WO2008075365A1 - Compositions and methods for treatment of age related degeneration of the retina - Google Patents

Abstract

The present invention relates to the use of random or ordered copolymers including the known copolymer glatiramer (also known as Copolymer 1) and Copolymer 1-related heteropolymers or ordered peptides, for treating, preventing, delaying or diminishing age-related deterioration of retinal function.

Description

COMPOSITIONS AND METHODS FOR TREATMENT OF AGE RELATED DEGENERATION OF THE RETINA

FIELD OF THE INVENTION

The present invention relates generally to compositions and methods for preventing, delaying, diminishing or treating retinal degeneration and more specifically concerns a method for the treatment of age related degeneration of the retina.

BACKGROUND OF THE INVENTION

The mammalian eye undergoes profound changes throughout life. The most significant changes are neuronal alterations that affect retinal anatomy and function and play a highly significant role in the development, maturation and aging of the visual system. Behaviorally, these changes impinge on vision by affecting the visual acuity, motion perception and contrast sensitivity.

The ERG (electroretinogram) is a sensitive tool that measures electrophysiological function of the retina, and serves as an objective measurement of visual function. The ERG undergoes many age-related changes throughout life. In humans, electrical responses to pattern visual stimulation peak between eleven to twenty years of age (Emmerson-Hanover et al. 1994, Electroencephalogr, Clin.

Neurophysiol. 92, 93-101). Thereafter an age-related decline in inner retinal function continues throughout adulthood into old age (Porciatti et al. 1992, Vision Res. 32,

1199-1209; Lovasik et al. 2003, Graefe 's Arch. Clin. Exp. Ophthalmol. 241, 48-55;

Justino et al. 2001, Clin. Neurophysiol. 112, 1343-1348).

Recently, the inventors of the present invention were able to demonstrate a similar age-related decline in inner retinal function in rats, which reaches peaking at the age of eleven weeks, before starting a gradual decline (Ben-Shlomo & Ofri,

2006, Exp. Eye Res. 83(2), 417-423). Similar declines were demonstrated in other species, including guinea pigs, and mice. Copolymer 1 and related copolymers

A high molecular weight synthetic basic random copolymer consisting of L-

AIa, L-GIu, L-Lys and L-Tyr residues in the molar ratio of about 6 parts Ala to 2 parts GIu to 4.5 parts Lys to 1 part Tyr, and having a molecular weight of 15,000-

25,000, was first described in U.S. Pat. No. 3,849,550 as an agent for treatment or prevention of experimental allergic encephalomyelitis (EAE), a disease resembling multiple sclerosis (MS) that can be induced in susceptible animals. Batches of this copolymer of average molecular weight 23,000, designated Copolymer 1 or Cop 1, were shown to be highly effective in protecting and suppressing EAE in several animal species (Teitelbaum et al. 1971, Eur. J. Immunol. 1(4), 242-248; Teitelbaum et al. 1974, Clin. Immunol. Immunopathol. 3(2), 256-262; Teitelbaum et al. 1974, Israeli Med. Set 13:1038).

Later, Cop 1 was found to significantly reduce the number of relapses in patients with the exacerbating-remitting form of multiple sclerosis (Bornstein et al.

1990, Handbook of Multiple Sclerosis, ed. Cook S.D. Marcel Dekker, Inc., p. 469; SeIa et al. 1990, Bull. Inst. Pasteur (Paris) 88, 303-314; Johnson et al. 1994, MS.

11th Annual Meeting A.N. A.). Copolymer 1, in the form of the acetate salts of synthetic polypeptides containing L-GIu, L-AIa, L-Tyr and L-Lys with an average molar fraction of 0.141, 0.427, 0.095 and 0.338, is the active ingredient of COPAXONE®, a medicament for the treatment of multiple sclerosis.

COPAXONE® is the registered trade name for glatiramer acetate.

The effect of Copolymer 1 in the treatment of multiple sclerosis is in the achievement of suppression or deactivation of autoimmune T cell reactivity to myelin antigens in multiple sclerosis patients. For this purpose, Copolymer 1 is administered without adjuvants by daily subcutaneous injection.

Cop 1 was originally designed to mimic myelin basic protein (MBP) and to induce EAE, but was found to be non-encephalitogenic and to even suppress EAE induced by MBP (Teitelbaum et al. 1971, Eur. J. Immunol. 1(4), 242-248), PLP

(Teitelbaum et al. 1996, J. Neuroimmunol. 64, 209-217), or MOG (Ben-Nun et al.

1996, J. Neurol. 243(4Supl), S 14-22). The precise mechanisms by which Cop 1 prevents the development of EAE and ameliorates multiple sclerosis (MS) are not yet known. Nevertheless, some important immunological properties of this copolymer have emerged. Studies have demonstrated partial cross-reactivity of Cop 1 with MBP at both the T cell (Webb et al. 1973, Immunol. Commun. 2(2), 185-192) and the antibody (Teitelbaum et al. 1988, Proc. Natl. Acad. ScI USA 85(24), 9724- 9728) level. Cop 1 can serve as an antagonist of the T-cell antigen receptor for the MBP immunodominant epitope (Aharoni et al. 1988, J Neuroimmunol. 91(1-2), 135-146). It can also bind to various MHC class II molecules and prevent them from binding to T cells with specific antigen-recognition properties (Fridkis-Hareli et al. 1999, Int. Immunol. 11(5), 635-641). Currently COPAXONE® is approved for reduction of the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis. The composition, its manner of manufacture and methods of treatment using same are fully described in US Patent Nos. 5,981,589; 6,054,430; 6,342,476; 6,362,161; 6,620,847; 6,939,539. Further extensive uses of Copolymer 1 and related peptides and polypeptides as well as T cells treated therewith for neuroprotective therapy is disclosed in numerous publications and patents including WO 01/93893, US Patent Nos. 6,835,711 and 6,844,314, among others. As COPAXONE® is known to be a neuroprotective drug, the inventors of the present invention in collaboration with others, recently found that COPAXONE® protects inner retinal function in a rat model of glaucoma (Bakalash et al. 2005, J. MoI. Med. 83, 904-916). The loss of inner retinal function in glaucomatous rats systemically or topically treated with COPAXONE® was significantly lower than the loss demonstrated in untreated rats.

