research", CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS, vol. 24, 2009, pages 289 - 302, XP002614559, DOI: 10.1089/CBR.2008.0626
NYGREN, P.A., FEBS J., vol. 275, no. 11, June 2008 (2008-06-01), pages 2668 - 76
NYGREN: "Alternative binding proteins: Affibody binding proteins developed from a small three-helix bundle scaffold", FEBS J, vol. 275, 2008, pages 2668 - 2676
ONO ET AL., BIOSCI BIOTECHNOL BIOCHEM, vol. 68, 2004, pages 803 - 7
ORTEGA-ESCALANTE ET AL., PLANT. J., vol. 97, 2019, pages 661 - 672
OSTERGAARD ET AL., BIOCONJUGATE CHEM., vol. 26, no. 8, 2015, pages 1451 - 1455
OTA, E. ET AL.: "Thienyl-Substituted a-Ketoamide: A Less Hydrophobic Reactive Group for Photo-Affinity Labeling.", ACS CHEM. BIOL., vol. 13, no. 4, 2018, pages 876 - 880
PACESA ET AL., BIORXIV, 2024
PARK ET AL., SENSORS (BASEL, vol. 16, no. 12, December 2016 (2016-12-01), pages 2068
PASTUZYN ELISSA D ET AL: "The Neuronal GeneArcEncodes a Repurposed Retrotransposon Gag Protein that Mediates Intercellular RNA Transfer", CELL, ELSEVIER, AMSTERDAM NL, vol. 172, no. 1, 11 January 2018 (2018-01-11), pages 275 - 288, XP085336482, ISSN: 0092-8674, DOI: 10.1016/J.CELL.2017.12.024 *
PEREZ-PINERA P ET AL.: "Synergistic and tunable human gene activation by combinations of synthetic transcription factors", NAT METHODS., vol. 10, 2013, pages 239 - 242, XP055206832, DOI: 10.1038/nmeth.2361
PETERS ET AL., PNAS, vol. 114, no. 35, 2017
PFLUEGER C.TAN D.SWAIN T.NGUYEN T.PFLUEGER J.NEFZGER C.POLO J.M.FORD E.LISTER R: "A modular dCas9-SunTag DNMT3A epigenome editing system overcomes pervasive off-target activity of direct fusion dCas9-DNMT3A constructs", GENOME RES., vol. 28, 2018, pages 1193 - 1206, XP055975093, DOI: 10.1101/gr.233049.117
PHARMACIA BIOTECH INCSMITHJOHNSON, GENE, vol. 69, 1988, pages 301 - 315
PINKERT ET AL., GENES DEV., vol. 1, 1987, pages 268 - 277
PLUCKTHUN ET AL., ANNU. REV. PHARMACOL. TOXICOL., vol. 55, no. 1, 2015, pages 489 - 511
POWELL ET AL.: "Compendium of excipients for parenteral formulations", PDA J PHARM SCI TECHNOL., vol. 52, 1998, pages 238 - 311, XP009119027
PROC. NATL. ACAD. SCI. USA., vol. 78, no. 3, 1981, pages 1527 - 31
QUEENBALTIMORE, CELL, vol. 33, 1983, pages 741 - 748
QUI ET AL., BIOTECHNIQUES, vol. 36, no. 4, 2004, pages 702 - 707
RAMIREZ ET AL., PROTEIN. ENG. DES. SEL., vol. 26, 2013, pages 215 - 233
REESLIU, NAT. REV. GENET., vol. 19, no. 12, 2018, pages 770 - 788
REESLIU, NAT. REV. GENT., vol. 19, no. 12, 2018, pages 770 - 788
REMY ET AL., BIOCONJUGATE CHEM., vol. 5, 1994, pages 647 - 654
RESHETNYAK ET AL., PROC. NAT. ACAD. SCI., vol. 110, no. 44, 2013, pages 17832 - 17837
RIVENBARK AG ET AL.: "Epigenetic reprogramming of cancer cells via targeted DNA methylation", EPIGENETICS, vol. 7, 2012, pages 350 - 360, XP002756482, DOI: 10.4161/epi.19507
ROHLOFF ET AL.: "Nucleic Acid Ligands With Protein-like Side Chains: Modified Aptamers and Their Use as Diagnostic and Therapeutic Agents", MOLECULAR THERAPY NUCLEIC ACIDS, vol. 3, 2014, pages 201
