Age Related Macular Degeneration Therapy

(a) Laser Photocoagulation:
This procedure uses laser to destroy the fragile, leaky blood vessels. A high energy beam of light (argon or krypton laser) is aimed directly onto the new blood vessels and destroys them, preventing further loss of vision. Though thermal laser treatment has been shown beneficial at reducing the likelihood of developing severe visual loss, there is usually an immediate decrease in visual acuity especially in subfoveal choroidal neovascularization (CNV). A CNV membrane is described as subfoveal if any part of the lesion lies beneath the centre of the foveal avascular zone (FAZ). The concern of subfoveal lesions is due to the fact that photocoagulation of such a CNV membrane necessarily results in the destruction of the overlying retina.2 Moreover, thermal laser is effective only in a small subgroup of patients with small, well-demarcated lesions that include a component of classic CNV. Therefore, many alternatives to laser photocoagulation are evolving mainly for subfoveal CNV.

(b) Photodynamic Therapy (PDT):
In 2000, USFDA approved Visudyne™ (Verteporfin for injection) for the treatment of predominantly classic subfoveal choroidal neovascularization due to AMD, pathologic myopia or presumed ocular histoplasmosis. It was the first approved drug therapy for the treatment of wet AMD. Visudyne™ is injected systemically and activated by a non-thermal laser to destroy leaking vessels.3 This therapy utilizes low-intensity light exposure (689 nm, 50 J/cm2 dose, for 83 s in Verteporfin PDT) which causes selective destruction of CNV with preservation of the overlying neuro sensory retina. There are various photosensitizing agents available for treatment. However, currently only Verteporfin is approved for the treatment of CNV. 4 Patients who receive this therapy become temporarily photosensitive and should avoid direct sunlight for 5 days.

(c) Anti Vascular endothelial growth factor (anti-VEGF)
VEGF is a naturally occurring large lipoprotein molecule consisting of at least 6 structurally related proteins. Studies have shown elevated VEGF levels in areas of laser induce CNV in primates and clinically in AMD patients. Macugen (Pegabtanib) was approved in 2004 to treat wet AMD, and is used solely or in combination with other AMD treatments.

The drug Lucentis (Ranibizumab) was approved by FDA for treating AMD in June 2006. It is a humanized antibody fragment designed to bind and inhibit the action of VEGF and thus prevent blood vessel growth and leakage. Avastin (Bevacizumab) is a drug similar to Lucentis that is used to treat colon cancer. Ophthalmologists may prescribe Avastin off label for the treatment of AMD.

VEGF Trap is a substance that blocks the action of vascular endothelial growth factor (VEGF), and prevents the growth of new blood vessels in a tumor. It belongs to the family of drugs called angiogenesis inhibitors. Angiogenesis is the term used to describe the proliferation of blood vessel growth. Substances that stop the growth of excessive blood vessels are anti-angiogenic .Bayer Healthcare and Regeneron have initiated a Phase 3 study of the VEGF Trap -Eye in the neovascular form of wet AMD. 5

(d) Combination therapy of Triamcinolone and Verteporfin
Triamcinolone acetonide has been used to modify the process of choroidal neovascularization. Corticosteroids have a multitude of anti-inflammatory effects and also seem to have direct anti-angiogenic properties. Steroids have an inhibitory effect on angiogenesis, fibrotic activity and inflammatory reaction by reducing the migration and activation of inflammatory cells. Up-regulation of extracellular matrix protein plasminogen activator inhibitor by steroids results in direct angiostatic effect. Corticosteroids stabilize endothelial and basement membranes and also reduce vascular permeability with beneficial effects.

PDT provides immediate angio-occlusion of CNV and intravitreal triamcinolone acetonide (IVTA) , prevents inflammation and up-regulation of VEGF, decreases subsequent regrowth of CNV and finally improves VA outcome. This provides substantial reasons for using verteporfin and triamcinolone in combination. 6, 7,8

Significant improvements in best-corrected visual acuity (VA) after 1 month and their maintenance over a 3-month period were observed after verteporfin Photodynamic therapy combined with intravitreal bevacizumab. These results should be confirmed in larger and long-term prospective randomized trials. 9

Alternative Therapies:

(a) Radiation Therapy:
Radiotherapy affects the evolution of exudative macular degeneration directly by endothelial toxicity, leading to capillary closure and/or indirectly through its attenuating effects on the inflammatory response, mediated by macrophages and other inflammatory cells.10 Low-dose ionizing radiation has been shown to prevent proliferation of endothelial cells of newly formed subretinal capillaries and may induce destruction of abnormal CNV tissue.

(b) Submacular Surgery:
Surgical removal of CNV with large subfoveal hemorrhages can limit toxicity to overlying photoreceptors by prompt evacuation of blood . 11 By preserving the overlying neurosensory retina it can limit visual field defect enlargement and central vision loss.
Moreover,surgery may apply to a wide range of lesions and adjunctive procedures such as RPE transplantation. However, the risks with submacular surgery are considerable and include acceleration of cataract, development of retinal tears and retinal / choroidal detachments.

(c) Retinal translocation:
Retinal translocation and limited macular translocation are being used with rationale to move the macular area from the underlying CNV to a healthier RPE region. The Choroidal neovascular membrane can then be treated with laser photocoagulaton, while sparing the foveal center. 12 However, there is risk of development of intractable proliferative vitreoretinopathy, total retinal detachment, and unpredictable long-term visual prognosis.

(d) Transpupillary thermotherapy (TTT):
A slit lamp delivery system is used to project a beam of diode laser on the lesion thereby causing heat transmission to RPE and choroid. Studies by Reichel et al 13 showed benefit for patients with occult CNV in terms of improvement of visual acuity and decreased exudation.