US Patent No. 6,835,711 discloses methods for treating neurodegeneration including retinal ganglion cell (RGC) death and/or lessening damage to the optic nerve arising from a condition selected from glaucoma, increased intraocular pressure and glutamate toxicity, by administering to an individual in need of such treatment an effective amount of poly-Glu,Tyr (a random copolymer consisting of only two amino acids). Much of the retinal damage that occurs in animal models of glaucoma as well as other retinal diseases has been shown to result from secondary neurodegeneration (due to increased levels of neurotoxins such as glutamate). The effect of COPAXONE® in these animal models is most probably due to activation of the local immune system, which ameliorates the mechanisms protecting the retina from the secondary neurodegenerative and neurotoxic processes. Currently approved drugs administered to glaucoma patients are designed to reduce the intra-ocular pressure. Their functionality stems from increasing the aqueous flow (parasympathomometics), decreasing of aqueous production (carbonic anhydrase inhibitors, alpha agonists), or the increase of serum osmolarity to reduce intraocular water content (hyperosmotic agents). These drugs are not effective in treating old-age deterioration of retina function in patients since they do not interfere with the cell death cycle itself. Based on studies of other neurodegenerative diseases, it is assumed that changes in expression levels of apoptotic genes are mediated by neurotoxic compounds. One of the first mediators of neuronal degeneration to be identified is glutamate, an excitatory neurotransmitter. Other mediators that may be involved in neuronal death in various models of retinal diseases have also been identified, including, but not limited to, endothelin-1, D-serine, nitric oxide, tumor necrosis factors α and β, and plasminogen activators. The end-result of these changes is a decline in the number and function of retinal neurons. There is an unmet medical need for methods and compositions suitable for treating or diminishing age related retinal decline in human and non-human subjects. In particular, nowhere in the background art is it disclosed or suggested that Cop 1 and related copolymers may be suitable to treat, prevent or diminish natural age related retinal decline, not associated with or resulting from a recognized overt pathology such as glaucoma or any other retinal disease.

SUMMARY OF THE INVENTION

The present invention provides pharmaceutical compositions and methods useful for the prevention or treatment of age-related decline in retinal function. In particular, the compositions and methods of the present invention are useful to prevent, delay or diminish decline in retinal function that it not associated with an overt pathology. Specifically, the compositions and methods of the present invention are useful to prevent, delay or diminish decline in retinal function that it not associated with retinal diseases. The present invention provides methods for treating decline in retinal function using heteropolymers of amino acids. Specifically, the methods of the present invention disclose for the first time random or ordered copolymers including

Copolymer 1 and Copolymer 1 -related heteropolymers or peptides, for treating or diminishing decline in retinal function. According to one aspect, the compositions and methods of the present invention are effective to treat or diminish natural age related decline of retinal function including, but not limited to, decline in the inner retinal function. According to another aspect, the compositions and methods of the present invention are effective to treat or diminish natural age related decline of retinal function including, but not limited to, decline in the outer retinal function.

The pharmaceutical compositions comprising copolymers of the present invention can be administered at any age to prevent or delay decline and to maintain the level of function. Advantageously the compositions may be administered at young ages up to puberty in order to extend the duration of increase in retinal function. According to the principles of the present invention this treatment during the prepubertal or juvenile ages is envisaged to increase the functional reservoir of the retinal cells. The pharmaceutical compositions of the present invention might also be administered at old ages, since the decline in retinal function continues throughout life due to normal age related degeneration or deterioration. The death of retinal ganglion cell as well as other damage to the optic nerve occurs at a rate of approximately 0.3% per year. Treatment of the elderly population may thus be advantageous as well.

According to the present invention it is now disclosed for the first time that in experimental animals treated with COPAXONE®, the neonatal period of increasing retinal function that normally occurs throughout the juvenile period until maturation can be extended. The present invention is based in part on the surprising discovery that neonatal animals treated with COPAXONE® were shown to have measurable increases in retinal function extending well past young adulthood, rather than achieving their peak retinal function in young adulthood and exhibiting a steady decline in function thereafter.

The present invention is based in part on the finding that while in untreated rats, retinal function gradually increases from birth to age 11 weeks, and then begins a gradual decline, in rats treated with COPAXONE® injections after birth, retinal function continues to increase beyond 22 weeks of age. This represents a 100% extension of the time period of increase in visual capabilities in these rats, and may represent a method of delaying age-related decline in visual function in humans and non-human subjects. Thus, the delay of normal changes in human retina and the optical nerve associated with aging, would have a significant impact on visual performance and life quality of elderly human beings.

According to a first aspect, the present invention provides compositions for the treatment of age-related deterioration in a subject of the retina or optic nerve fibers, comprising: administering to a subject in need of such treatment a therapeutically effective amount of glatiramer acetate, a derivative or analogue thereof.

The term "treatment" in the context of the present invention refers to improvement in at least one parameter of vision, which typically declines with age. The improvement may be in a parameter that already deteriorated due to old age, preferably in cases where the damage only began. However, in accordance with a preferred embodiment of the invention, the "treatment" refers to prevention of the deterioration of the parameter of the eye (preferably retina or optic nerve) that typically deteriorates with age. The prevention may be complete abolishment of the deterioration, decrease in the level of deterioration as compared to untreated control, decrease in the rate of deterioration, or postponement in the age of the onset of deterioration as compared to untreated control. The term "at least one parameter of the eye that deteriorates with age"- concerns any physiological (electrical, metabolic), structural (histological), biochemical or functional parameter, or combination of parameters that are known in the field to decrease with old age. Preferably these are parameters relating to the physiological functions of the retina. These parameters include ERG which measures the electrophysiological function of the retina; behavioral tests including perimetry, contrast sensitivity, motion perception, visual acuity, binocular vision, visual threshold and color perception; the number of cells in the outer, mid or inner retina and RPE; retinal layer thickness; and changes in genetic, molecular and cellular processes controlling apoptosis in the retina. Additional parameters of the visual system relating to optic nerve fiber include the number and size of optic nerve axons; thickness of the optic nerve and its meningeal sheaths; number of glial cells and the related GFAP-immunoreactive area in the optic nerve; changes in optic nerve gene expression controlling the above processes; and changes in the optic nerve responses controlling the above processes.

The "subject" to which the drug is administered is preferably not a subject suffering also from retinal disease, but merely suffers from deterioration vision due to old age, not related to retinal disease. Preferably, where the administration is parenteral, the subject to which the drug is administered does not suffer simultaneously from multiple sclerosis. Furthermore, the subject to which the drug is administered is preferably at prepubertal ages and does not suffer from retinal disease such as glaucoma, intra-ocular pressure and the like.

According to various embodiments of the present invention, the random or ordered copolymers and peptides to be used in the combination therapy comprise a suitable quantity of an amino acid of positive electrical charge, such as lysine or arginine, in combination with an amino acid with a negative electrical charge (preferably in a lesser quantity), such as glutamic acid or aspartic acid, optionally in combination with an electrically neutral amino acid such as alanine or glycine, serving as a filler, and optionally with phenylalanine, tyrosine or tryptophan, the optional amino acids adapted to confer on the copolymer immunogenic properties.