ROLDAO ET AL., COMPREHEN. BIOTECH., 2017, pages 633 - 656
ROSENBLUM DGUTKIN AKEDMI R ET AL.: "CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy", SCI ADV., vol. 6, no. 47, 2020, pages 9450
ROSEWELL ET AL., J. GENET. SYNDR. GENE THER., 2011
ROSIN ET AL., MOLECULAR THERAPY, vol. 19, no. 12, December 2011 (2011-12-01), pages 1286 - 2200
ROSMALEN ET AL., BIOCHEM., vol. 56, no. 50, 2017, pages 6565 - 6574
SAMUELS ET AL., NUCLEIC ACIDS RES., vol. 26, no. 11, 1998, pages 2625 - 2637
SAMULSKI ET AL., J. VIROL., vol. 63, 1989, pages 03822 - 2378
SAUDEK ET AL., NEW ENGL. J. MED., vol. 321, 1989, pages 574
SCHIFFELERS ET AL., NUCLEIC ACIDS RESEARCH, vol. 32, no. 19, 2004
SCHOLTHOF ET AL., ANNU REV PHYTOPATHOL., vol. 34, 1996, pages 299 - 323
SCHROEDER A ET AL., J INTERN MED., vol. 267, no. 1, January 2010 (2010-01-01), pages 9 - 21
SCHULTHEIS ET AL., J. CLIN. ONCOL., vol. 32, no. 36, 20 December 2014 (2014-12-20), pages 4141 - 48
SCHULTZ ET AL., GENE, vol. 54, 1987, pages 113 - 123
SCINTO ET AL., ANGEWANDTE CHEMIE, vol. 61, no. 45, 2022, pages 202207661
SEED, NATURE, vol. 329, 1987, pages 840
SEMPLE ET AL., NATURE BIOTECHNOLOGY, vol. 28, no. 2, February 2010 (2010-02-01), pages 172 - 177
SHMAKOV ET AL.: "Discovery and Functional Characterization of Diverse Class 2 CRISPR-Cas Systems", MOLECULAR CELL, 2015
SHUJI ET AL., MOL. THER., vol. 19, 2011, pages 76 - 82
SIDDIQUE AN ET AL.: "Targeted methylation and gene silencing of VEGF-A in human cells by using a designed Dnmt3a-Dnmt3L single-chain fusion protein with increased DNA methylation activity", J MOL BIOL., vol. 425, 2013, pages 479 - 491, XP055623261, DOI: 10.1016/j.jmb.2012.11.038
SIERIG G ET AL., INFECT IMMUN, vol. 71, 2003, pages 446 - 55
SILVERMAN ET AL., NAT. BIOTECHNOL., vol. 23, no. 12, 2005, pages 1493 - 1494
SILVERMAN ET AL.: "Multivalent avimer proteins evolved by exon shuffling of a family of human receptor domains", NAT BIOTECHNOL, vol. 23, 2005, pages 1556 - 1561, XP009088629, DOI: 10.1038/nbt1166
SIMONELLI ET AL., J AM SOC GENE THER., vol. 18, 2010, pages 643 - 650
SINGH ET AL.: "Attachment Site Selection and Identity in ]3xbl Serine Integrase-Mediated Site-Specific Recombination", PLOS GENET., no. 5, 9 May 2013 (2013-05-09), XP002768719, DOI: 10.1371/annotation/fd6f4425-3d84-4017-a012-a5df6ddee13a
SKERRA: "Alternative binding proteins: Anticalins-harnessing the structural plasticity of the lipocalin ligand pocket to engineer novel binding activities", FEBS J, vol. 275, 2008, pages 2677 - 2683, XP055099855, DOI: 10.1111/j.1742-4658.2008.06439.x
SKERRA: "Alternative non-antibody scaffolds for molecular recognition", CURR OPIN BIOTECHNOL, vol. 18, 2007, pages 295 - 304
SKERRA: "Engineered protein scaffolds for molecular recognition", J MOL RECOGNIT, vol. 13, 2000, pages 167 - 187, XP009019725, DOI: 10.1002/1099-1352(200007/08)13:4<167::AID-JMR502>3.0.CO;2-9
SMITH ET AL., MOL. CELL. BIOL., vol. 3, 1983, pages 2156 - 2165
SNOWDEN AWGREGORY PDCASE CCPABO CO: "Gene-specific targeting of H3K9 methylation is sufficient for initiating repression in vivo", CURR BIOL., vol. 12, 2002, pages 2159 - 2166, XP009157323, DOI: 10.1016/S0960-9822(02)01391-X
