Transthyretin ligands for treatment of age-related comorbidities

This technology is a structural class of transthyretin (TTR) ligands that can be used to simultaneously treat dry age-related macular degeneration (AMD) and wild-type transthyretin amyloidosis (ATTRwt).

Unmet Need: Safe treatment for patients with dry AMD and ATTRwt

Age-related macular degeneration (AMD) is the most common cause of blindness in developed countries, particularly in people older than 60 years. Wild-type transthyretin amyloidosis (ATTRwt) is a late-onset non-genetic disease associated with aggregation of wild-type transthyretin (TTR). There is no treatment for the most prevalent dry form of AMD. While retinol-binding protein 4 (RBP4) antagonists can be an optimal treatment option for most dry AMD patients, this class of drugs can be counter-indicated for a subset of individuals with genetic or age-related predisposition to TTR amyloidosis. There is a significant medical need for a treatment for dry AMD without complications due to ATTRwt.

The Technology: Single treatment for dry AMD and ATTRwt

This technology is a structural class of transthyretin ligands capable of dissociating the RBP4-TTR complex to partially reduce the retinol traffic to the retina and inhibit the formation of lipofuscin bisretinoids. A TTR tetramer released from the RBP4-TTR complex is then stabilized with the same ligand thus preventing its potential aggregation. This class of TTR ligands may be effective at treating a host of macular degeneration diseases as well as TTR amyloidosis-based diseases. The technology may be used to treat uncomplicated forms of macular degeneration (such as dry AMD and Stargardt disease), as well as different genetic or sporadic forms of TTR amyloidosis not associated with macular degeneration.

Applications:

• Simultaneous treatment for dry AMD and ATTRwt
• Treatment for excessive lipofuscin accumulation in the retina and bisretinoid-mediated macular degeneration
• Treatment for macular degeneration diseases, including dry AMD, age-related macular degeneration, Stargardt disease, Best disease, adult vitelliform maculopathy, and Stargardt-like macular dystrophy
• Treatment for TTR aggregation amyloid aggregate deposition
• Treatment for TTR amyloidosis diseases, including ATTRwt, ATTR amyloidosis peripheral polyneuropathy (ATTR-PN), transthyretin amyloid cardiomyopathy (ATTR-CM), late-onset familial amyloid polyneuropathy (FAP), and familial amyloid cardiomyopathy (FAC)
• Treatment for diseases characterized by excessive lipofuscin accumulation in the retina

Advantages:

• Highly potent pharmacological inhibitor of the lipofuscin bisretinoid formation in animal models
• Administered orally
• Intended to treat dry AMD without increasing risk of ATTRwt
• Can be used clinically as a kinetic TTR stabilizer for genetic and sporadic forms of TTR amyloidosis
• Stabilizes transthyretin tetramers
• Prevents transthyretin aggregate
• Can lower the serum concentration of retinol-binding protein 4
• Broad applications and therapeutic window

Lead Inventors:

Konstantin Petrukhin, Ph.D.

Patent Information:

Patent Pending (US20240150297)

Related Publications:

• Cioffi CL, Raja A, Muthuraman P, Jayaraman A, Jayakumar S, Varadi A, Racz B, Petrukhin K. “Identification of Transthyretin Tetramer Kinetic Stabilizers That Are Capable of Inhibiting the Retinol-Dependent Retinol Binding Protein 4-Transthyretin Interaction: Potential Novel Therapeutics for Macular Degeneration, Transthyretin Amyloidosis, and Their Common Age-Related Comorbidities.” J Med Chem. 2021 Jul 8; 64(13): 9010-9041.

Tech Ventures Reference:

• IR CU20308

• Licensing Contact: Kristin Neuman