HK1115731A - Presbyopia treatment by lens alteration - Google Patents

Description

Treatment of presbyopia by lens changes

[0001] This application is a continuation-in-part application of U.S. application serial No. 10/050,879 filed on month 1, 18, 2002. U.S. application Ser. No. 10/050,879, filed on 8/16/2001, is a continuation-in-part application of U.S. application Ser. No. 09/930, now abandoned and claiming the benefit of provisional application 60/262,423, filed on 19/1/2001, in accordance with 35 USC (119 e). In accordance with 35 USC (119e), U.S. application Ser. No. 09/930,287 claims provisional application 60/225,659 filed on 8, 16, 2000. Each of the above applications is incorporated by reference herein in its entirety.

Technical Field

[0002] The present invention relates to methods and devices for correcting and treating presbyopia.

Background

[0003] Presbyopia affects almost every person over the age of 44 years. According to the Jobson optical database, 93% of people aged 45 and over 45 are presbyopic. Presbyopia results in a progressive loss of the amplitude of accommodation of vision that occurs with aging. "Adler's Physiology of the eye" (incorporated herein by reference) discloses that the amplitude of vision accommodation in humans decreases with age, and thus vision accommodation is substantially lost by the age of 50 to 55 years. The accommodative power, as defined in U.S. patent 5,459,133 to Neufeld (incorporated herein by reference in its entirety), is the ability of the eye to focus near vision by changing the lens to a more convex shape.

[0004] Ocular tissues involved in the accommodative effect include the lens, zonules (zonules), lens capsule, and ciliary muscle. Among them, the lens is the main tissue. By changing the shape of the lens, these structures act on each other to focus the eye on near objects. The lens is suspended primarily between the anterior and posterior chambers behind the pupillary opening of the iris. The lens is supported by a series of radially oriented zonular fibers extending from the lateral edge (Iateral edge) of the lens to the inner edge of the annular ciliary muscle. The ciliary muscle is attached to the scleral surface of the eye. When the eye is at rest, it is focused in the distance and the lens is in a slightly flattened or less convex position. This shape is due to the pulling force exerted by the zonules on the convex surface of the lens. The zonules pull the lens edge toward the ciliary body.

[0005] During accommodation, the lens shape becomes more prominent by contraction of the ciliary muscle, which causes the eyelash attachment of the zonules to turn towards the lens, reducing the tension in the anterior zonules. The reduction in tension causes the middle of the lens to bulge out, thereby enabling near objects to be imaged on the retina. Including the accommodative effects of the lens, zonules, ciliary body, rectus muscle (rectus muscle) and iris, which bring about the ability of the eye to focus sharply near the retina, among other effects, are methods of accommodation.

[0006] There have been several theories to explain the loss of accommodation with age. These theories include stiffening of the lens with age, a decrease in the strength of the ciliary muscles, factors associated with the physical growth of the lens, and a loss of elasticity of the lens capsule. With respect to loss of ciliary muscle strength, it has been indicated that despite the appearance of age-related morphological changes, there is little evidence of a decrease in ciliary muscle strength. In fact, under the influence of pilocarpine (pilocarpine), the ciliary muscle contracts violently even in presbyopia.

[0007] The lens develops throughout the life of an individual and theories suggest: this is to prevent the zonules from acting to affect a dimensional increase in the change in lens shape. To date, recent studies to explore this possibility have not gained widespread acceptance. Most of the lens development is not in its diameter, but in its anterior-posterior dimensions.

[0008] As for the change in lens capsule, it is assumed that the elasticity of the capsule is reduced, and in fact it is a contributing factor in presbyopia. In addition, it has been found that the modulus of elasticity (modulus of elasticity) of the lens capsule in young people has decreased by almost 50% since the young to the age of 60, while the accommodation has decreased by 98%. Thus, it is now believed that the primary cause of presbyopia is "lens hardening" or stiffening of the lens.

[0009] Cataracts are the condition in which the lens becomes less clear. Cataract studies provide insight into changes in the lens and capsular sac. When removed from the eye, conventional senile cataracts are relatively disc-shaped, with the appearance being determined by the hard lens material. When removed, the liquefied overmature cataract is spherical, vaulted by the elastic lens capsule. This is indirect evidence of correcting the changes in the lens associated with presbyopia and that the lens capsule still has sufficient elasticity.

[0010] Nowadays, conventional treatments for presbyopia include presbyopia, bifocal, or monocular contact lenses. Both of these methods require the use of instruments which present additional disadvantages.

[0011] Another theory for treating presbyopia includes scleral dilation and orthokeratology. The efficacy of the techniques is not constant and it is important that in the loss of the amplitude of lens accommodation (which is often associated with the natural aging process) these techniques do not attempt to alter the effects believed by the inventors of the above application, the true cause of which is more fully set forth below. In addition, because scleral ectasia and orthokeratology involve macroscopic changes in morphology in the lens and/or cornea, this does not correct presbyopia.

[0012] Finally, the use of excimer laser surgery for orthokeratology purposes to create a multifocal refractive surface has been disclosed in us patent 5,395,356. Although this approach appears promising, it still requires altering the structure of the cornea to counteract the age change of the lens. Techniques such as this merely compensate for the loss of accommodation caused by changing another eye structure, rather than attempting to account for changes caused by presbyopia.

