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WO1997000083A1 - Procede de traitement de la diminution du nombre des lymphocytes t cd4+ chez des patients presentant une deficience immunitaire - Google Patents

Procede de traitement de la diminution du nombre des lymphocytes t cd4+ chez des patients presentant une deficience immunitaire Download PDF

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Publication number
WO1997000083A1
WO1997000083A1 PCT/US1996/010362 US9610362W WO9700083A1 WO 1997000083 A1 WO1997000083 A1 WO 1997000083A1 US 9610362 W US9610362 W US 9610362W WO 9700083 A1 WO9700083 A1 WO 9700083A1
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Prior art keywords
adenosine
effective amount
adenosine deaminase
human
cell
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PCT/US1996/010362
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English (en)
Inventor
Robert G. L. Shorr
Mike A. Clark
David H. Goddard
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Enzon Pharmaceuticals Inc
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Enzon Inc
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Priority to AU62802/96A priority Critical patent/AU6280296A/en
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Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/50—Hydrolases (3) acting on carbon-nitrogen bonds, other than peptide bonds (3.5), e.g. asparaginase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • the present invention relates to methods of increasing CD4+ T cells in patients infected with the human immunodeficiency virus (HIN).
  • the present invention relates to a novel use of adenosine deaminase for treating CD4+ T cell lymphopenia.
  • Acquired immunodeficiency syndrome (AIDS) is a disease characterized by a progressive loss of function of the immune system. As a result, those afflicted with the syndrome are susceptible to a variety of opportunistic infections.
  • the etiologic agent of AIDS is a cytopathic retrovirus designated the human immunodeficiency virus (HIN).
  • HIN human immunodeficiency virus
  • One of the major targets of the HIN in humans is T helper cells (CD4+ cells).
  • T helper cells The infection of T helper cells by HIN results in a profound dysregulation of the immune system including both depleted numbers and impaired functioning of T lymphocytes. Although the exact mechanism is unknown, the number of T helper cells predictably declines during HIN infection. Clinicians monitor this decline as an indicator of disease progression. Research in the AIDS field has focused on several goals: preventing HIN infections, treating HIN-infected individuals with anti-viral agents, treating opportunistic infections with antimicrobial agents, and restoring the immune system of infected patients.
  • Initial contact between the virus and the T cell is believed to occur by interaction of the external viral glycoprotein gpl20 and the CD4 protein present on the surface of the T cell.
  • the CD26 receptor may also be involved with facilitating HIN entry into T cells.
  • CD26 also binds adenosine deaminase (ADA) on the surface of T lymphocytes and may play a role in T cell activation.
  • ADA adenosine deaminase
  • the immune system is chronically activated. This chronic activation is believed to play a primary role in the pathology of the disease.
  • Apoptosis is essential in the normal maturation of the immune system. Apoptic cell death is part of the normal development of self-tolerance. Apoptosis, however, can be triggered in immature thymocytes by several events including specific activation of the T cell receptor CD3 complex. Mature T cells are usually resistant to these apoptic stimuli and respond to T cell receptor stimulation by cell proliferation and cytokine secretion. Abnormal induction of apoptosis in mature T cells, however, is also known. Apoptosis in CD4+ T cells has also been observed in HIN-infected individuals, especially upon T cell receptor activation. It has been speculated that the complexing of the external glycoprotein gpl20 of HIN with the CD4+ receptor may cause apoptosis even in noninfected cells. See Science vol. 260 May 28, 1993, 1269-1270.
  • CD4+ lymphopenia could be addressed therapeutically. It would also be advantageous to effectively treat HIN-initiated apoptosis of CD4 + T cells.
  • the present invention addresses these needs.
  • a method of treating CD4+ T cell lymphopenia in humans includes administering an effective amount of an adenosine degrading agent to a human in need of such treatment to provide a significant increase in the CD4+ levels and dierefore reduce or eliminate the lymphopenia.
  • a method of reducing CD4+ T cell apoptosis in susceptible mammals includes a method of increasing the therapeutic effect of reverse transcriptase inhibitor agents or anti-viral agents used in the treatment of mammals.
