Small-molecule antagonists for treating visual loss associated with Stargardt disease

This technology is a class of small-molecule antagonists that prevents visual loss associated with Stargardt disease by downregulating serum retinol to inhibit the accumulation of cytotoxic A2E in the retina.

Unmet Need: A therapeutic to delay visual loss from Stargardt disease

Stargardt disease is the most common form of inherited juvenile-onset macular degeneration characterized by similar cytotoxic components as age-related macular degeneration (AMD), which is the leading cause of blindness in developing countries. There are currently no FDA approved therapies for Stargardt disease and dry AMD. Both diseases are associated with a build-up of lipofuscin in the retinal pigment epithelium (RPE), wherein cytotoxic bisretinoid components of lipofuscin, such as A2E, lead to retinal degeneration and subsequent loss of vision. Therefore, there is a need for treatments that limit the accumulation of cytotoxic components in the retina, in order to slow or even preventing the loss of vision associated with Stargardt disease and AMD.

The Technology: Small-molecule therapeutics for treating Stargardt disease and AMD

This technology describes a class of small-molecule antagonists to downregulate the production of cytotoxic bisretinoids such as A2E in the retina. Bisretinoid accumulation in the retina depends on the influx of serum retinol to the RPE. These small-molecule RBP4 antagonists are capable of reducing serum retinol concentrations, effectively reducing the uptake of serum retinol and synthesis of A2E in the RPE. Therefore, they indirectly reduce the formation of cytotoxic lipofuscin bisretinoids, preventing their accumulation to treat vision loss. This technology has the potential to slow or prevent visual loss associated with Stargardt disease and related diseases such as dry AMD.

This technology has been validated in a genetic mouse model of potentiated lipofuscin production.

Applications:

• Slowing or preventing visual loss associated with Stargardt disease
• Slowing or preventing visual loss associated with dry AMD
• Treatment for Best’s disease
• Treatment for adult vitelliform maculopathy

Advantages:

• Delays visual loss in patients with Stargardt disease
• Oral drug that does not require invasive intraocular injections for delivery
• May treat multiple types of macular degeneration

Lead Inventor:

Konstantin Petrukhin, Ph.D.

Patent Information:

Patent Status

Related Publications:

• Racz B, Varadi A, Kong J, Allikmets R, Pearson PG, Johnson G, Cioffi CL, Petrukhin K. “A non-retinoid antagonist of retinol-binding protein 4 rescues phenotype in a model of Stargardt disease without inhibiting the visual cycle” J Biol Chem. 2018 Jul 20; 293(29): 11574-11588.

• Cioffi CL, Dobri N, Freeman EE, Conlon MP, Chen P, Stafford DG, Schwarz DM, Golden KC, Zhu L, Kitchen DB, Barnes KD, Racz B, Qin Q, Michelotti E, Cywin CL, Martin WH, Pearson PG, Johnson G, Petrukhin K. “Design, synthesis, and evaluation of nonretinoid retinol binding protein 4 antagonists for the potential treatment of atrophic age-related macular degeneration and Stargardt disease” J Med Chem. 2014 Sep 25; 57(18): 7731-57.

Tech Ventures Reference:

• IR CU17176

• Licensing Contact: Kristin Neuman