Summary of The Invention

[0013] While not wishing to be bound by any particular theory, it is now believed that presbyopia is caused by lens hardening due to changes in structural proteins or increased adhesion between lens fibers. It is also believed that viscosity within the lens increases with age due to the formation of certain chemical bond structures in the lens. Accordingly, the present invention teaches methods and devices for preventing and or correcting presbyopia by treating the lens so as to reduce the tackiness of the lens, restore the elasticity and movement of the lens fibers, and increase the accommodative amplitude of the lens.

[0014] The claimed invention also teaches methods of correcting or treating presbyopia caused by fundamental changes in structural and/or molecular interactions, including ocular components associated with the accommodative process, most notably the lens and/or lens capsule.

[0015] In embodiments, the present invention provides a novel molecular method of correcting presbyopia by restoring the amplitude of accommodation of the lens, and in another preferred embodiment, a method of correcting presbyopia while also reducing the tendency of the lens to lose accommodation and thus restoring the amplitude of accommodation.

[0016] In another embodiment of the invention, the onset of presbyopia is prevented by a regular administration treatment that restores the elasticity and accommodation of the lens. By applying the therapy described herein to the eyes of a human in the middle or even younger age 30 years, the onset of presbyopia (defined as loss of accommodation) can be prevented such that the accommodation of the eye is less than 2.5 diopters. In one embodiment of the invention, the treatment, whether suitable for the purpose of preventing or correcting presbyopia, is repeated occasionally throughout the patient's lifetime. The treatment frequency is determined by the extent to which loss of accommodation needs to be restored, wherein the amount of accommodation can be safely restored to the desired amount of restoration in a single treatment session.

[0017] In one embodiment, the present invention teaches a method for correcting and/or treating presbyopia by breaking disulfide bonds in molecules, including eye tissue, most notably the lens and lens capsule, believed to be the true cause of progressive loss of accommodation amplitude. In another embodiment, the cleavage of the disulfide bond is accompanied by a chemical modification of the sulfur moiety in the cysteine molecule formed by the cleavage of the disulfide bond, wherein the chemical modification is such that the sulfur moiety is less likely to form a new disulfide bond. Such methods therefore include methods of preventing, and/or reducing the recurrence of presbyopia by reducing the likelihood of new disulfide bond formation. Specifically, the present invention affects the change in the amplitude of accommodation of the human lens by the following process: (1) use of various reducing agents that cause a change in the accommodative power of the human lens, and/or (2) use of applied energy to affect a change in the accommodative power of the human lens. It is believed that the present invention improves the elasticity and distensibility of the lens cortex, lens nucleus, and/or lens capsule by breaking bonds (e.g., disulfide bonds that cross-link lens fibers to one another and increase lens stickiness leading to stiffening of the lens cortex and lens nucleus).

[0018] Presbyopia, or loss of accommodative amplitude of the lens, often occurs in the typical population aged 45 years or older to the point where corrective lenses or other treatments in the form of some presbyopic glasses are needed. It will be appreciated that loss of accommodative amplitude may occur in people younger or older than 45 years of age, and thus the present invention is not to be considered as limited to treating presbyopia in certain age groups. The invention is more effective for use in those populations where the magnitude of modulation has been less than recoverable to the desired extent. However, the present invention is not limited to correcting presbyopia, but may also be used to prevent the occurrence of presbyopia.

[0019] In one embodiment of the invention, the method of correcting or preventing presbyopia results in an increase in accommodative amplitude of at least about 0.5 diopters. In another embodiment of the invention, the method of correcting or preventing presbyopia results in an increase in accommodative amplitude of at least about 2.0 diopters. In yet another embodiment, the method of the present invention for correcting or preventing presbyopia can result in an increase in accommodative amplitude of at least about 5 diopters. In another embodiment of the invention, the method of the invention for correcting or preventing presbyopia can result in an increase in the amplitude of accommodation of the lens until a lens having a normal amplitude of accommodation of 2.5 diopters or greater is restored. It should be noted that while it is clearly more beneficial to restore the amplitude of accommodation of the lens to a normal amplitude of accommodation, a lesser degree of restoration is also beneficial. For example, sometimes late presbyopia can cause a severe drop in amplitude of accommodation, so that it is not possible to achieve a full recovery of the amplitude of accommodation.

Detailed Description

[0020] The accommodative amplitude of the lens was measured in diopters (D). The loss of accommodation begins at a very early age, so that 10 years old eyes have an average of 10D, 30 years old eyes have 5D, and 40 years old eyes have only 2.5D of accommodation. The lens of a person who does not have presbyopia (i.e., a person with normal lens accommodation) typically has an accommodative amplitude of about 2.5 diopters or greater. The terms "correcting presbyopia" or "treating presbyopia" as used herein mean increasing the amplitude of accommodation of the lens.

[0021] According to the description, the inelasticity of the lens or the hardening thereof is considered to be a cause of presbyopia. Hardening of the lens is due to changes in structural proteins or increased adhesion between lens fibers. In addition, it is believed that lens tackiness also increases with age due to the increased concentration of certain chemical bond structures in the lens. In one embodiment, the present invention teaches treating presbyopia by altering molecular and/or cellular bonding in the fibrous cortex of the lens so that they move freely with respect to each other. Means for increasing the elasticity of the lens can restore the amplitude of lost accommodation. In particular, disulfide bonds in molecules (including structures of the eye responsible for proper accommodation) are believed to be a real factor in lens hardening and the concomitant loss of accommodation amplitude.