  • These methods also include administering an effective amount of an adenosine degrading agent to the patient in need thereof in order to reduce the T cell apoptosis and/or increase the therapeutic effect of the anti- viral agent in patients receiving the agents.
  • the invention also includes a new use of adenosine deaminase or other adenosine degrading substances for treatment of certain medical conditions in mammals. The new use includes administering an effective amount of the adenosine deaminase in combination with one or more reverse transcriptase inhibitor agents or anti-viral agents a patient in need of such treatment.
  • the adenosine deaminase is a useful adjunct in the treatment of Acquired Immunodeficiency Disease (AIDS) by assisting in the metabolism of various anti ⁇ viral drugs into active metabolites.
  • AIDS Acquired Immunodeficiency Disease
  • adenosine deaminase appears to metabolize agents such as dideoxyinosine, halogenated derivatives of dideoxypurines and dideoxyadenosine and its derivatives.
  • the adenosine deaminase metabolites of many deoxynucleoside analogs have anti- viral activity which, in some cases, is activity greater than that of the parent compound.
  • the adenosine deaminase agents can be used in treatments as a facilitator which acts to assist in the release of active agents from prodrugs.
  • the anti-viral activity of these types of agents can be completely abrogated in the presence of adenosine deaminase inhibitors. Consequently, administering me adenosine deaminase agents described herein can block or limit the abrogation of anti-viral activity of the concomitantly administered anti- viral agent.
  • adenosine degrading agents useful in carrying out the methods described herein include enzymes obtained from suitable mammalian sources as well as those prepared using recombinant techniques.
  • One particularly preferred adenosine degrading agent is bovine adenosine deaminase (ADA).
  • ADA bovine adenosine deaminase
  • Such agents are administered in amounts which are described as being "an effective amount” .
  • amounts which are sufficient to substantially reduce or eliminate the lymphopenia and/or T cell apoptosis generally range from about 5 IU/kg/week to about 50 IU/kg/week and preferably from about 10 IU/kg/week to about 30 IU/kg/week.
  • the adenosine degrading agent is a bovine adenosine deaminase enzyme administered as a polyethylene glycol conjugate such as that available from Enzon, Inc. under the trademark ADAGEN'
  • lymphopenia shall be understood to mean T-cell levels of less than 200 cells/ ⁇ l, as measured by fluorescence activated cell sorting (FACS).
  • FACS fluorescence activated cell sorting
  • infectious infection shall be understood to mean an infection which usually occurs only in patients whose resistance is compromised or lowered by an unrelated condition, disease or as a result of drug therapy.
  • the artisan is provided with a useful alternative or supplement to currently available AIDS therapies. While the treatment methods of the present invention are not anti-viral treatments, they nonetheless cause increases in CD4+ T cell lymphocytes and substantially reduce CD4+ T cell apoptosis, especially when given in combination with an anti- viral agent such as AZT. Patients receiving effective amounts of the agents described herein will therefore be better able to combat opportunistic-infections and have an improved quality of life.
  • a method of treating CD4+ T cell lymphopenia in HIV-infected patients includes admimstering an effective amount of an adenosine degrading agent such as an adenosine enzyme to a human in need thereof, whereby the rate of decline of die CD4+ T cell counts in the human is substantially reduced or reversed. Since the progressive decline in the T cell count is the hallmark of AIDS caused by infection with HIV, the ability to arrest and/or prevent falls in the CD4+ cell count below about 200/ ⁇ l; or even reverse such low cell counts, will reduce or eliminate the patient's susceptibility to opportunistic infections.
  • an adenosine degrading agent such as an adenosine enzyme
  • die method includes maintaining CD4+ levels of at least about 200 cells/ ⁇ l or raising CD4+ cell counts above that level by administering a sufficient amount of d e adenosine degrading agents described herein to a patient in need of such treatment.
  • the amounts of adenosine degrading agent used in me methods of die present invention are generally described as amounts which effectively achieve the sought after therapeutic effect, i.e. reversing the lymphopenic condition or increasing the therapeutic effect of anti-viral agents which inhibit reverse transcriptase in mammals.
  • the maximal dosage is me highest dosage which does not cause clinically important side effects.