The copolymers to be used in the combination therapy can be composed of L- or D-amino acids or mixtures thereof. As is known by those of skill in the art, L- amino acids occur in most natural proteins. However, D-amino acids are commercially available and can be substituted for some or all of the amino acids used to make the copolymers of in the present invention. The present invention contemplates the use of copolymers containing both D- and L-amino acids, as well as copolymers consisting essentially of either L- or D-amino acids.

In various embodiments of the present invention, the copolymer may be a random polypeptide from about 15 to about 100 amino acids, preferably from about 40 to about 80 amino acids in length. In alternative embodiments, the agent is an ordered synthetic peptide of 6 to 25 amino acids, preferably of 10 to 20 amino acids. In yet other embodiments oligomeric forms of these the peptides may be produced having from about 15 to about 100 amino acids, preferably from about 40 to about 80 amino acids in length. More specifically, in one embodiment of the invention, the pharmaceutical composition to be used in the combination therapy for preventing and treating age- related retinal degeneration comprises at least one random or ordered copolymer, said copolymer comprises at least three different amino acids, each one selected from the following groups: (a) lysine and arginine;

(b) glutamic acid and aspartic acid;

(c) alanine and glycine;

(d) phenylalanine, tyrosine and tryptophan,

A preferred copolymer for use in the therapy comprises in combination alanine, glutamic acid, lysine, and tyrosine, of net overall positive electrical charge. In a preferred embodiment, the pharmaceutical composition comprises Copolymer 1 of molar ratio of the amino acids as follows: glutamic acid about 0.14, alanine about 0.43, tyrosine about 0.10, and lysine about 0.34. In another preferred embodiment, the molar ratios of the amino acid residues include the relative molar ratios of 0.17 glutamic acid to 0.38 lysine to 0.49 alanine to 0.1 tyrosine, or alternatively 0.19 glutamic acid to 0.4 lysine to 0.6 alanine to 0.1 tyrosine.

In one embodiment, average molecular weight of the copolymer of the invention is about 2,000 - 40,000 Da, preferably of about 2,000 -13,000 Da, more preferably of about 4,700 - 13,000 Da, even more preferably of about 5,000 - 9,000 Da, and most preferably of about 6,000 - 8,000 Da.

It is clear that this is given by way of example only, and that the composition can be varied both with respect to the constituents and relative proportions of the constituents if the above general criteria are adhered to. According to another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one copolymer, the copolymer selected from copolymer 1 and a copolymer 1 -related heteropolymer, wherein said copolymer comprises at least three amino acids each one selected from at least three of the following groups: a. lysine and arginine; b. glutamic acid and aspartic acid; c. alanine, glycine and valine; d. tyrosine, tryptophan and phenylalanine; for treating or preventing age-related retinal deterioration. In one embodiment, the present invention provides a pharmaceutical composition comprising glatiramer acetate for treating or preventing age-related retinal deterioration. The term "glatiramer acetate, a derivative or analogue thereof refers to a compound formerly known as Copolymer 1 that is sold under the trade name COPAXONE® and consists of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L- lysine with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively. The average molecular weight of glatiramer acetate in COPAXONE® is 5,000-9,000 daltons. The term also refers to chemical derivatives and analogues of the compound. Typically the compound is prepared and characterized as specified in any of US Patent Nos. 5,981,589; 6,054,430; 6,342,476; 6,362,161; 6,620847; and 6,939,539.

Furthermore, the present invention is based on the surprising discovery that specific ordered Copolymer 1 -related heteropolymers can be used as a single active ingredient for the treatment or prevention of retinal decline. Specifically, the inventors of the present application disclose herein for the first time the use of ordered Copolymer 1 -related heteropolymers for increasing or preserving retinal function. According to yet another aspect, the present invention provides use of at least one copolymer selected from copolymer 1 and a copolymer 1 -related heteropolymer, wherein said copolymer comprises at least three amino acids each one selected from at least three of the following groups: a. lysine and arginine; b. glutamic acid and aspartic acid; c. alanine, glycine and valine; d. tyrosine, tryptophan and phenylalanine; for the preparation of a medicament for treating or preventing age-related retinal deterioration. In one embodiment, the present invention further provides use of Cop 1 and a Cop 1 -related heteropolymer compounds for increasing at least one functional parameter of the retina. In another embodiment, the present invention provides use of Cop 1 and a Cop 1 -related heteropolymer compounds for delaying age-related retinal deterioration or decline. Yet another use provided by the present invention is for extending the duration of increase in retinal function.

As indicated hereinabove, heteropolymers having ordered amino acid sequence (ordered copolymers) are within the scope of the present invention. Examples of such heteropolymers or peptides are those disclosed in WO 00/05249, the entire contents of which being incorporated herein by reference. Thirty-two of the peptides specifically disclosed in said application are reproduced in Table 1, hereinbelow. Such peptides and other similar peptides are expected to have similar activity as Cop 1. Such peptides, and other similar peptides, are also considered to be within the definition of Cop 1 -related peptides or polypeptides and their use is considered to be part of the present invention.

Table 1: ORDERED PEPTIDES

The administration of the drug product may be accomplished by any suitable means known in the art including by parenteral administration (e.g., subcutaneous, intravenous, intramuscular, intradermal, intraperitoneal and the like), oral administration or by direct application into the eye, (by topical application to the eye in any ocular acceptable carrier), for example in the form of eye drops, eye ointment or implantable ocular devices. BRIEF DESCRIPTION OF THE FIGURES

Figure IA. Electroretinogram amplitude demonstrating the maturation and decline of retinal function in response to 5 different types of visual stimuli of normal rats.

Figure IB. Age-related changes in human retinal function (signal amplitude) indicating gender differences (adopted from Emmerson-Hanover R. et al. 1994, Electroencephalogr. Clin. Neurophysiol. 92:93-101). Upper and lower curves correspond to female and male populations respectively.

Figure 2A. Signal latency demonstrating retinal function of normal rates. Data fit: y = 0.2145x² - 4.0065x + 103.55; R² = 0.80.

Figure 2B. Age-related changes in human retinal function (signal latency) during development (adopted from Emmerson-Hanover R. et al. 1994, Electroencephalogr. Clin. Neurophysiol. 92:93-101).

Figure 3A. Electroretinogram amplitude demonstrating retinal function of rats treated with COPAXONE® in response to 5 different types of visual stimuli.

Figure 3B. Signal latency demonstrating retinal function of rates treated with COPAXONE®.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of random or ordered copolymers including Copolymer 1 and Copolymer 1 -related heteropolymers or ordered peptides, for treating or preventing decline or deterioration of retinal function.