[0022] Thus, in one embodiment of the invention, the treatment involves breaking disulfide bonds and protonating the newly formed sulfur moiety with a reducing agent (e.g., glutathione) to impart a hydrogen atom thereto. These steps may be performed simultaneously or sequentially. In either case, a reducing agent may be present at the time of cleavage of the disulfide bond, so as to eliminate the recombination of the disulfide. That is, after cleavage of the disulfide bonds, the reducing agent may introduce and bond a moiety (moiey) to the monomeric sulfur, such that the possibility of recombination of additional disulfide bonds is prevented or at least reduced. When the reducing agent introduces a hydrogen atom to the monomeric sulfur and thus forms a mercapto group (-SH), the synthesized-SH group can be oxidized again to form a new disulfide bond. Thus, it is advantageous to introduce groups such as lower alkyl, methylated compounds or other agents into the monomeric sulfur moiety, which can reduce the tendency to form new disulfide bonds. This method can be used to prevent recurrence of presbyopia.

[0023] As noted above, it is believed that disulfide bonds may form between lens fibers, between lens proteins and various thiols in and on the lens fibers. These bonds substantially reduce the ability of the lens fibers to move easily relative to each other and thus reduce the ability of the lens to accommodate properly. While not wishing to be bound by some particular theory, absorption of light energy can form bonds that create sulfhydryl bonds on lens proteins to oxidatively remove two hydrogen atoms adjacent to-SH groups and generate water and disulfide bonds. Reduction of disulfide bonds requires hydrogen donors such as glutathione or other molecules. Other reasonable theories include that protein-thiol mixed disulfide bonds can form, for example, protein-S-S-glutathione or protein-S-S-cysteine. Glutathione is therefore part of the solution and part of the problem. Therefore, the use of glutathione in any therapy should be carefully monitored, with the possibility of increased undesirable bond formation.

[0024] The total refractive power of the lens is greater than the desired refractive power based on curvature and refractive index. As described herein, contraction of the ciliary muscle may cause the ciliary body to move forward, up to the equator of the lens. This causes the zonules to relieve their tension on the lens capsule, thus causing the central lens to assume a more spherical shape. The main change during accommodation is the more important radius of curvature of the anterior surface of the lens, which is 12mm in the non-accommodated state and mainly 3mm during accommodation. The curvatures of the anterior and posterior surfaces of the lens periphery change little during accommodation. As the diameter decreases, the axial thickness increases. The central anterior lens capsule is thinner than the remainder of the anterior capsule. This may explain why the lens expansion is more prominent during accommodation. The thinnest portion of the balloon is the posterior balloon, which has a greater curvature than the anterior balloon in the unaccommodated state. The protein content of the lens is approximately 33% by weight higher than any other organ in the body. In the lens, there are many compounds of particular interest. For example, although there is little glutathione in the fluid, high concentrations of glutathione are found in the lens cortex. Therefore, the lens has a great novelty and power suitable for glutathione, and can activate the absorption, transport and synthesis of glutathione. Glutathione is in a reduced state in about 93% of the lens. Glutathione is associated with lens proteins, sulfhydryl groups (-SH), which remain in a reduced state. That is, after cleavage of disulfide bonds and efficient production of sulfur moieties, glutathione can impart hydrogen atoms to form sulfhydryl groups, thereby preventing or minimizing the recombination of disulfide bonds. In addition, ascorbic acid is also found in very high concentrations in the lens. It is actively transported out of the aqueous solution and at a concentration 15 times higher than that present in the blood. Inositol and taurine are found in high concentrations in the lens for reasons that are not known.

[0025] According to one embodiment of the invention, the increase in accommodative amplitude is achieved by treating the outer (cortex) or inner (nucleus) region of the lens with radioactive, sonic or electromagnetic energy, thermal, chemical, particle beam energy, plasma beam energy, enzymes, gene therapy, nutrients, other applied energy sources, and/or any combination of the above sufficient to break the disulfide bonds, believed to be responsible for the formation of lens inelasticity. Chemicals can be used to reduce disulfide bonds, which are believed to immobilize the lens fibers, thereby preventing them from free movement and elasticity. By making the anterior cortex and/or nucleus more elastic, the viscosity is reduced and the lens can again assume its characteristic central bulge during accommodation.

[0026] By way of example only, chemicals suitable for causing reduction include, for example, glutathione, ascorbic acid, vitamin E, tetraethylthiuram disulfide (tetraethylthiouramdisulfyl), i.e., a reducing agent, any biologically suitable compound that is readily oxidized, opthalmic acid, inositol, beta-carboline, any biologically suitable reducing compound, a reducing thiol derivative having the structure:

or

Or a sulfur derivative having the structure:

wherein R is₁、R₂、R₃And R₄Independently is a straight or branched lower alkyl group which may be substituted, for example by hydroxy, lower alkoxy or lower alkylcarboxyloxy, and derivatives or pharmaceutically acceptable salts thereof. Preferred exemplary reducing agents include diethyl dithiocarbamate, 1-methyl-1H-tetrazol-5-yl-thiol, and 1- (2-hydroxyethyl) -1H-tetrazol-5-yl-thiol or and pharmaceutically acceptable salts thereof. Other useful compounds are disclosed in U.S. patent 5,874,455, which is incorporated herein by reference in its entirety for background information. The above chemicals are merely illustrative and other reducing agents that exhibit similar properties of breaking disulfide bonds are included within the scope of the present invention.

