Selective transthyretin ligands for treatment of age-related comorbidities

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

AMD is the leading cause of blindness in developed countries, particularly in people older than 60 years. ATTRwt is a late-onset, non-genetic disease caused by accumulation of TTR amyloid deposits, mainly in the heart (ATTRwt-CM). Case reports and epidemiological studies support significant rates of AMD and ATTRwt-CM comorbidity, likely due to the high population frequency of both conditions in older individuals.

We previously developed a class of selective RBP4 antagonists as a potential therapy for dry ADM and Stargardt disease. While RBP4 antagonists can be an optimal treatment option for the majority of dry AMD patients, this class of drugs can be counter-indicated for a subset of individuals with genetic or age-related predisposition to ATTR. There is a significant medical need for a treatment for dry AMD without complications due to ATTR.

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 thereby inhibit the formation of lipofuscin bisretinoids. The same ligand stabilizes the released TTR tetramer, thus preventing its dissociation to monomer and potential pathological 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)

Advantages:

Highly potent pharmacological inhibitor of the lipofuscin bisretinoid formation in animal models
Administered orally
Intended to treat dry AMD without exacerbating or increasing risk of ATTR
Can be used clinically as a kinetic TTR stabilizer for genetic and sporadic forms of ATTR

Lead Inventors:

Konstantin Petrukhin, Ph.D.

Christopher Cioffi, Ph.D.

Patent Information:

Patent Status

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