Prevention:
There is evidence that dietary supplements can help prevent the onset and progression of age-related macular degeneration. Lutein and zeaxanthin is found in leafy green vegetables, corn, egg yolk, squash, broccoli and peas. These carotenoids are proposed to reduce the risk of AMD by absorbing the blue light that could damage the macula, by preventing free radicals from damaging eye cells and by strengthening eye cell membrane. 14

Undergoing Research
Research is in progress to transiently enhance vascular permeability in PDT to selectively release an anti-angiogenic or anti-inflammatory factor to prevent recurrence of neovasculature in case of AMD or to release chemotherapeutic agents in the case of PDT of a malignant tumour. 15
A study was done to evaluate the safety, efficacy & durability of systemic Bevacizumab therapy for neovascular ARMD. The results were good for a small group of patients however the risks associated with systemic anti-VEGF therapy versus the safety of intra vitreal therapy deters the involvement of a large number of patients. 16

Micro and nano particulates have been used primarily on a pre-clinical basis as new drug delivery devices in experimental models of neovascular AMD 17 .The development of polymeric micelles with smart functions such as environment-sensitivity and specific tissue-targetability may enhance the activity of potent bioactive compounds, facilitating their clinical applications. Also, polymeric micelles response to external stimuli, such as light, might exert the activity of the loaded compounds in a site-directed manner, ensuring the effectiveness and safety of the nanocarrier-mediated targeting therapy. Thus, polymeric micelle-based nanocarriers will continue to hold promise for the delivery of drugs and genes . 18

All types of nucleic acids have been developed for the treatment of infectious and cell proliferative diseases affecting mostly the posterior segment of the eye. The eye is therefore a good target for this type of molecules mainly because it is a confined compartment and their delivery is close to the target site. However, to improve the efficiency of such molecules, the use of controlled and/or targeted delivery systems is needed since they allow protection against degradation, increase intracellular penetration and permit long-term delivery avoiding repeated administrations. 19

Conclusion:
Early detection of AMD can stop the progress of the disease. Patients need to be educated about the condition and consistent follow up is required. Drug delivery to the posterior segment of the eye still remains a challenge. Rapid pre corneal elimination, poor corneal absorption, rapid anterior chamber elimination and large diffusional path lengths combine to prevent topically administered drugs from reaching the posterior segment of the eye.

Lot of research is being undertaken and many Pharmacophores are being investigated. A fundamental understanding of the patho physiology of AMD integrated with a mechanistic understanding of drug delivery to the posterior segment is requisite for the design of drugs and drug delivery systems for macular degeneration.

References:
1. Verma L, Das T, Binder S. Heriot W.J., New approaches in the management of choroidal neovascular membrane in age-related macular degeneration, Current Ophthalmology, (48) (4) (2000) 263-78.
2. Beatty et al, Photocoagulation of subfoveal choroid neovascular membrane in age related macular degeneration, British Journal of Ophthalmology (83) (1999) 1103-1104.
3.Orest O., Patrick H., Drug delivery strategies to treat age related macular degeneration, Advanced drug delivery reviews (57) (14) (2005) 1991-1993.
4. Kulkarni A. D., Kuppermann B. D., Wet age related macular degeneration, Advanced drug delivery reviews (57) (14) (2005) 1994-2009.
5. http://www.fiercebiotech.com/press-releases/press-release-bayer-healthcare-regeneron-initiate-phase-3-vegf-trap-
6. Kumar A., Visual acuity and contrast sensitivity outcomes in Indian eyes undergoing photodynamic therapy with intravitreal injection of triamcinolone acetonide in age-related macular degeneration, Indian journal of ophthalmology (55) ( 3)(2007) .
7.Gillies M. C. ,Sompson J. M. ,Luo W, Penfold P., Hunyor A. B.,Chua W., A randomized clinical trail of a single dose of intravitreal Triamcinolone Acetonide for neovascular age-related macular degeneration: One-year results. Arch Ophthalmol (121) (2003) 667-673.
8. Jonas J. B.,Kreissing I.,Hugger P., Sauder G , S. Panda-Jonas, Degenring R., Intravitreal triamcinolone acetonide for exudative age-related macular degeneration, British Journal of Ophthalmology (87) (2003) 462-468.
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11. Lewis H , Intraoperative fibrinolysis of submacular haemorrhage with tissue plasminogen activator and surgical drainage, American.Journal of Ophthalmology (118) (1994) 559-568.
12. Potter M., Improvement in macular function after translocation surgery in a patient with age-related macular degeneration, American Journal of Ophthalmology (129) ( 4) (2000) 547-549
13. Reichel E.,Berrocal A. M ,Desai V., Duker J.S. ,Pulfiafito C. A, Transpupillary thermotherapy of occult subfoveal choroidal neovascularization in patients with age related macular degeneration, Ophthalmology (106) (1999) 1908-1914.
14. http:// www.nutraingredients .com Europe 16/08/2006.
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16. Rosenfeld J. P, Systemic bevacizumab (Avastin) Therapy for neovascular age-related macular degeneration twenty-four-week results of an uncontrolled open-label clinical study, Ophthalmology (11 ) (113) (2006) 2002-2011.
17. Moshfeghi A.A ,Peyman G. A., Micro and nano particulates, Advanced Drug Delivery Reviews (57) (14) (2005) 2047-2052.
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19. Fattal E. , Ocular delivery of nucleic acids: antisense oligonucleotides, aptamers and siRNA, Advanced Drug Delivery Reviews (58) (11) (2006) 1203-1223.