[0027] Chemical reducing agents may be used alone or in conjunction with a catalyst, such as an enzyme. Enzymes and other nutrients suitable for causing or promoting reduction include, for example, aldose reductase, glyoxidase, glutathione S-transferase, hexokinase, thiol glutathione reductase, thiolatsyltransferase (thiolansferase), tyrosine glutathione reductase, or any suitable glutathione reductase. The need for an applied energy source for reducing disulfide bonds can be met by adding glucose-6-phosphate, which is present in the lens, but generally an enzyme that converts glucose to the G6P energy state (hexokinase), appears nonfunctional due to the process of thiol oxidation. Furthermore, it should be noted that the above listed enzymes are illustrative and not all lists are intended. The enzyme may be naturally present in the eye or added to the eye along with or separate from the chemical reducing agents or energy means disclosed herein. Likewise, other chemically and biologically corresponding enzymes that contribute to the cleavage of disulfide bonds or exhibit similar properties should be considered to fall within the scope of the present invention.

[0028] In one embodiment of the invention, the reduction of disulfide groups of lens proteins to sulfhydryl groups is accomplished by delivering compounds, such as glutathione, thiols, or other compounds in sufficient amounts to reduce disulfide bonds and other molecules and reduce cell adhesion to the lens. Other enzymes or chemicals that affect methylation at the monomeric sulfur atom include, for example, methyl-methanethiosulfonate, methyl glutathione, S-transferase, and other biologically compatible methylating agents. The use of emulsions such as nanocapsules, albumin microspheres, the use of carrier molecules such as inositol, taurine, or the use of other biologically suitable means such as viral phages used to deliver reducing agents or enzymes to the lens are all part of the present invention. The chemical reducing agent is typically delivered in the form of a solution or suspension in an ophthalmically acceptable carrier. In some cases, it is beneficial to use energy that can affect or catalyze disulfide bond reduction as well as break other bonds and adhesion. Energy alone can be used to break disulfide bonds. The energy applied may be of any form, by way of example only, laser energy, ultrasonic energy, particle beam energy, plasma beam energy, X-ray energy, ultraviolet energy, visible light energy, infrared energy, thermal energy, ionization energy, light energy, magnetic energy, microwave energy, acoustic energy, electrical energy, or other energy not specifically mentioned, or any combination of these energy types, may be used alone or in combination with a reducing agent that may affect the treatment of presbyopia.

[0029] In a similar manner, the agent is delivered to the lens capsule, which may bond or interact with the capsule to affect greater elasticity or distensibility. The agent may cause a contraction in the surface area of the capsular membrane or increase the tension of the lens capsule on the anterior or posterior portion of the lens periphery. The energy applied may be of any form, by way of example only, laser energy, ultrasonic energy, particle beam energy, plasma beam energy, X-ray energy, ultraviolet energy, visible light energy, infrared energy, thermal energy, ionization energy, light energy, magnetic energy, microwave energy, acoustic energy, electrical energy, or other energy not specifically mentioned, or any combination of these energy types, may be used alone or in combination with a reducing agent that may affect the treatment of presbyopia.

[0030] In another embodiment of the invention, the energy applied may act as a catalyst to induce or increase the rate of the reduction reaction. Thus, by applying energy, the peri-capsular portion is preferentially affected, leaving the central 4mm annulus of accommodation unaffected. This allows the lens to assume a more accommodating state. The applied energy can also be used alone to promote the reduction reactions and cellular changes that ultimately affect the lens cortex. For example, lasers useful in the present invention include: excimer laser, argon ion laser, krypton ion laser, carbon dioxide laser, helium-neon laser, helium-cadmium laser, xenon laser, nitric oxide laser, iodine laser, holmium laser, yttrium lithium laser, dye laser, chemical laser, neodymium laser, erbium laser, ruby laser, titanium-sapphire laser, diode laser, femtosecond or picosecond laser, harmonic oscillation laser, or any other electromagnetic radiation. Illustrative forms of thermal radiation include: infrared, heat, infrared laser, radiotherapy, or any other method of heating the lens. Finally, illustrative forms of acoustic energy that may be used in embodiments of the present invention include: ultrasound, any audible and non-audible sonication, and any other biologically compatible acoustic energy.

[0031] In yet another embodiment of the invention, radiant energy, such as ultraviolet, visible, infrared, microwave or other electromagnetic energy, is applied to the eye to promote disulfide bond cleavage. This then makes reduction of the disulfide bonds possible.

[0032] The energy applied in the various embodiments and methods of the present invention may be used by contact with the sclera or cornea, by non-contact techniques, or by delivery methods within the eye. More than one process may be required to affect an appropriate increase in the modulation amplitude. When more treatment patterns are desired, the chemical treatment is applied before, after, or simultaneously with the application of energy.

