Small Molecule Pharmacological Chaperone for the Treatment of Autosomal Dominant Retinitis Pigmentosa

Autosomal dominant retinitis pigmentosa (adRP) is a rare genetic disease of the eye, characterized by the loss of the light-sensing cells of the retina. Most patients have night blindness in their early teens, typically progressing to legal blindness by age 40. There are no approved treatments for adRP. Researchers have investigated many genes associated with adRP. The most common genes have changes in the protein opsin. The lead collaborator for this project has identified and begun developing compounds that correct abnormal forms of opsin. The purpose of this project is to fully develop one of these candidate compounds into a drug that may be taken orally and to perform the studies needed for testing in adRP patients.

Scientific Synopsis

adRP is an orphan genetic disease of the eye, affecting about 75,000 patients worldwide. Nearly 15,000 patients carry the class II (misfolded opsin) mutation. The disease is characterized clinically by the loss of rod photoreceptor cells, followed by cone cell degeneration. The most common adRP-associated mutations affect opsin, a protein integral to the function of the visual cycle. Opsin combines with the pigment 11-cis-retinal to form rhodopsin in the rod cells. In adRP with class II mutations, mutant opsin does not traffic normally to the outer segment but rather aggregates in the photoreceptor cell’s endoplasmic reticulum, causing toxicity, cell death and retinal degeneration. As rod function degenerates due to proteotoxicity, decreased night vision appears as the first symptom. When rod photoreceptors die, cone photoreceptors destabilize, resulting in loss of visual acuity and color/central vision.

The principal investigators have identified several series of small molecule pharmacological chaperones that promote the correct folding of mutant forms of human opsin. The lead molecule was confirmed in vitro to be a pharmacological chaperone that induces normal rhodopsin conformation, enabling its translocation to the plasma membrane of the retinal rod cell. The lead molecule is effective in transgenic mouse models representative of the human disease after oral administration, preserving rod photoreceptor cell viability and function. It has progressed successfully through a battery of non-clinical de-risking studies, and the collaborators seek the resources and expertise of TRND to complete the preclinical course and achieve a successful Investigational New Drug filing with the Food and Drug Administration.

Lead Collaborator

BIKAM Pharmaceuticals, Inc., Cambridge, Massachusetts

William F. Brubaker, Ph.D.

Public Health Impact

There are no approved treatments for adRP. The disease typically results in legal blindness by age 40.


TRND confirmed the chaperone activity of the lead molecule in cells and significantly improved the throughput of the key assay which can be applied to the screening for new lead compounds. TRND contributed to de-risking the lead molecule by completing a dose range-finding toxicology study to support a future IND filing. After completion of these activities, BIKAM Pharmaceuticals was acquired by Shire Pharmaceuticals to continue the development of the de-risked lead molecule for the treatment of adRP.