  • the lowest dosage contemplated is mat which is still effective enough to achieve the results described above.
  • me adenosine degrading agent will usually be administered in amounts ranging from about 5 IU/kg/week to about 50 IU/kg/week and preferably in amounts ranging from about 10 IU/kg/week to about 30 IU/kg/week. It will be understood mat die doses are described as being based on me amount of adenosine deaminase (ADA) administered. Such doses are given for purposes of illustration and d ose of ordinary skill in the art will determine optimal dosing of me adenosine degrading agent (ADA or related compound) based on clinical experience.
  • ADA adenosine degrading agent
  • adenosine degrading agent will also be dependent upon die individual patient.
  • diat the adenosine degrading agent will be administered on a chronic basis in an effort to combat the HIV effects
  • episodic administration of the adenosine degrading agent on an as needed basis is also contemplated.
  • the adenosine degrading agent administered is bovine adenosine deaminase (ADA) covalently conjugated to polyethylene glycol strands which is available under the tradename ADAGEN * , (PEG-ADEMASE, bovine) a product of Enzon, Inc., (Piscataway, NJ).
  • ADAGEN * a product of Enzon, Inc.
  • This particular agent is administered in accordance with the methods of the present invention parenterally in pharmaceutically acceptable solutions in amounts ranging from 10 IU/kg/week to about 30 IU/kg/week based on the ADA. Intramuscular administration of die ADA conjugate is particularly preferred.
  • the ADA- polyethylene glycol conjugates can also be prepared using the techniques described in U.S. Patent No.
  • the '844 patent describes, among other things, forming a substantially hydrolysis-resistant urethane bond between the epsilon amino groups of enzymes and a functionalized terminal group.
  • the linkage by which the enzyme is joined to die polymer strand(s) can be any moiety known in the art which sufficiently unites the enzyme and polymer so that the conjugate may be administered in a pharmaceutically acceptable manner.
  • amide linkages are also preferred.
  • An example of amide-linked polymer enzymes is found in U.S. Patent No. 5,349,001, the disclosure of which is incorporated by reference herein.
  • the '001 patent describes, inter alia cyclic imide-activated polyalkylene oxides and conjugation tiiereof with therapeutic proteins and enzymes induding adenosine deaminase.
  • ADAGEN is currently used to treat human patients with severe combined immunodeficiency disease (SCID) secondary to an inborn mutation inactivating the gene for adenosine deaminase.
  • SCID severe combined immunodeficiency disease
  • ADA levels are essentially undetectable (less tiian 1 % of normal levels; see Hirschhorn, Pediatnc Research 33 (suppl. ):535-541, 1993).
  • ADA deficiency results in accumulation of adenosine metabolites, especially deoxyadenosine triphosphate, which inhibit DNA synthesis and thus cause deatii of T cells.
  • ADAGEN treatment reverses SCID by reducing deoxyadenosine triphosphate levels. See Blaese and Culver, Immunodeficiency Reviews 3:329-249 (1992).
  • adenosine degrading agents such as adenosine deaminase are administered to HIV-infected patients in order to treat or prevent CD4 + lymphopenia. It is believed that accumulation of adenosine metabolites, especially deoxyadenosine triphosphate, does not play a significant role in the lymphopenic condition and therefore administration of adenosine degrading agents could not have been predicted to successfully treat die lymphopenic condition.
  • the adenosine degrading agents which can be administered in accordance with the methods of the present invention can be prepared or obtained from a variety of sources, including recombinant or mammalian-extracted ADA.
  • bovine adenosine deaminase is particularly preferred when it is included as part of a polyethylene glycol conjugate, it is to be understood that the methods described and claimed herein can also be carried out using gene therapy techniques.
  • ADA or a similar adenosine degrading agent is administered using, for example, the procedures described by Blaese and Culver in Immunodeficiency Reviews 3:329-349 (1992) and die references cited dierein. The disclosure of the aforementioned Immunodeficiency Reviews 3:329-349 (1992) is inco ⁇ orated by reference herein.
  • LASN vector contains the human adenosine deaminase gene. Treated CD34+ cells containing the transduced ADA gene are then reinfused into the patient.