[0033]Embodiments of the present invention also relate to agents that penetrate the outer surface of the eye and affect the accommodative power of the eye by reducing aberrant lenticular bonds in the eye. More specifically, the agent, with or without an energy source, can penetrate the cornea and affect the eye to increase its accommodation. More specifically, the agent may affect the anterior lens surface of the eye to enhance accommodation. The effect of the agent is to reduce or eliminate abnormal biochemical bonds that can lead to elastic loss in the lens. As discussed earlier, the abnormal biochemical bonds can produce adhesion between lens fibers, resulting in a decrease in lens elasticity and accommodation. By way of example only, an aberrant biochemical bond may include or be formed by: covalent adsorption of various sugar groups, phosphate groups (PO), forming glycoproteins₄ ^2-) Or sulfate radicals (SO)₄ ^2-) Disulfide bonds between tyrosine (one amino acid that makes up most of the protein) or adjacent cysteines. Aberrant biochemical bonds include any kind of oxidized bonds, of which disulfide bonds are only one example。

[0034] In embodiments, the agent may be a prodrug (pro-drug). The meaning of "prodrug" as used herein includes the meaning having the property of being converted from an inactive state to an active state. In its inactive state, the prodrug is able to cross the membrane more easily than in its active state, making the inactive prodrug more easily transported to a specific site. However, once at this site, the prodrug is caused to assume an active state, which allows the prodrug to produce any desired therapeutic effect. Activating a prodrug (i.e., causing the prodrug to assume an active state) may involve changing the chemical properties of the compound or of the compound that constitutes or is present in the prodrug. Thus, by "prodrug" is meant also a compound having the ability to convert or transform a first biochemical or pharmacological substance into a second biochemical or pharmacological substance, wherein the second biochemical or pharmacological substance has a different property than the first substance.

[0035] For the eye, the reductant can be administered to the outer eye in the form of a prodrug, e.g., in the form of a droplet. When initially applied, the prodrug may be in an inactive state. The inactive state of the prodrug enables the prodrug to more readily pass through the outer surface of the eye to the interior of the eye than if the prodrug was in the active state. More specifically, the prodrug can pass through the outside of the cornea to the aqueous humor (aqueous humor) of the eye inside the eye. For example, the prodrug also has solubility or acidic/basic properties that allow it to cross the corneal boundary. An example of a prodrug agent is N-acetyl carnosine (N-acetyl camosine). In the anterior chamber, substances such as N-acetyl carnosine have the ability to pass through the cornea and then be converted to other agents (e.g., carnosine).

[0036] Once inside the eye, the prodrug can be activated/converted. In its active form/converted form, the prodrug may act as a reducing agent. To the end, the prodrug in the active state comprises a reduced compound. The conversion of a prodrug from its inactive state to its active state may be caused by one or more of several factors. For example, enzymes naturally present in the aqueous humor of the eye may cause a switch. Alternatively or additionally, energy may be applied to the surface, as described earlier. That is, radiant, sonic or electromagnetic energy, thermal energy, chemical energy, particle beam energy, plasma beam energy, enzymes, gene therapy, nutritional energy, other applied energy, and/or any combination of any of the foregoing may be applied. The energy used either causes the conversion of the prodrug from the inactive to the active state or breaks the abnormal biochemical bonds that are believed to cause the lens to be inelastic. The activated prodrug then acts to reduce the broken bonds. In particular, an activated prodrug is a substance to which the lens exerts a force such that, once passed through the cornea and into the interior of the eye, the lens actively absorbs the prodrug.

[0037] According to a further embodiment of the invention, enzymes or enzymes can also be introduced into the eye in the form of prodrugs. For example, a large number of enzymes such as thiol reductase (thiolase) may be used in eye drops. In eye drops, a large amount of the enzyme may be in a dispersed form exhibiting its inactivity. In the case of enzymes, the disassembled form of the enzyme allows it to readily cross the corneal boundary to the inner eye and be absorbed by the lens. Once in the inner eye, the enzyme is activated. In this context, activation involves the reassembly of the enzyme component. Activation may be caused by the use of various externally applied forms of energy as discussed above, or by various intracorneal enzymes already present in the lens. Once assembly is complete in the lens, the enzyme may act to promote the reduction reaction by breaking aberrant biochemical bonds, including but not limited to disulfide bonds, and by inhibiting bond reformation by transporting reducing molecules (protons) from the reducing compound to the broken bonds. Thus, the reducing agent for supplying the reducing molecule may be introduced simultaneously with the enzyme. Alternatively, the reducing agent may be introduced before or after the enzyme is introduced. The reducing agent may be in the form of a prodrug.

[0038] According to another embodiment of the invention, agents that affect the accommodative power of the eye can be introduced by direct injection. The agent comprises an enzyme or an enzyme that catalyzes a reduction reaction and/or a reducing substance. For example, injection can be directly into the lens or into the anterior chamber, into the vitreous or into the posterior chamber. For example, methods suitable for such injection may be through the cornea or sclera. The injection may be followed by external application of energy to additionally facilitate the reduction reaction.

[0039] For example, if injected into the aqueous humor of the eye instead of the lens, the injected substance is one that can pass through the lens capsule boundary and into the lens. For example, the injected substance is one for which the lens has a new force, such that once it enters the interior of the eye, the lens can actively absorb the substance. The injected substance may also be one that is transformed into a substance that affects the accommodative power of the eye after entering the lens, such as a reducing substance.