The term "therapeutically effective amounts" is intended to qualify the amount of copolymer that will achieve the goal of preventing or substantially delaying age-related decrease or deterioration of retinal function as measured by at least one recognized parameter of retinal function. According to some aspects of the present invention the therapeutically effective amount will achieve retinal function greater than what would be observed in the absence of such treatment.

Age-related changes in inner retinal function The mammalian visual system undergoes profound changes throughout life.

Some of these changes are the result of altered ocular optics, including aging changes in the lens, pupil and ocular media. The most significant changes, however, are neuronal alterations that affect retinal anatomy and function and play a highly significant role in the development, maturation and aging of our visual system.

Age-related decline in cell populations takes place in all of the retinal layers, including retinal pigment epithelium, photoreceptors and RGCs. Several studies have shown a gradual loss of RGCs in both humans and non-human primates, and it has been suggested that the loss rate is linear. It was further shown that in the human retina, the concentration of cones and rods decreases at a rate of 0.18% per year and 0.37% per year, respectively. Overall, the number of rods by the age of 90 decreases by 30%, and the number of bipolar cells at the ages of 35-62 and 60-90 decreases by 21% and 27%, respectively. The inner retina is also affected, with losses of 25% of all RGCs by the age of 75, according to one study. In another study a 38% decrease in RGC numbers, and 39% decrease in overall retinal thickness was reported for the elderly. Obviously, these losses have a dramatic impact on the pattern ERG (PERG) in humans, as signal amplitudes have been shown to decline by 29%-41%. More significantly, the loss of retinal neurons impacts the quality of life, as it is associated with altered visual acuity, motion perception and contrast sensitivity. As the population of the world ages, an increasing number of people suffer from reduced quality of life due to age-related decline in retinal cell numbers and function.

Evidently, age-related loss of retinal neurons is not restricted to primates. Similar declines have been shown in rats. The thickness of the rat inner plexiform layer (the RGC synaptic layer) increases post-natally, peaks at 40 days and gradually declines; and the thickness of RGC axonal layer peaks at the age of 16 days before declining. The number of RGCs in the rat also decreases significantly in the early post-natal period. It has been estimated that 35% of the rat's RGCs are lost during the first two and a half years of life, thus validating the rat as a model for aging of the inner retina in primates. A steady decline of photoreceptor concentration, starting in the peripheral retina at 6 months of age, has also been reported in rats, resulting in reduced thickness of the outer nuclear layers by 27-90%. Measurement of retinal DNA also supports the conclusion that significant retinal cell loss occurs during senescence. These studies thus validate the rat as a model for aging of the inner as well as outer retina in humans, further described as the" optimal model for studies on neuronal maturation and ageing", having a retina that is "particularly sensitive to developmental changes and senile decay".

As exemplified herein the treatment of newborn rats with Cop 1 can affect the age-related changes in inner retinal function. Instead of decreasing from 11 weeks of age, as they do in untreated rats, PERG amplitudes keep rising, with the increase reaching significant levels by 22 weeks of age and beyond. Signal latencies were also affected by the treatment, as they kept decreasing, rather than increasing, as the animals aged.

This effect of Cop 1 treatment in normal, newborn may have two potential benefits. The first implication of delaying age-related RGC death is that elderly subjects will have a greater number of functioning RGCs, thus preventing or delaying some of the deterioration in visual performance which characterizes old age. The second potential benefit of having more RGCs, is to better resist to diseases that cause RGC death, such as glaucoma or ischemia, as the subject will have a larger "reservoir" of functioning RGCs at the disease onset. Remarkably, Cop 1 was shown to be effective in delaying age-related changes when experimental animals were treated neonatally. It is important to note that newborn animals were treated as a "proof of concept", since this is the age when the most significant RGC death occurs and therefore dramatic results could be expected. However, RGC death continues throughout life, at a rate of 1.5% per month in rats and a rate of 0.3% per year in humans. Therefore, such treatment is believed to be of benefit at any age, though its effect may be less dramatic when commenced later.

It is noteworthy, that similar processes of age-related cell death also take place in the outer retinal layers, and affect the photoreceptors and RPE. These processes have a profound effect on the visual performance of the individual as well. Recently, the inventors, in collaboration with others, demonstrated that COPAXONE® protects outer retinal function in rats that were subjected to laser burn injury (Belokopytov et al. 2007, Lasers in Surg, and Med., in press). In this study, the loss of outer retinal function following retinal laser burns in rats treated systemically with

COPAXONE® was significantly lower than the loss demonstrated in untreated rats.

According to the principles of the present invention, it is suggested that treatment with Cop 1 may also delay the age-related apoptotic processes that occur in the outer retina, thus further contributing to improved vision and resistance to retinal disease.

Similarly to inner retina, the preservation of outer retinal function further ameliorates the treatment through the creation of a larger reservoir of outer retinal cells. Conservation of inner as well as outer retinal function is thus within the scope of the present invention.

These findings are believed to be applicable to humans, having a profound impact on the quality of life of elderly subjects as well as of those suffering from inner and outer retinal diseases.

Thus, there is an unmet need to prevent retinal deterioration in normal aging.

Furthermore, at present there are no approved drugs used for preventing age related retinal loss of function, and no known treatment to alleviate the symptoms associated with this decline. Therefore, there is an unmet need for therapeutic modalities directed to treat, delay or diminish retinal loss of function at its early stages.

Identification of the pathways responsible for retinal neuronal death enables the decrease in neuronal death by inhibiting these pathways. Neuroprotection is a therapeutic approach that aims at preventing death of neurons, such as RGCs and photoreceptors, by inhibiting cellular apoptosis in various retinal diseases. Without wishing to be bound by any theory or mechanism of action, the inhibition of age- related cellular apoptosis, according to the principles of the present invention, can be mediated through processes that do not involve the immune system. The present invention provides a novel application of neuroprotective therapy aimed at inhibiting the molecular cascade leading to age-related apoptosis of retinal neurons, thus delaying and/or ameliorating the decline in visual function of the elderly. The present invention overcomes the drawbacks of the background art by providing a novel method for preventing or substantially delaying age-related loss of retinal function or alternatively treating this condition at its early stages by administering therapeutically effective amount of a copolymer selected from Cop 1 or Cop 1 -related heteropolymers or ordered peptides, to a subject in need thereof, wherein the copolymer correspond to one of the following copolymers:

A. A copolymer comprising at least three amino acids selected from at least three of the following groups:

(a) lysine and arginine;

(b) glutamic acid and aspartic acid;

(c) alanine, glycine and valine; (d) tyrosine, tryptophan and phenylalanine;

B. A copolymer comprising at least three different amino acids, each selected from a different group selected from:

(a) lysine and arginine; (b) glutamic acid and aspartic acid;

(c) alanine, glycine and valine;

(d) phenylalanine, tyrosine and tryptophan;

C. A copolymer comprising alanine, glutamic acid, lysine, and tyrosine, of net overall positive electrical charge;

D. Copolymer 1 comprising alanine, glutamic acid, lysine, and tyrosine in the molar ratios of: glutamic acid about 0.14 to alanine about 0.43 to tyrosine about 0.10 to lysine about 0.34; E. Copolymer 1 comprising alanine, glutamic acid, lysine, and tyrosine in the molar ratios of: 0.17 glutamic acid to 0.38 lysine to 0.49 alanine to 0.10 tyrosine;

F. Copolymer 1 comprising alanine, glutamic acid, lysine, and tyrosine in the molar ratios of: 0.19 glutamic acid to 0.4 lysine to 0.6 alanine to 0.1 tyrosine; G. Anyone of the aforementioned copolymer having an average molecular weight of about 2,000 - 40,000 Da; preferably, about 13,000 -18,000 Da.