  • ADA can be obtained from mammalian sources such as bovine, ovine, human, etc. It is to be understood that other substances including pro-enzymes, fractions of enzymes, and catalytic antibodies can also be included in the present invention.
  • adenosine degrading agents means all suitable substances which demonstrate in vivo activity to reduce adenosine levels and treat CD4+ T cell lymphopenia and/or combat the HJN-mediated CD4+ T cell apoptosis. These substances are prepared by using techniques known to those of ordinary skill in the art such as tissue culture, extraction from plant or animal sources or by recombinant D ⁇ A methodologies. Transgenic sources of enzymes, pro-enzymes and fractions thereof are also contemplated. Such materials are obtained from transgenic animals, i.e. mice, pigs, cows, etc. wherein the enzyme is expressed in milk, blood, or tissues.
  • the catalytic antibodies can be prepared using recombinant technologies.
  • the method by which the enzymatic substance is prepared or obtained for the treatment methods and conjugates of the present invention is not limited to those described herein.
  • Substantially non-antigenic polymer substances can be included in the ADA conjugates.
  • alpha-substituted polyalkylene oxide derivatives such as metiioxypolyethylene glycols or other suitable alkyl substituted derivatives such as C r C 4 alkyl groups. It is preferred, however, that the non-antigenic material be a monomethyl-substituted PEG homopolymer.
  • polymers such as other polyethylene glycol homopolymers, polypropylene glycol homopolymers, other alky 1-poly ethylene oxides, bis-polyethylene oxides and co ⁇ polymers or block co-polymers of poly (alkylene oxides) are also useful.
  • PEG-based polymers it is preferred that they have molecular weights of from about 1,000 to about 100,000. Molecular weights of about 2,000 to 40,000 are preferred and molecular weights of about
  • non-antigenic polymeric substances include materials such as dextran, polyvinyl pynolidones, polysaccharides, starches, polyvinyl alcohols, polyacryl amides or other similar non-immunogenic polymers.
  • materials such as dextran, polyvinyl pynolidones, polysaccharides, starches, polyvinyl alcohols, polyacryl amides or other similar non-immunogenic polymers.
  • Those of ordinary skill in the art will realize that the foregoing is merely illustrative and not intended to restrict the type of non-antigenic polymeric substances suitable for use herein.
  • a covalent modification of the adenosine degrading agent, enzyme or enzyme-like material with PEG or a related substantially related non- antigenic polymer is prefened to provide the hydrolysis-resistant conjugate.
  • the covalent modification reaction of an adenosine degrading agent includes reacting a substance having the desired adenosine degrading activity with a substantially non- antigenic polymeric substance under conditions sufficient to effect conjugations while maintaining at least a portion of the ADA activity.
  • a substance having the desired adenosine degrading activity with a substantially non- antigenic polymeric substance under conditions sufficient to effect conjugations while maintaining at least a portion of the ADA activity.
  • Covalent linkage by any atom between the adenosine degrading agent and polymer is possible. Moreover, non-covalent associations between polymer and adenosine degrading agent such as lipophilic or hydrophilic interactions are also contemplated.
  • the desired product is recovered using known techniques and purified using column chromatography or similar apparatus if necessary.
  • the conjugates have from about 1 to about 25 polymeric strands attached to each molecule of the enzyme-like substance. By controlling die molar excess of the polymer reacted with the enzyme, for example, the artisan can tailor the number of polymeric strands attached. Conjugates containing from about 5 to about 20 polymeric strands are prefened while conjugates containing from about 10 to 18 polymeric strands are most prefened.
  • the adenosine degrading agent is administered in a liposome.
  • a non-limiting example of such liposomes can be found in U.S. Patent No.4,534,899, die disclosure of which is incorporated herein by reference.
  • Still further aspects of the invention include administering die adenosine degrading agent in the form of an oral dosage form which allows the agent to be bioavailable. It is to be understood from the foregoing that the delivery system selected or the means of administering the adenosine degrading agent to d e patient is not to be construed nanowly and it is contemplated that any pharmaceutically acceptable delivery system can be used to carry out the inventive treatment methods.