SOMMNERFELT ET AL., VIROL., vol. 176, 1990, pages 58 - 59
SPEIR ET AL., STRUCTURE, vol. 3, 1995, pages 63 - 78
SPUCHNAVARRO, JOURNAL OF DRUG DELIVERY, vol. 2011
STEPPER PKUNGULOVSKI GJURKOWSKA RZ ET AL.: "Efficient targeted DNA methylation with chimeric dCas9-Dnmt3a-Dnmt3L methyltransferase", NUCLEIC ACIDS RES., vol. 45, no. 4, 2017, pages 1703 - 1713, XP055459985, DOI: 10.1093/nar/gkw1112
STRECKER ET AL., SCIENCE, 2019
STRUMBERG ET AL., INT. J. CLIN. PHARMACOL. THER., vol. 50, no. 1, January 2012 (2012-01-01), pages 76 - 8
STUMPP ET AL.: "DARPins: a new generation of protein therapeutics", DRUG DISCOV TODAY, vol. 13, 2008, pages 695 - 701, XP023440383, DOI: 10.1016/j.drudis.2008.04.013
SUN W ET AL., ANGEW CHEM INT ED ENGL., vol. 54, no. 41, 5 October 2015 (2015-10-05), pages 12029 - 33
SUN W ET AL., J AM CHEM SOC., vol. 136, no. 42, 22 October 2014 (2014-10-22), pages 14722 - 5
SVITASHEV ET AL., NAT. COMM., vol. 7, 2016, pages 13274
SYDING LANICKL PKASPAREK PSEDLACEK R.: "CRISPR/Cas9 Epigenome Editing Potential for Rare Imprinting Diseases: A Review", CELLS, vol. 9, no. 4, 2020, pages 993
TAKAOKA ET AL., CHEM. SCI., vol. 6, 2015, pages 3217 - 3224
TAKEDA ET AL., NEURAL REGEN RES., vol. 10, no. 5, May 2015 (2015-05-01), pages 689 - 90
TELLINGHUISEN ET AL.: "Genetic and biochemical studies of the assembly of an enveloped virus", GENETIC ENGINEERING (N Y, vol. 23, 2001, pages 83 - 112
TENG KW ET AL., ELIFE, vol. 6, 2017, pages 25460
TERAMATO ET AL., LANCET, vol. 355, 2000, pages 1911 - 1912
THAKORE PIBLACK JBHILTON IBGERSBACH CA: "Editing the epigenome: technologies for programmable transcription and epigenetic modulation", NAT METHODS, vol. 13, no. 2, 2016, pages 127 - 137, XP055623879, DOI: 10.1038/nmeth.3733
THAKORE PID'IPPOLITO AMSONG L ET AL.: "Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements", NAT METHODS., vol. 12, no. 12, 2015, pages 1143 - 1149, XP055623949, DOI: 10.1038/nmeth.3630
THRASHER ET AL., NATURE, vol. 443, 2006, pages 5 - 7
TOU ET AL., BIORXIV
TRATSCHIN ET AL., MOL. CELL. BIOL., vol. 4, 1984, pages 2072 - 2081
TRATSCHIN ET AL., MOL. CELL. BIOL., vol. 5, 1985, pages 3251 - 3260
TRAVASSOS DA ROSA ET AL., AM. J. TROPICAL MED. & HYGIENE, vol. 33, 1984, pages 999 - 1006
TROBRIDGE. EXP. OPIN. BIOL. THER., vol. 9, 2009, pages 1427 - 1436
UNO Y ET AL., HUM GENE THER., vol. 22, no. 6, June 2011 (2011-06-01), pages 711 - 9
VAN DE BROEK BDEVOOGDT ND'HOLLANDER AGIJS HLJANS KLAGAE L ET AL.: "Specific cell targeting with nanobody conjugated branched gold nanoparticles for photothermal therapy", ACS NANO., vol. 5, no. 6, June 2011 (2011-06-01), pages 4319 - 28, XP055012818, DOI: 10.1021/nn1023363
VERGHESE ET AL., NUCLEIC ACID RES., vol. 42, 2014, pages 53
WAGNER ET AL., NAT BIOTECHNOL., vol. 34, no. 11, 2016, pages 1145 - 1160
WAHLGREN ET AL., NUCLEIC ACIDS RESEARCH, vol. 40, no. 17, 2012
WALEV I ET AL., PROC NATL ACAD SCI U S A, vol. 98, 2001, pages 3185 - 90
