Novel medicine for rare disease prompts $10M gift for trials

A $10 million gift from the Clayco Foundation will accelerate the development of a new therapy designed to help the body’s cells identify and destroy the malformed proteins that damage the cells of people living with retinal vasculopathy with cerebral leukoencephalopathy (RVCL), a rare genetic and fatal disease with no cure. The therapy is based on a small molecule “degrader” drug and will be guided through pre-clinical safety trials by a team of researchers at the Perelman School of Medicine at the University of Pennsylvania who are dedicated to the study of RVCL and work with many of the roughly 200 patients who have it.

Caused by a mutation prevalent in and passed down through about 200-plus patients around the world, RVCL affects many of the body's organs—including the brain, liver, eyes, and kidneys—because the malignant proteins kill the cells in the body’s small blood vessels, causing significant damage in them.

“This is a disease that affects so many organs across the body, so a typical targeted gene therapy doesn’t work,” said Jonathan Miner, MD, PhD, an associate professor of Rheumatology, who will lead the work. “We have developed something that labels abnormal proteins—just like you would a package. The body’s cells can then read that label and ship the protein to a specific location in the cell for destruction.”

Amanda Finck, PhD, director of translational research for the RVCL Research Center at Penn Medicine, is co-leading the work with Miner, which will work to prove the safety of the drugs—which could eventually be taken as a pill—and hopefully set the stage for a clinical trial in the near future.

What RVCL looks like, untreated

RVCL occurs when a person has an inherited mutation in their TREX1 gene. That mutation causes the TREX1 proteins produced by the gene to be shorter than usual. The shortened protein doesn’t stick to cell membranes like it’s supposed to and, instead, floats freely in a cell, causing damage.

This damage manifests in the destruction of small blood vessels and affects many different organs, causing them to eventually fail.

People with RVCL often don’t start getting symptoms until they’re in their 40s, but once severe symptoms set in—such as vision loss, strokes, and memory problems—most only live for another 5 to 10 years.

For Shawn Clark, chairman of The Clayco Foundation and chief executive officer of CRG, the work is personal. His mother, Ellen, died from RVCL, and affected his grandfather before her.

“I watched this disease take the people I love, and I made a decision that no other family should have to feel powerless against it,” Clark said. “There is nobody else leading the effort to find a treatment or a cure for RVCL, so we are going to be the ones to do it. This gift moves us closer to that goal.”

The black spot

In “Treasure Island,” getting a paper with a black spot from a pirate meant the recipient was marked for death. In effect, Miner and his chemist colleagues at the University of Michigan—led by Nouri Neamati, PhD, a professor of Medicinal Chemistry—have developed a way to give abnormal TREX1 proteins a black spot.

Through a 7-year partnership, in which the Michigan team “cooks up” new molecules for the Penn team to test, the degrader drug was developed.  The small molecule binds both the shortened TREX1 protein and an enzyme called E3 ligase, which labels damaged or unstable proteins for removal. This forces the abnormal TREX1 proteins into the cell’s trash bin. Importantly, healthy proteins are not labeled and help prevent damage from the disease.

“In mice with the human mutation who get this disease, the degrader molecule saves their lives,” Miner said. “It stops organ damage and stabilizes them from further harms.”

Philanthropy as a catalyst

Rare diseases occupy a difficult space in medical research. Given the small patient population, securing funding sources is challenging. Miner said that without such a sizable donation, it would be very difficult to develop small molecules, like TREX1 protein degraders, and bring them through investigational new drug (IND)-enabling studies and future clinical trials.

“We’re doing this on a shoestring budget compared to others who develop these types of medicines,” Miner said. “But what we have is the ability to study what we want and do it on our own terms. That’s how we were able to get here for a rare disease.”

Miner and Finck will move forward with their lead candidate molecule while also refining next-generation degraders in collaboration with Neamati’s team at the University of Michigan.