[0040] The reduction of abnormal lenticular bonds is particularly beneficial when the eye is focused from the weight of a distant object to a near object, since most of the naturally occurring changes in lens shape occur in the anterior central region of the lens, and more particularly in the anterior central region of the lens where the shape may change during accommodation. The anterior central region of the lens is most accessible by medication and application of energy. Accordingly, embodiments of the present invention are particularly directed to targeting the anterior central portion of the lens for treatment. In another aspect, embodiments of the present invention are additionally particularly directed to targeting regions of the lens other than the anterior central region for treatment. Embodiments of the present invention are additionally particularly directed to targeting the anterior central region of the lens for treatment and regions outside the anterior central region of the lens.

[0041] For example, targeted applications according to embodiments of the invention include applying a reducing substance to the eye in a non-selective or non-targeted manner, e.g., by instilling the eye. The reducing substance is capable of passing through the corneal boundary and into the inner eye. Energy is then applied to only selected portions of the lens, such as the anterior central portion of the lens. In the targeted application, the inactive reducing agent is formulated such that it can reduce abnormal lenticular bonds in the absence of applied energy, and upon application of energy, the reducing agent is activated and can reduce broken lenticular bonds. Thus, targeted or focused application of energy can break the lens bonds in selected portions of the lens and can also activate reducing agents present in the selected portions. Reducing agents having the latter properties may be obtained by a person skilled in the art, for example, by suitable selection of the agent, by suitable formulation of the compound components of the agent, by suitable control of the concentration of the agent or of the respective compound components thereof, or by any combination of the above. For example, the reducing agent is a prodrug. On the other hand, when administered, the reducing agent is in an activated form, capable of crossing the corneal border into the inner eye, and does not require the application of energy to be activated.

[0042] The targeted treatment as described above illustrates the important factors involved in the treatment of presbyopia by reducing or reducing aberrant lenticular bonds, since in the unaltered lens there are many important and essential bonds. For example, disulfide bonds are one of the basic protein bonds that result in the three-dimensional conformation of enzymes and proteins. If all disulfide bonds are removed (e.g., by breaking and reducing the disulfide bonds), the lens will no longer have a true three-dimensional structure. At this point, the lens has a number of fluid pockets (capsule bag). On the other hand, disulfide bonds, as discussed earlier, are considered to be factors causing presbyopia. Using targeted treatments as described above, the amount of reduction or decrease in lens bonds in a particular portion of the eye can be controlled to be within a particular range, thereby preserving the beneficial bonds while selectively restoring other bonds. In one range, aberrant lenticular bonds in the target zone are reduced by 10% to 70%. In another range, aberrant lenticular bonds in the target zone are reduced by 20% -50%.

[0043] In embodiments of the invention, the targeted treatment need not include the application of a reducing agent along with the application of energy. Rather, the substance can be suitably formulated (e.g., in terms of compound composition, concentration, etc., as described above) such that the substance can both break aberrant biochemical bonds and reduce broken bonds in a particular portion of the eye. For example, the specific portion is located in the anterior-middle part of the eye. For example, to target a particular portion of the eye, a substance is prepared that has a novel affinity for the particular portion. The amount of decrease in the lenticular key is controlled within a specific range. In one range, aberrant lenticular bonds in the target zone are reduced by 10% to 70%. In another range, aberrant lenticular bonds in the target zone are reduced by 20% -50%.

[0044] In embodiments of the invention, iontophoresis may be used to help the reductive substance be transported into the eye and into the lens. The application of energy may or may not be used with the latter.

[0045] In still other embodiments of the invention, one or more enzymes for promoting or facilitating the reduction reaction may be introduced into the lens by use of viral phages. Rather than introducing the enzyme itself, the lens cells can be transfected with a gene using a viral phage, the genetic code of which is transcribed in the cells of the lens using RNA or DNA transcribing enzymes already present in the lens cells. Once the genetic code has entered the lens cell, the natural protein synthesis machinery present in the cell will generate the enzyme according to the genetic code. This technique involves passing a large amount of enzyme through the lens capsule and into the lens. The lens may then also be treated by any form of reducing agent and application of energy, including energy that is targeted or focused on a particular portion of the lens.

[0046] Finally, it was observed that various human tissues derive from the same epithelial cell line as the embryonic cells of the lens. Skin is one example. Skin undergoes various forms of oxidation, which results in typical changes due to aging. The method as described above may be applied to skin-like epidermal tissue to reduce oxidized biochemical bonds in the epidermal tissue, thereby regenerating the tissue. Each of the various epidermal tissues is treated with a specific design in view of tissue location and accessibility. For example, the skin is treated directly with a reducing agent and then energy is used to promote breaking of the oxidative bonds. Additionally or alternatively, a combination of an enzyme and a catalyst may be used to facilitate the reduction reaction. Specific portions of skin or other epidermal tissue may be treated by targeted application of energy.

[0047] As noted above, the reducing agents and enzymes used to treat skin or other epidermal tissue may be applied in an activated form, or will have any one or any combination of the properties described above in connection with the treatment of the eye for presbyopia. That is, the reducing agent and enzyme are in a prodrug form, or a form that requires the application of energy to be activated, and the like.

[0048] Several embodiments of the present invention are specifically illustrated and described herein. However, it should be understood that: modifications and variations of the present invention are covered by the above teachings and within the purview of the appended claims without departing from the spirit and intended scope of the invention.

Claims (96)

1. A method comprising applying an agent to an outer surface of an eye, the agent capable of passing through the outer surface of the eye and affecting the accommodative power of the eye by reducing aberrant lenticular bonds in the eye.