WALTNER ET AL., J. BIOL. CHEM., vol. 271, 1996, pages 21226 - 21230
WANG ET AL., ACS SYNTHETIC BIOLOGY, vol. 1, 2012, pages 403 - 07
WANG ET AL., ADV. HEALTHC MATER., vol. 3, no. 9, September 2014 (2014-09-01), pages 1398 - 403
WANG ET AL., AGNEW CHEM INT ED ENGL., vol. 53, no. 11, 10 March 2014 (2014-03-10), pages 2893 - 8
WANG ET AL., J. CONTROL RELEASE, 31 January 2017 (2017-01-31), pages 0168 - 3659
WANG ET AL., PLOS ONE, vol. 10, no. 11, 3 November 2015 (2015-11-03), pages 0141860
WANG ET AL., PNAS, vol. 113, no. 11, 15 March 2016 (2016-03-15), pages 2868 - 73
WANG ET AL., PNAS, vol. 113, no. 11, 2016, pages 2868 - 2873
WANG J, QUAKE SR., PROC NATL ACAD SCI, vol. 111, 2014, pages 13157 - 62
WANG W.: "Lyophilization and development of solid protein pharmaceuticals.", INT. J. PHARM., vol. 203, no. 1-2, 2000, pages 1 - 60, XP055005330, DOI: 10.1016/S0378-5173(00)00423-3
WARD ESGÜSSOW DGRIFFITHS ADJONES PTWINTER G: "Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli", NATURE, vol. 341, no. 6242, pages 544 - 6
WEISS ET AL., NUC. ACID. RES., vol. 22, no. 5, 1994, pages 780 - 786
WEST ET AL., VIROLOGY, vol. 160, 1987, pages 38 - 47
WILCOX ET AL., PNAS USA, vol. 102, 2005, pages 15435 - 15440
WINOTOBALTIMORE, EMBO J., vol. 8, 1989, pages 729 - 733
WONG ET AL., ADV. GENET., vol. 89, 2015, pages 113 - 152
WONG ET AL., HUM. GEN. THER., vol. 17, 2002, pages 1 - 9
WU ET AL., COMPLEX AND INTELLIGENT SYSTEMS, vol. 10, 2024, pages 2067 - 2082
WU Y ET AL., CELL RES, vol. 25, 2015, pages 67 - 79
XU ET AL., CELL DISCOV., vol. 2, 3 May 2016 (2016-05-03), pages 16009
XU ET AL., SCI. CHINA LIFE SCI., vol. 59, 2016, pages 1024 - 1033
YAMAMOTO ET AL., PLANT J, vol. 12, 1997, pages 255 - 65
YARNALL ET AL., NAT BIOTECHNOL, 2022
YE L ET AL., PROC NATL ACAD SCI USA, vol. 111, 2014, pages 9591 - 6
YE Y ET AL., BIOMATER SCI., 28 April 2020 (2020-04-28)
YEO NCCHAVEZ ALANCE-BYRNE A ET AL.: "An enhanced CRISPR repressor for targeted mammalian gene regulation", NAT METHODS., vol. 15, no. 8, 2018, pages 611 - 616, XP093069177, DOI: 10.1038/s41592-018-0048-5
YOUNG ET AL., NANO LETT., vol. 12, 2012, pages 3867 - 71
YUSA ET AL., PNAS, vol. 108, no. 4, 2011, pages 1531 - 1536
ZADORI ET AL., DEV. CELL, vol. 1, no. 2, August 2001 (2001-08-01), pages 291 - 302
ZAKERIA ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 109, no. 12, 2012, pages 690 - 7
ZHANG ET AL., ACS NANO., vol. 5, 2011, pages 6962 - 6970
ZHANG ET AL., NATURE BIOTECHNOLOGY, vol. 29, 2011, pages 149 - 153
ZHANG ET AL., PLOS ONE., vol. 8, no. 10, 2013, pages 76771
ZHANG Y.: "Transcriptional regulation by histone ubiquitination and deubiquitination", GENES DEV., vol. 17, no. 22, 2003, pages 2733 - 2740
ZHENG ET AL., PROC. NATL. ACAD. SCI. USA., vol. 109, 2012, pages 11975 - 80
ZIMMERMAN ET AL., NATURE LETTERS, vol. 441, 4 May 2006 (2006-05-04)
ZOU W ET AL., HUM GENE THER., vol. 22, no. 4, April 2011 (2011-04-01), pages 465 - 75
ZUCKERMANN M ET AL., NAT COMMUN, vol. 6, 2015, pages 7391

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