Retinal Degenerations (RD) are the leading cause of blindness in the United States. The degeneration of the Retinal Pigment Epithelium (RPE) is associated with various types of RD such as Stargardt’s disease, retinitis pigmentosa, choroideremia, Late-Onset Retinal Degeneration (L-ORD), and Age-related Macular Degeneration (AMD). The RPE as a layer of cells in the back of the eye. Therefore, it is essential to maintain the health and integrity of retinal photoreceptors. RPE dysfunction and degeneration leads to photoreceptor cell death and vision loss, a common factor among several forms of RD.

To resolve these challenges, researchers at the National Eye Institute (NEI) generated iPS cells from two L-ORD patients with a dominant mutation in CTRP5 protein and two of their unaffected siblings. They then differentiated all iPS cells into authenticated RPE cells. A comparative analysis of RPE differentiated from these iPS cells showed sub-RPE deposits and increased VEGF secretion; two of the shared characteristics of different RDs including AMD. Interestingly, the baseline activity of AMP-protein Kinase (AMPK) – a nutrient and energy sensor that maintains energy homeostasis – was changed: in L-ORD patient-derived RPE cells, the lowered baseline intracellular calcium would likely affect lysosomal function. Thus, the reduced AMPK activity leads to lower autophagy in L-ORD patient RPE cells. Researchers at the NEI have shown that: (i) native CTRP5 activates AMPK; and (ii) Metformin, as an FDA-approved drug currently used for the treatment of diabetes, activates AMPK, reduce VEGF secretion, and corrects baseline calcium levels in patient RPE cells.

The NEI seeks licensing and/or co-development research collaborations for Metformin as an FDA-approved drug to treat Age-related Retinal Degeneration. 

Competitive Advantages:

• Metformin provides an upstream therapy that rescues metabolic dysfunction and decline associated with aging, thereby potentially delaying the onset of retinal disease
• L-ORD patient RPE cells demonstrate reduced AMPK activity (leading to lower autophagy), increased VEGF secretion, and unbalanced calcium levels. Metformin might be able to correct/prevent vision loss of L-ORD patients (and possibly others with retinal degenerations) through its activation of AMPK, reduction of VEGF secretion, and correction of baseline calcium levels (as demonstrated in L-ORD patient RPE cells) 

Commercial Applications:

Treatment for retinal diseases:

• Age-related Macular Degeneration (AMD)
• Late-onset retinal degeneration (L-ORD)
• Stargardt’s disease
• Retinitis pigmentosa
• Choroideremia