2. The method of claim 1, wherein said aberrant lenticular bonds are oxidized bonds.

3. The method of claim 1, wherein the agent has a first form that facilitates passage through the outer surface, the first form is converted to a second form after passage through the outer surface, and the second form comprises a biochemical substance that affects the accommodative ability of the eye.

4. The method of claim 3, further comprising applying energy to the eye to convert the agent from the first form to the second form.

5. The method of claim 3, wherein said agent is converted to the second form by an enzyme naturally present in the aqueous humor of the eye.

6. The method of claim 3, wherein the biochemical substance comprises a reducing substance.

7. The method of claim 3, wherein the biochemical substance comprises an enzyme that facilitates a reduction reaction.

8. The method of claim 7, wherein the first form comprises the enzyme in a dispersed form and the enzyme is reassembled into an active enzyme in the eye.

9. The method of claim 1, wherein said agent is a prodrug.

10. A method, comprising:

administering to the eye an agent adapted to affect the accommodative power of the lens of the eye; and

applying energy to a specific portion of the eye to cause the agent to affect said accommodation.

11. The method of claim 10, wherein the agent comprises a reducing substance and the applied energy causes a reduction reaction to occur.

12. The method of claim 11, wherein the applied energy cleaves oxidized lenticular bonds and the reducing substance reduces the cleaved oxidized lenticular bonds.

13. The method of claim 10, wherein the specific portion is located in the anterior central region of the lens.

14. The method of claim 10, wherein the specific portion is located outside of the anterior central region of the lens.

15. The method of claim 10, wherein aberrant lenticular bonds are reduced by 10% to 70% in a specific portion of the eye.

16. The method of claim 10, wherein aberrant lenticular bonds are reduced by 20% to 50% in a specific portion of the eye.

17. The method of claim 11, wherein the reducing species is inactive in the absence of applied energy.

18. The method of claim 11, wherein the reducing substance comprises glutathione.

19. The method of claim 11, wherein the reducing substance comprises N-acetyl carnosine.

20. A method for treating presbyopia, comprising injecting a first biochemical substance capable of crossing the boundary of the lens capsule into the aqueous humor of the eye, wherein the first biochemical substance is further capable of being converted to a second biochemical substance capable of affecting the accommodative ability of the eye.

21. The method of claim 20, wherein the second biochemical substance comprises a reducing substance.

22. The method of claim 20, wherein the second biochemical substance comprises an enzyme that facilitates a reduction reaction.

23. The method of claim 20, wherein the first biochemical substance comprises a viral phage containing genetic information that produces an enzyme that facilitates a reduction reaction.

24. The method of claim 20, wherein the first biochemical substance comprises a glutathione derivative and the second biochemical substance comprises reduced glutathione.

25. The method of claim 20, wherein the first biochemical substance comprises N-acetyl carnosine and the second biochemical substance comprises carnosine.

26. A method of causing a reduction in epidermal tissue oxidized throughout the body, comprising:

applying to the skin or epidermal tissue a reduced biochemical substance adapted to affect oxidized bonds as a prodrug or active agent; and applying energy to a specific portion of the skin or epidermal tissue to effect reduction of the oxidized bonds by a reduction reaction of the reducing substance.

27. The method of claim 26, wherein the bond being reduced is a disulfide bond.

28. The method of claim 26, wherein the energy is any form of electromagnetic energy.

29. The method of claim 26, wherein the electromagnetic energy is one or more of laser energy, visible light energy, ultraviolet energy, infrared energy, one or more microwave energy.

30. The method of claim 26, wherein the biochemical substance comprises a reducing compound.

31. The method of claim 26, wherein the biochemical substance comprises an enzyme.

32. The method of claim 26, wherein the biochemical is activated by the applied energy.

33. The method of claim 26, wherein the energy breaks an oxidized bond.

34. A method for treating presbyopia, comprising:

administering a biochemical substance capable of passing through the outer surface of the eye into the interior of the eye into the eye; and

causing the substance capable of affecting the accommodative power of the eye to switch from an inactive state to an active state.

35. The method of claim 34, wherein the substance is capable of reducing aberrant lenticular bonds in the eye in order to affect the accommodative power of the eye.

36. The method of claim 34, wherein the substance is capable of promoting a reduction reaction in the eye in order to affect the accommodative power of the eye.

37. The method of claim 33, wherein the substance comprises an enzyme.

38. The method of claim 34, wherein the switch is caused by an enzyme naturally present in the eye.

39. The method of claim 31, wherein the converting is caused by the application of external energy.

40. The method of claim 31, wherein the biochemical substance comprises N-acetyl carnosine.

41. A method for treating presbyopia, comprising:

applying a reducing agent to the eye; and

focusing energy on a particular portion of the eye to break the lenticular bonds in the particular portion.

42. The method of claim 41, wherein the reducing agent is reactive and reduces broken lenticular bonds without the need for focused energy.

43. The method of claim 41, wherein the focused energy activates the reducing agent to reduce the broken lenticular bonds.

44. The method of claim 41 wherein the reducing substance comprises glutathione.

45. The method of claim 44, wherein said energy is an ultraviolet laser.

46. The method of claim 44, wherein the energy is visible laser light.

47. The method of claim 41, wherein the reducing substance comprises N-acetyl carnosine.

48. The method of claim 47, wherein the energy is an ultraviolet laser.

49. The method of claim 47, wherein the energy is visible laser light.

50. A method for treating presbyopia, comprising administering a substance to an eye, wherein the substance is formulated to affect the accommodation of the eye in a specific portion of the eye.