H. Glatiramer acetate having an average molecular weight of about 5,000- 9,000 Da; I. Terpolymer having three different amino acids each one selected from groups (a) to (d);

J. Ordered terpolymer consisting of three different amino acids, each selected from a different one of the following groups: (a) lysine and arginine;

(b) glutamic acid and aspartic acid;

(c) phenylalanine, tyrosine and tryptophan; K. A terpolymer YEK substantially free of alanine and containing glutamic acid, tyrosine, and lysine, in the molar ratio of any of the following: from about 0.005 to about 0.300 glutamic acid, from about 0.005 to about 0.250 tyrosine, and from about 0.3 to about 0.7 lysine; L. A terpolymer YEK substantially free of alanine and containing glutamic acid, tyrosine, and lysine, in the molar ratio of about 0.26 to about 0.16 to about 0.58, respectively.

M. YEK as detailed above, with an average molecular weight of about 2,000 - 40,000 Da, preferably about 13,000 -18,000 Da, wherein it is possible to substitute arginine for lysine, aspartic acid for glutamic acid or phenylalanine or tryptophan for tyrosine.

N. A YAK terpolymer consisting of three different amino acids, each selected from a different one of the following groups:

(a) lysine and arginine;

(b) alanine, glycine and valine;

(c) phenylalanine, tyrosine or tryptophan; O. A YAK terpolymer substantially free of glutamic acid containing tyrosine, alanine and lysine, in the molar ratio of any of the following: from about 0.005 to about 0.25 tyrosine, from about 0.3 to about 0.6 alanine, and from about 0.1 to about 0.5 lysine, alternatively, the molar ratios of tyrosine, alanine and lysine are about 0.10 to about 0.54 to about 0.35, respectively;

P. YAK as detailed above, with an average molecular weight of about 2,000 - 40,000 Da, preferably about 13,000 -18,000 Da wherein it is possible to substitute arginine for lysine, glycine or valine for alanine or phenylalanine or tryptophan for tyrosine;

Q. A YEA terpolymer consisting of three different amino acids, each selected from a different member of the following groups:

(a) glutamic acid and aspartic acid; (b) alanine, glycine and valine;

(c) phenylalanine, tyrosine and tryptophan;

R. YEA terpolymer containing tyrosine, glutamic acid and alanine, in the molar ratio of any of the following: from about 0.005 to about 0.25 tyrosine, from about 0.005 to about 0.3 glutamic acid, and from about 0.005 to about 0.8 alanine, alternatively, the molar ratios of glutamic acid, alanine, and tyrosine are about 0.21 to about 0.65 to about 0.14, respectively; and S. YEA as detailed above, having average molecular weight of about 2,000 -

40,000 Da, preferably about 13,000 -18,000 Da, wherein it is possible to substitute aspartic acid for glutamic acid, glycine for alanine, and phenylalanine or tryptophan for tyrosine. As disclosed previously in US Patent No. 6,844,314 all of the above detailed heteropolymers have been indicated to possess neuroprotective properties in other systems. Anyone of the foregoing copolymers used in the method of the present invention may have random amino acid sequence (random copolymers), ordered amino acid sequence (ordered copolymers) or peptides having ordered amino acid sequence (ordered peptides).

Moreover, the copolymers for use in the present invention may be composed of L- or D-amino acids or mixtures thereof. As is known by those of skill in the art, L-amino acids occur in most natural proteins. However, D-amino acids are commercially available and can be substituted for some or all of the amino acids used to make the terpolymers and other copolymers of the present invention. The present invention contemplates copolymers containing both D- and L-amino acids, as well as copolymers consisting essentially of either L- or D-amino acids.

In a preferred embodiment, the mole fraction of amino acids of the heteropolymers for use in the method of the invention is about what is preferred for Copolymer 1. The mole fraction of amino acids in Copolymer 1 is glutamic acid about 0.14, alanine about 0.43, tyrosine about 0.10, and lysine about 0.34. According to certain embodiments, the average molecular weight for Copolymer 1 is between about 13,000 and about 18,000 daltons. The activity of Copolymer 1 in the treatment or prevention of retinal deterioration is expected to remain if one or more of the following substitutions are made: aspartic acid for glutamic acid, glycine for alanine, and arginine for lysine

Copolymer 1 has been approved in several countries for the treatment of Multiple Sclerosis (MS) under the trade name, COPAXONE®, Glatiramer acetate.

Several clinical trials demonstrated that Copolymer 1 is well tolerated with only minor side reactions, which were mostly mild reactions at the injection site (Johnson et al. 1995, Neurology, 1, 65). The molar ratios of the monomers of the more preferred terpolymer having glutamic acid, alanine, and tyrosine, or YEA, are about 0.21 to about 0.65 to about 0.14.

The molar ratios of the monomers of the more preferred terpolymer having glutamic acid, tyrosine, and lysine, or YEK, are about 0.26 to about 0.16 to about 0.58.

The molar ratios of the monomers of the more preferred terpolymer having tyrosine, alanine and lysine, or YAK, are about 0.10 to about 0.54 to about 0.35. As indicated hereinabove, heteropolymers having ordered amino acid sequence (ordered copolymers) are within the scope of the present invention. Examples of such heteropolymers and peptides are those disclosed in WO 00/05249, the entire contents of which being incorporated herein by reference. Thirty-two of the peptides specifically disclosed in said application are reproduced in Table 1, hereinabove. Such peptides and other similar peptides are expected to have similar activity as Cop 1, and are also considered to be within the definition of Cop 1 -related peptides or polypeptides. Their use is thus considered to be part of the present invention.

As disclosed herein for the first time and exemplified herein below, exogenous intraperitoneal administration of Glatiramer Acetate inhibits the development of age related decline in retinal function exemplified on experimental animals. Impressively the retinal function of rats has improved by more than a 100%, following treatment with COPAXONE® in comparison to untreated populations.

