223
AMD Future Perspectives: New promising drugs
receive treatment
(59)
. Enrollment is still underway for this
clinical trial.
13. Immunomodulator
13.1Glatiramer Acetate:Thelper 2 inducer -DryAMD
Subcutaneous
Another proposed new treatment of dry AMD is a sub-
cutaneous injection of glatiramer acetate (Copaxone,
Teva Pharmaceutical Industries).
Glatiramer acetate has been shown to reduce cognitive
decline, eliminate plaque formation, and induce neu-
ron survival and neurogenesis in a mouse model for
Alzheimer’s disease (AD).
Drusen formation in age-related macular degeneration
(AMD) shares some similarities with Alzheimer’s dis-
ease (AD), which is associated with amyloid deposits.
Aggregated beta-amyloid induces microglia to become
cytotoxic and block neurogenesis.
This medication, increases the proportion of T helper
2 lymphocytes (these T cells are anti-inflammatory in
nature). It seems that these glatiramer–acetate-specific
T helper 2 cells would produce cytokines such as inter-
leukin (IL)-4 and reduce amyloid-induced retinal micro-
glial cytotoxicity in AMD
(60)
.
Copaxone® is administered as a subcutaneous injec-
tion. Two double blind, randomized clinical trials at the
New York Eye & Ear Infirmary and the Kaplan Medical
Center, Rehovot, Israel, have been initiated in 2006 and
2007 respectively, and are enrolling up to 60 patients
combined. The primary outcome tested in these trials
is the reduction in the total area of drusen
(61,62)
. Results
have not been published yet.
14. Prevent injury (anti-oxidants)
14.1 OT-551 - Dry AMD
Topical
OT-551 is administered topically, developed by Othera
Pharmaceuticals, Inc. (Exton, PA)
(63)
. This eyedrop con-
tains a small molecule that downregulates the overex-
pression of the protein complex nuclear factor (NF)- B.
NF- B is a transcription factor that is highly activated
when oxidative stress, inflammation, and angiogenesis
occurs. In preclinical models, OT-551 has demonstrated
anti-oxidative, anti-inflammatory and anti-angiogenic
activity. These results support the development in dis-
eases such as AMD and cataract. OT-551 is the first eye
drop to be tested in a clinical trial as a treatment for dry
AMD. There are 2 phase II, 2-year trials ongoing for
patients with GA secondary to AMD
(64,65)
.
14.2 Fenretinide (Compound ST-602) - Dry AMD
Oral
Fenretinide, or (N-[4-hydroxyphenylretinamide), is an
oral compound that decreases serum retinol by bind-
ing to retinol-binding protein, and promotes renal
clearance of retinol. This in turn decreases the bio-
availability of retinol for the retinal pigment epithelium
(RPE) and photoreceptors. A2E (N-retinylidene-N-
retinylethanolamine), a retinoid byproduct, is a major
fluorophore in lipofuscin and a significant source of
RPE cytotoxicity
(66)
. It is hypothesized that by reducing
toxic retinoid byproducts of visual cycling, there will be a
slowing of GA progression.
Sirion Therapeutics, Inc. (Tampa, FL), is sponsoring a
phase II trial to assess the benefit of fenretinide in the
treatment of GA
(67)
. The study group is ongoing. Patients
have been randomized to 1 of 2 doses (100 mg or 300
mg) or placebo, and they are being followed for 2 years.
15. RPE transplantation
Another potential treatment for AMD is replacing dam-
aged and unhealthy RPE by healthy tissue. In a study
series of ten patients (four had AMD), human neural ret-
inal progenitor cell layers and RPE were transplanted. All
four patients with AMD had vision of 20/200 or worse
and experienced improved visual acuity, none improved
to better than 20/200. There was no graft rejection dur-
ing a follow-up time of up to six years
(68)
.
16. sFlt-1
Soluble (s)Flt-1 is a naturally occurring protein antago-
nist of VEGF formed by alternative splicing of the pre-
mRNA for the full length VEGFR-1
(69)
. The angiostatic
activity of sFlt-1 results from inhibition of VEGF.
It is not clear if sFlt-1 has a role in normal eyes, but
several studies show the evidence of the effect of
overexpression of sFlt-1 in ocular neovascularization
models
(70-73)
.