51. The method of claim 50 wherein the substance is capable of breaking and reducing abnormal biochemical bonds including but not limited to disulfide bonds in specific moieties.

52. The method of claim 50, wherein said substance has a neo-fusion force on said specific moiety.

53. The method of claim 50, wherein the specific portion is located in the anterior-central region of the eye.

54. The method of claim 50 wherein 10% to 70% of the abnormal biochemical bonds including but not limited to disulfide bonds are broken and reduced in a specific part of the eye.

55. The method of claim 50 wherein 20% to 40% of abnormal biochemical bonds including but not limited to disulfide bonds are broken and reduced in a specific part of the eye.

56. A method comprising injecting a prodrug reagent into an eye, wherein the prodrug reagent comprises a biochemical substance that affects the accommodative ability of the lens of the eye.

57. The method of claim 56, wherein the biochemical reduces aberrant lenticular bonds in the lens.

58. The method of claim 56, further comprising applying energy to the eye to activate the reduction reaction.

59. A method comprising using iontophoresis to facilitate the introduction of a biochemical substance across a corneal boundary, wherein the biochemical substance is capable of affecting the lens accommodation of an eye.

60. The method of claim 58, wherein the biochemical reduces aberrant lenticular bonds in the lens.

61. A method comprising using a viral bacteriophage to facilitate the introduction of a biochemical substance across the corneal boundary, wherein said biochemical substance is capable of affecting the lens accommodation of the eye.

62. The method of claim 61, wherein the biochemical substance comprises the genetic code of an enzyme.

63. The method of claim 61, wherein the viral bacteriophage transfects a gene into the cells of the lens to transcribe the genetic code into the cells of the lens.

64. The method of claim 63, wherein said genetic code transcribes a mercaptotransferase.

65. The method of claim 63, wherein the genetic code transcribes hexokinase.

66. The method of claim 63, wherein the genetic code transcribes glutathione reductase.

67. The method of claim 61, further comprising treating the eye with a reducing agent.

68. The method of claim 67, wherein the reducing agent is reduced glutathione.

69. The method of claim 67, wherein the reducing agent is a reducing thiol derivative.

70. The method of claim 67, wherein said reducing agent is a substituted indole.

71. The method of claim 67, further comprising applying energy to the eye.

72. The method of claim 71, wherein said energy is an ultraviolet laser.

73. The method of claim 71, wherein the energy is visible laser light.

74. A method comprising administering a reducing agent to human epidermal tissue, wherein said reducing agent is adapted to reduce biochemical bonds in the tissue.

75. The method of claim 74, further comprising applying energy to the epidermal tissue to activate the reducing agent.

76. A pharmaceutical composition for treating presbyopia, comprising an agent that penetrates the outer surface of the eye and affects the accommodative power of the eye by reducing aberrant lenticular bonds in the eye.

77. The pharmaceutical composition of claim 76, wherein the agent is converted to a biochemical capable of affecting the accommodative ability of the eye by the application of energy.

78. The pharmaceutical composition of claim 77, wherein said agent is capable of being converted to a biochemical by an enzyme naturally present in the aqueous humor of the eye.

79. The pharmaceutical composition of claim 78, wherein the agent comprises N-acetylcarnosine.

80. The pharmaceutical composition of claim 78, wherein the pharmaceutical agent comprises any glutathione derivative.

81. The pharmaceutical composition of claim 76, wherein the biochemical substance comprises a reducing substance.

82. The pharmaceutical composition of claim 81, wherein the reducing substance comprises reduced glutathione.

83. The pharmaceutical composition of claim 81, wherein the reducing substance comprises a reducing thiol derivative.

84. The pharmaceutical composition of claim 81 wherein the reducing substance comprises a substituted indole.

85. The pharmaceutical composition of claim 81, wherein the reducing substance comprises a reducing carnosine.

86. The pharmaceutical composition of claim 76, wherein the biochemical substance comprises an enzyme that catalyzes a reduction reaction.

87. The pharmaceutical composition of claim 86, wherein said enzyme comprises a mercaptotransferase.

88. The pharmaceutical composition of claim 86, wherein the enzyme comprises hexokinase.

89. The pharmaceutical composition of claim 86, wherein said enzyme comprises glutathione reductase.

90. The pharmaceutical composition of claim 86, wherein said enzyme comprises glutathione-S-transferase.

91. The pharmaceutical composition of claim 86, wherein the agent comprises the enzyme in a dispersed form and the enzyme is reassembled into the active enzyme in the eye.

92. A pharmaceutical composition for treating epidermal tissue, comprising a biochemical substance adapted to effect reduction of an aberrant oxidized bond in the tissue.

93. The pharmaceutical composition of claim 92, wherein the reduction of the oxidized bond is performed by activating a biochemical substance by applying energy and causing a reduction reaction by the biochemical substance.

94. The pharmaceutical composition of claim 92, wherein the biochemical substance comprises a reducing agent.

95. The pharmaceutical composition of claim 92, wherein the biochemical comprises an enzyme.

96. The pharmaceutical composition of claim 92, wherein the biochemical substance comprises a prodrug.