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C. Bavik, K. Murata, T. McGinn, S. Zhong, S. Hayes, K. Lieu, I. Scott, R. Kubota; Novel Therapy for Non-Exudative AMD. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1217.
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Currently approved medicinal therapies for age-related macular degeneration (AMD) are specifically indicated for treatment of exudative AMD, a form of the disease that constitutes less than 15% of total AMD prevalence. No approved medicinal therapeutic treatment is available for non-exudative AMD (dry AMD). The pathophysiology of AMD, as well as some other degenerative retinal diseases, (e.g., Stargardt’s Disease) has been associated with accumulation of lipofuscin in eye tissues. Modulation of the visual cycle would decrease the rate of accumulation of toxic by-products from this process. A by-product of interest is a bis-retinoid pyridinium salt (A2E), which has been demonstrated to be one of the main components of retinal lipofuscin and is thought to be a major contributor to the retinal degenerative conditions.We present here a new, unique therapeutic class of AMD drugs we have designated Visual Cycle Modulators (VCMs).
VCMs are designed to attenuate isomerization of all-trans-retinol to 11-cis-retinol in vitro and in vivo thus "modulating" the production of visual cycle intermediates, to inhibit generation of by-products (e.g., A2E and lipofuscin) with a minimum of toxicity.
Data will be presented demonstrating that the VCM ACU-4429 is a potent inhibitor of isomerization activity in vitro and in vivo. Furthermore, in vivo studies indicate that ACU-4429 protects the photoreceptors from acute light damage and reduces A2E/lipofuscin accumulation in a genetic animal model (ABCA4).
ACU-4429 is being developed as small molecule for treatment of dry AMD. A single daily oral dose could slow or even halt the progression of dry AMD. This may be the first medical treatment available for this serious, vision-threatening disease.
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