The copolymers useful according to the principles of the present invention can be prepared and characterized as specified in any of US Patent Nos. 5,981,589; 6,054,430; 6,342,476; 6,362,161; 6,620,847 and 6,939,539. The process disclosed in U.S. Patent No. 3,849,650 can also be used for preparing the copolymers of the invention. For example, the N-carboxyanhydrides of tyrosine, alanine, γ-benzyl glutamate and N, ε-trifluoroacetyl-lysine are polymerized at ambient temperatures in anhydrous dioxane with diethylamine as an initiator. The γ-carboxyl group of the glutamic acid can be deblocked by hydrogen bromide in glacial acetic acid. The trifluoroacetyl groups are removed from lysine by one molar piperidine.

One of skill in the art readily understands that the process can be adjusted to make peptides and polypeptides containing the desired amino acids, that is, three of the four amino acids in Copolymer 1, by selectively eliminating the reactions that relate to any one of glutamic acid, alanine, tyrosine, or lysine. For purposes of this application, the terms "ambient temperature" and "room temperature" refer to a temperature ranging from about 20 to about 26°C.

The molecular weight of the terpolymers can be adjusted during polypeptide synthesis or after the terpolymers have been made. To adjust the molecular weight during polypeptide synthesis, the synthetic conditions or the amounts of amino acids are adjusted so that synthesis stops when the polypeptide reaches the approximate desired length. After synthesis, polypeptides having the desired molecular weight can be obtained by any available size selection procedure, such as chromatography of the polypeptides on a molecular weight sizing column or gel, and collection of the molecular weight ranges desired. The present polypeptides can also be partially hydrolyzed to remove high molecular weight species, for example, by acid or enzymatic hydrolysis, and then purified to remove the acid or enzymes.

In one embodiment, the terpolymers with a desired molecular weight may be prepared by a process that includes reacting a protected polypeptide with hydrobromic acid to form a trifluoroacetyl-polypeptide having the desired molecular weight profile. The reaction is performed for a time interval and at a temperature which are predetermined by one or more test reactions. During the test reaction, both time and temperature are varied and the molecular weight range of a given batch of test polypeptides is determined. The test conditions, which provide the optimal molecular weight range of polypeptides are used for a particular batch. Thus, a trifluoroacetyl-polypeptide having the desired molecular weight profile can be produced by a process which includes reacting the protected polypeptide with hydrobromic acid at conditions predetermined by test reaction. The trifluoroacetyl-polypeptide with the desired molecular weight profile is then further treated with an aqueous piperidine solution to form a low toxicity polypeptide having the desired molecular weight.

In a preferred embodiment, a test sample of protected polypeptide from a given batch is reacted with hydrobromic acid for about 10-50 hours at a temperature of about 20-28°C. The best conditions for that batch are determined by running several test reactions. For example, in one embodiment, the protected polypeptide is reacted with hydrobromic acid for about 17 hours at a temperature of about 26⁰C.

Pharmaceutical compositions

The random and ordered copolymers used in the present invention can be formulated into pharmaceutical compositions containing a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any or all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, sweeteners and the like. The pharmaceutically acceptable carriers may be prepared from a wide range of materials including, but not limited to diluents, binders and adhesives, lubricants, disintegrants, coloring agents, bulking agents, flavoring agents, sweetening agents and miscellaneous materials such as buffers and absorbents that may be needed in order to prepare a particular therapeutic composition. The use of such media and agents with pharmaceutically active substances are well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. For injection, the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants for example DMSO, or polyethylene glycol are generally known in the art.

For ocular administration, the compounds of the present invention may further include any ocular acceptable carrier and may be administered in any of the forms selected from: ophthalmic solution, emulsion, dispersion etc. and semisolids such as ophthalmic gel, ointment etc. Diluents for the aqueous solution or suspension include, for example, distilled water and physiological saline. Diluents for nonaqueous solution and suspension include, for example, vegetable oils e.g. olive oil, liquid paraffin, mineral oil, and propylene glycol and p-octyldodecanol. The compounds of the present invention may further contain isotonization agents such as sodium chloride, boric acid, sodium citrate, etc. to make isotonic with the lacrimal fluid and buffering agents such as borate buffer, phosphate buffer, etc. to maintain pH about 5.0 to 8.0. Further, stabilizers such as sodium sulfite, propylene glycol, etc., chelating agents such as sodium edetate, etc., thickeners such as glycerol, carboxymethylcellulose, carboxyvinyl polymer, etc. and preservatives such as methyl paraben, propyl paraben, etc. may also be added. These can be sterilized e.g. by passing through a bacterial filter or by heating.

The ophthalmic ointment may contain vaseline, Plastibase, Macrogol, etc. as a base and surfactant for increasing hydrophilicity. It may also contain gelling agents such as carboxymethylcellulose, methylcellulose, carboxyvinyl polymer, etc.

For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient. Some pharmacological preparations for oral use are disclosed in US Patent Nos. 6,214,791; 6,932,983; 6,977,070; 7,022,663 and 7,033,582 in which various manners for oral administration of Cop 1 and other similar compounds are described. The pharmacological preparations of the present invention can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Pharmaceutical compositions, which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.

In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the active ingredients in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds, to allow for the preparation of highly concentrated solutions.

U.S. Patent No. 6,214,791 discloses methods for treating multiple sclerosis by oral administration of copolymer- 1 through ingestion or inhalation. When copolymer- 1 is introduced orally, it may be mixed with other food forms and consumed in solid, semi-solid, suspension, or emulsion form; and it may be mixed with pharmaceutically acceptable carriers, including water, suspending agents, emulsifying agents, flavor enhancers, and the like. In one embodiment, the oral composition is enterically-coated. Copolymer- 1 may also be administered nasally in some of the above-mentioned forms by inhalation or nose drops. Furthermore, oral inhalation may be employed to deliver copolymer- 1 to the mucosal linings of the trachea and bronchial passages.

According to various embodiments of the present invention, the therapeutically effective amount of the at least one copolymer ranges from about 1.0 mg to about 500.0 mg/day. Alternatively, such therapeutically effective amounts of the at least one copolymer are from about 20.0 mg to about 100.0 mg/day.

The following examples are presented in order to more fully illustrate certain embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention. One skilled in the art can readily devise many variations and modifications of the principles disclosed herein without departing from the scope of the invention.

Example 1: Rat Pattern Electroretinogram (PERG) as a model for the development of inner retinal function.