  • ADA may act by blocking the binding of HJN to the CD4+ T lymphocytes by competitively blocking the gpl20 binding coreceptor sites which are designated CD26 and it has been postulated tiiat in order for the HIN to gain entry into the T cells, this coreceptor must also be available.
  • ADA- based therapies may also have a direct effect on CD4+ cells.
  • ADAGEN is an FDA approved drug which has been shown to promote maturation of T lymphocytes.
  • the benefits from the ADA-based treatment method include an increase in patient's personal sense of well being, decreases in the numbers of infections and a sustained increase in die numbers of circulating CD4+ T cells in their blood.
  • ti ere is provided anotiier method of treating HJN-infected humans.
  • tiiere is provided a metiiod enhancing the therapeutic effect of antiviral agents in HIN-infected humans.
  • This method would appear every weekly
  • This aspect includes administering an effective amount of an adenosine degrading agent as described above in combination with an effective amount of an antiviral agent.
  • Suitable antiviral agents include without limitation, 3' azidothymadine (AZT, zidovudine),
  • the term "in combination with” shall be understood to mean that the adenosine degrading agent is administered at not only the same time as the antiviral agent but also within a time which allows the combination of antiviral and adenosine degrading agent to have its synergistic effect.
  • the adenosine degrading agent can be administered at die start of, during or substantially immediately after a course or antiviral agent(s). In this aspect of die invention, synergistic effects are observed.
  • a method of treating adenosine-induced T-cell toxicity in humans includes administering an effective amount of an adenosine degrading agent to a patient in need thereof .
  • This method of treatment is to be contrasted with the treatments used for SCID (described above) since it is not necessary that patients in need of die treatment described herein, to anest adenosine induced toxicity, have the severely deficient ADA levels observed in patients presenting witii SCID.
  • the amounts of the adenosine degrading agent administered in this aspect of the invention will be in the same range as those described herein for the other treatments described.
  • bovine adenosine deaminase obtained from Sigma Chemical Co. (St. Louis, MO) is conjugated wid the activated poly(eti ⁇ ylene glycol)-N-succinimide carbonate (SC-PEG) described in U.S. Patent number 5,324,844.
  • the PEG polymer has a molecular weight of about 5,000. 10 mg of ADA in 92 Mm NaOAc pH 5.8/10 % glycerol/18 % EtOH is dialyzed witii 0.1 M sodium phosphate buffer solution, pH 7.0 using a Centricon-10 (a product of die Amicon Corporation of Beverly, MA). The final concentration of the ADA is -0.5 mg/ml.
  • ADAGEN * PEG-ADEMASE,bovine
  • Enzon, Inc. Piscataway, NJ
  • the drug was administered to 17 patients enrolled in this study. Entry criteria into the study included a CD4- T lymphocyte count of about 200 cells/ ⁇ l or less and no past history of substance abuse. Patients remained under die care of their treating physician, and no alterations were made to odier drug therapy.
  • the patients were evaluated at baseline to determine tiieir history, including documentation ofthe numbers of opportunistic infections, physical examination, and a baseline hematologic profile including T cell subsets.
  • Kahn et al. for example, the decline in efficacy over time for AZT is documented.
  • Anotiier study (Spruance, S.L. et al. Annals of Internal Medicine Vol. 120, No.
  • die average CD4 + cell count improved an average of 17.1 in the patients treated with ADAGEN.
  • the historical control data indicates tiiat an average decrease of about 23 to 25% in CD4 + cells would have been expected.
  • An additional result observed was die fact tiiat none of the patients in the smdy had an adverse reaction caused by d e ADAGEN.
  • the patients in die study also did not experience any opportunistic infections during the course of tiie study.
  • ADA is admimstered by gene therapy methods following the procedures described in Blaese and Culver, Immunodeficiency Reviews 3:329-349 (1992) and the references cited dierein.
  • CD34+ cells isolated from tiie blood of an HIV-infected human patient by the methods of Chelucci et al., (Blood 85:1181- 1187, 1995).