The aim of this study was to evaluate age-related changes in retinal function of the rat during the first 18 weeks of life. The pattern electroretinogram (PERG) was used to monitor inner retinal activity in 16 developing rats. In each animal, recordings were conducted at ages 3, 5, 7, 11, 14 and 18 weeks to assess age-related changes in function. Signals were evoked by 5 stimuli of progressively increasing check size (82 — 1304 minutes of arc/phase) that were projected directly onto the fundus through a specially modified ophthalmoscope, which allowed visual and manual control of stimulus quality. Poor signal to noise ratio prevented signal analysis at the age of 3 weeks. Subsequently, PERG amplitude increased significantly, by up to 242% (depending on stimulus check size), during weeks 5-11.

After peaking at 11 weeks, signal amplitude began to decline moderately, and by 18 weeks of age it had declined by 15-25% (depending on stimulus size; Figure IA).

Signal latency mirrored that of the amplitude, decreasing during the first 11 weeks, and then increasing steadily (Figure 2A). It was not affected by stimulus check size. Age was highly correlated with Pl latency (R² = 0.80) and moderately correlated with N2 latency (R² = 0.52). These changes in rat signal amplitude and latency show a remarkable correlation with the age-related changes in pattern visual evoked potential recordings in humans (Figure IB & 2B; adopted from Emmerson-Hanover R. et al. 1994, Electroencephalogr. CHn. Neurophysiol. 92: 93-101). In recordings in people 6-80 years of age, it has been shown that signal amplitude reaches a maximum (and the latency reaches a minimum) at approximately 13 years of age. It is thus proposed that the rat PERG undergoes many of the age-related changes that have been reported in humans. Apparently, in both species, retinal activity peaks at the age of sexual maturity, and declines thereafter. Thus, the rat may serve as an animal model to study development and aging of retinal function in humans.

Example 2: COPAXONE® as a treatment for age-related deterioration of retinal activity

The experimental design as described in Example 1 hereinabove was repeated, with the modification of 15 experimental rats that were treated with

COPAXONE®. At age 1-11 weeks, each rat received biweekly IP injections of

COPAXONE® (33-100μg, adjusted for body weight). ERG recordings were performed as in the first experiment, only they were extended beyond 18 weeks, since the age-related decline seen in Example 1 was not observed. Rather, the injections of COPAXONE® had a beneficial effect on retinal function in the rat, and the activity of the retina continued to increase instead of declining. By 22 weeks of age, ERG amplitudes were significantly higher than at 11 weeks of age, and remained so throughout the experimental period (PO.01) (Figure 3A; in comparison to Figure IA). Signal latency was likewise affected by the treatment. Instead of increasing from 11 weeks of age, it continued decreasing (PO.01) (Figure 3B; in comparison to Figure 2A). These experiments thus show that age-related decline in visual function as seen in Figures IA & 2 A to begin at 11 weeks, is halted following biweekly administration of COPAXONE®.

Example 3: Increased resistance to retinal diseases

The end-result of virtually every retinal disease is death of retinal cells, and reduced retinal function and visual performance. As can be seen from Table 2, the leading causes of blindness in Israel increase dramatically as a function of age. With the exception of cataract, all leading causes of blindness are retinal diseases, and all of them have their highest prevalence in people of age groups 41-65 or 66-80 years old.

Table 2: Age distribution of leading causes of blindness in Israel (published by the Ministry of Labor and Welfare)

This prevalence of retinal diseases is not unique to Israel, and similar results have been reported in epidemiological studies throughout the western world. The costs of these diseases, and their impact on the quality of life of millions of people and on the national economy, are evident.

Without wishing to be bound by any theory or mechanism of action, it is suggested that the prophylactic Cop 1 treatment creates a larger "reserve" of functional retinal neurons (by delaying age-related cell death). The treatment suggested by the present invention thus prevents or substantially decreases the detrimental effect of these diseases on visual function. The evaluation of proposed mechanism is performed using pattern ERG and flash ERG technology, in model rats. Rat animal models exist in many of these diseases, including diabetic retinopathy, retinitis pigmentosa and retinal detachment. The severity of disease in these models is evaluated in animals that have been pre-treated with Cop 1, compared to control animals.

Example 4: Dose-response and other studies in rats

As noted, pattern ERG and flash ERG may be used to assess inner and outer retinal function, respectively, in rats treated with Cop 1 in order to evaluate the effect of the drug on age-related changes in visual function and on the resistance to retinal diseases. In addition, the following studies are conducted in rats treated with Cop 1 or a Cop 1 related copolymer in order to assess efficacy of the copolymers in diminishing visual decline:

1. Routes of drug delivery - oral, injection or topical (eye drops) delivery; various manners of drug delivery are examined including particularly ocular non-invasive routes of administration. Preferably, oral or ocular administration, which are considered to be the most convenient routes are tested.

2. Optimal dosing, duration of treatment, number of treatments and their interval; these parameters are examined for each successful route of administration. Specifically, therapeutic effective doses are being assessed according to various parameters such as, but not limited to, body mass, age and gender. 3. Age range at which treatment is most beneficial; advantageously the compositions are administered at young ages up to puberty in order to extend the duration of increase in retinal function. The age range for treatment previously assessed focused on prepubertal or juvenile ages to maximize the functional reservoir of the retinal cells. These results are now extended to establish the utility of treatment in older subjects in preserving retinal function.

4. The mechanisms of the Cop 1 effect at the morphological, biochemical, molecular and genetic levels. The exact cellular, molecular and genetic mechanisms regulating age-related decline of the retinal neurons in both humans and rats have yet to be elucidated. However, it has been demonstrated that in newborn rats, retinal neurons are more susceptible to apoptosis involving the Caspase pathways than adult cells. It has thus been suggested that these processes are responsible for at least some of the age-related cell death that occurs at the retina. Additional pathways controlling age-related death of retinal neurons involve the Bcl-2 gene family. The expression ratio of two protein products of this family, the pro-apoptotic Bax and the anti-apoptotic Bcl-2, is shifted with aging towards the pro-apoptotic product. Thus, an increased expression of the pro-apoptotic protein Bax together with a down-regulation of the anti- apoptotic protein Bcl-2 were correlated with age-related apoptosis of retinal neurons. These identified genes are likely to represent only some of the molecular pathways involved in the pathogenesis of retinal aging.

While certain embodiments of the invention have been illustrated and described, it is to be clear that the invention is not limited to the embodiments described herein. Numerous modifications, changes, variations, substitutions and equivalents will be apparent to those skilled in the art without departing from the spirit and scope of the present invention as described by the claims, which follow.

Claims

1. A method for treating or preventing age-related retinal deterioration in a subject in need thereof comprising administering a pharmaceutical composition comprising a therapeutically effective amount of at least one copolymer, the copolymer selected from copolymer 1 and a copolymer 1- related heteropolymer, wherein said copolymer comprises at least three amino acids each one selected from at least three of the following groups: a. lysine and arginine; b. glutamic acid and aspartic acid; c. alanine, glycine and valine; d. tyrosine, tryptophan and phenylalanine.

2. The method according to claim 1, wherein the at least one copolymer is selected from the group consisting of a random copolymer, an ordered copolymer and an ordered peptide.

3. The method according to claim 2, wherein the at least one copolymer comprises at least one amino acid of positive electrical charge in combination with at least one amino acid of negative electrical charge.

4. The method according to claim 3, wherein said at least one copolymer further comprises at least one amino acid of electrical neutral charge.

5. The method according to claim 1, wherein said at least one copolymer comprises amino acids selected from the group consisting of: L- amino acids, D- amino acids and a mixture of L- and D-amino acids.

6. The method according to claim 1, wherein said at least one copolymer contains four different amino acids each selected from one of groups (a) to (d).

7. The method according to claim 6, wherein said at least one copolymer has an average molecular weight in the 2000-40,000 dalton range.

8. The method according to claim 7, wherein said at least one copolymer having a net overall positive electrical charge, comprises alanine, glutamic acid, lysine and tyrosine.

9. The method according to claim 8, wherein said at least one copolymer consists of alanine, glutamic acid, lysine, and tyrosine in the molar ratios of about 0.14 glutamic acid, about 0.43 alanine, about 0.10 tyrosine and about 0.33 lysine.

10. The method according to claim 1, wherein said copolymer is glatiramer acetate.

11. The method according to claim 1 , wherein the at least one copolymer is a random copolymer comprising about 15 to about 100 amino acids.

12. The method of claim 2, wherein the ordered peptide is selected from SEQ ID NOS: 1-32.

13. The method according to claim 1, wherein said retinal deterioration comprises an age-related deterioration of the inner retina.

14. The method according to claim 1, wherein said retinal deterioration comprises an age-related deterioration of the outer retina.

15. The method according to claim 1, wherein said deterioration comprises a decline in at least one retinal parameter selected from the group consisting of: physiological, structural, biochemical and functional.

16. The method according to claim 15, wherein said functional parameter is selected from the group consisting of: electrophysiology, perimetry, contrast sensitivity, motion perception, visual acuity, binocular vision, visual threshold and color perception.

17. The method according to claim 1, wherein said subject does not suffer from multiple sclerosis.

18. The method according to claim 1, wherein said subject does not suffer from retinal disease selected from the group consisting of: glaucoma, increased intra-ocular pressure and glutamate toxicity.

19. The method according to claim 1, wherein the administration is selected from: parenteral, oral and ocular.

20. The method according to claim 19, wherein said parenteral administration is selected from the group consisting of: subcutaneous, intravenous, intramuscular, intradermal and intraperitoneal.

21. A method of increasing at least one functional parameter of the inner retina in a subject comprising administering a pharmaceutical composition comprising a therapeutically effective amount of at least one copolymer, the copolymer selected from copolymer 1 and a copolymer 1 -related heteropolymer, wherein said copolymer comprises at least three amino acids each one selected from at least three of the following groups: a. lysine and arginine; b. glutamic acid and aspartic acid; c. alanine, glycine and valine; d. tyrosine, tryptophan and phenylalanine.

22. The method according to claim 21, wherein said at least one copolymer is glatiramer acetate.

23. The method according to claim 21, wherein at least one function of the inner retina is selected from the group of parameters consisting of: electrophysiology, perimetry, contrast sensitivity, motion perception, visual acuity, binocular vision, visual threshold and color perception.

24. A method of increasing at least one functional parameter of the outer retina in a subject comprising administering a pharmaceutical composition comprising a therapeutically effective amount of at least one copolymer, the copolymer selected from copolymer 1 and a copolymer 1 -related heteropolymer, wherein said copolymer comprises at least three amino acids each one selected from at least three of the following groups: a. lysine and arginine; b. glutamic acid and aspartic acid; c. alanine, glycine and valine; d. tyrosine, tryptophan and phenylalanine.

25. The method according to claim 24, wherein said at least one copolymer is glatiramer acetate.

26. The method according to claim 24, wherein at least one function of the outer retina is selected from the group of parameters consisting of: electrophysiology, perimetry, contrast sensitivity, motion perception, visual acuity, binocular vision, visual threshold and color perception.

27. A method of delaying retinal deterioration or decline in a subject comprising administering a pharmaceutical composition comprising a therapeutically effective amount of at least one copolymer, the copolymer selected from copolymer 1 and a copolymer 1 -related heteropolymer, wherein said copolymer comprises at least three amino acids each one selected from at least three of the following groups: a. lysine and arginine; b. glutamic acid and aspartic acid; c. alanine, glycine and valine; d. tyrosine, tryptophan and phenylalanine.

28. The method according to claim 27, wherein said at least one copolymer is glatiramer acetate.

29. A method of extending the duration of increase in retinal function in a subject comprising administering a pharmaceutical composition comprising a therapeutically effective amount of at least one copolymer, the copolymer selected from copolymer 1 and a copolymer 1 -related heteropolymer, wherein said copolymer comprises at least three amino acids each one selected from at least three of the following groups: a. lysine and arginine; b. glutamic acid and aspartic acid; c. alanine, glycine and valine; d. tyrosine, tryptophan and phenylalanine.

30. The method according to claim 29, wherein said at least one copolymer is glatiramer acetate.

31. A pharmaceutical composition comprising a therapeutically effective amount of at least one copolymer, the copolymer selected from copolymer 1 and a copolymer 1 -related heteropolymer, wherein said copolymer comprises at least three amino acids each one selected from at least three of the following groups: a. lysine and arginine; b. glutamic acid and aspartic acid; c. alanine, glycine and valine; d. tyrosine, tryptophan and phenylalanine; for treating or preventing age-related retinal deterioration.

32. The pharmaceutical composition according to claim 31 for increasing at least one functional parameter of the retina.

33. The pharmaceutical composition according to claim 31 for delaying age- related retinal deterioration or decline.

34. The pharmaceutical composition according to claim 31 for extending the duration of increase in retinal function.

35. Use of at least one copolymer selected from copolymer 1 and a copolymer 1- related heteropolymer, wherein said copolymer comprises at least three amino acids each one selected from at least three of the following groups: a. lysine and arginine; b. glutamic acid and aspartic acid; c. alanine, glycine and valine; d. tyrosine, tryptophan and phenylalanine; for the preparation of a medicament for treating or preventing age-related retinal deterioration.

36. Use according to claim 35 for increasing at least one functional parameter of the retina.

37. Use according to claim 35 for delaying age-related retinal deterioration or decline.

38. Use according to claim 35 for extending the duration of increase in retinal function.

39. A pharmaceutical composition comprising glatiramer acetate for treating or preventing age-related retinal deterioration.

40. Use of glatiramer acetate for treating or preventing age-related retinal deterioration.