  • the CD34+ cells may optionally be rendered resistant to HIV infection by transformation with an anti-HIV vector such as that of Buonocore et al. , PNAS 90:2695-2699, 1993) or that of Marasco et al., (PNAS 90:7889-7893, 1993), the disclosures of which are incorporated by reference herein.
  • a portion of me culture is then treated by retroviral-mediated transduction witii the LASN vector described by Blaese and Culver, supra.
  • the LASN vector contains the human adenosine deaminase gene. Treated T cells containing the transduced ADA gene are then reinfused into the patient. The patient exhibits increased levels of ADA resulting in increased levels of CD4+ T lymphocytes and decreased occunence of opportunistic infections. While there have been described what are presently believed to be die prefened embodiments of die present invention, those skilled in die art will realize that changes and modifications may be made tiiereto without departing from the spirit of the invention. It is intended to claim all such changes and modifications as fall widiin the true scope of the invention.

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Abstract

La présente invention se rapporte à des procédés de traitement de la diminution du nombre des lymphocytes T CD4+ chez des patients infectés par le VIH. Ces procédés consistent à administrer une quantité efficace d'adénosine désaminase ou d'une substance enzymatique apparentée à un patient ayant besoin de ce traitement. Selon des aspects préférés de l'invention, le procédé est mis en application sur des patients infectés par le VIH et dont les taux de lymphocytes T CD4+ sont inférieurs à environ 200/νl. Des quantités efficaces de l'enzyme sont comprises entre environ 5 et environ 50 IU/kg/semaine. Selon un aspect particulièrement préféré de l'invention, l'adénosine désaminase est conjuguée à un ou plusieurs brins de polyéthylène glycol pour prolonger l'activité in vivo.
PCT/US1996/010362 1995-06-16 1996-06-14 Procede de traitement de la diminution du nombre des lymphocytes t cd4+ chez des patients presentant une deficience immunitaire Ceased WO1997000083A1 (fr)

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AU62802/96A AU6280296A (en) 1995-06-16 1996-06-14 Method of treating cd4+ t cell lymphopenia in immuno-compromised patients

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US26795P 1995-06-16 1995-06-16
US60/000,267 1995-06-16
US1255296P 1996-02-29 1996-02-29
US60/012,552 1996-02-29
US1536596P 1996-04-12 1996-04-12
US60/015,365 1996-04-12

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995012618A1 (fr) * 1993-11-04 1995-05-11 Eurogenetics N.V. Ligand apte a se lier au site de liaison d'adenosine desaminase de cd26

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995012618A1 (fr) * 1993-11-04 1995-05-11 Eurogenetics N.V. Ligand apte a se lier au site de liaison d'adenosine desaminase de cd26

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
I.K. KIM ET AL.: "INDUCTION OF APOPTOSIS AND c-myc IN L1210 LYMPHOCYTIC LEUKEMIA CELLS BY ADENOSINE", JOURNAL OF BIOMEDICAL SCIENCE, vol. 1, no. 3, June 1994 (1994-06-01), BASEL, CH, pages 154 - 157, XP000604913 *
J. VIEIRA ET AL.: "PEG ADENOSINE DEAMINASE AS A THERAPEUTIC ADJUVANT IN THE TREATMENT OF HUMAN ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)", FASEB JOURNAL FOR EXPERIMENTAL BIOLOGY, vol. 10, no. 3, 8 March 1996 (1996-03-08), BETHESDA, MD US, pages A131, XP002015403 *
L.D. FAIRBANKS ET AL.: "ADENOSINE DEAMINASE (ADA) DEFICIENCY AS THE UNEXPECTED CAUSE OF CD4+ T-LYMPHOCYTOPENIA IN TWO HIV-NEGATIVE ADULT FEMALE SIBLINGS.", ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY, vol. 370, 1994, NEW YORK, N.Y., US, pages 471 - 474, XP000604900 *
R.M. BLAESE ET AL.: "GENE THERAPY FOR PRIMARY IMMUNODEFICIENCY DISEASE.", IMMUNODEFICIENCY REVIEWS, vol. 3, no. 4, 1992, YVERDON, CH, pages 329 - 349, XP000605213 *

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