Kentucky Study Looking to Treat Genetic Form of ALS with Clusters in Appalachia
A university-led clinical trial will assess the therapeutic effect of Celestone (betamethasone) injections in amyotrophic lateral sclerosis (ALS) patients with mutations in the FUS gene — a particular genetic type of ALS that seems to be clustered in a nearby region.
Inherited ALS is rare and only affects up to 10% of all patients. Several genes have been linked to ALS, with mutations in C9orf72 and SOD1 being the most common. Those in the FUS gene account for about 5 percent of familial ALS cases.
Edward Kasarskis, director of ALS Multidisciplinary Clinic at the University of Kentucky, found that mutations in FUS were common among ALS patients from the central Appalachian region in the United States, a university news article written by Mallory Powell reports.
Kasarskis’ observation grew out of more than 15 years of clinical follow-up into what became a cluster of patients either born in or with family from that part of the country. Looking through public records, Kasarskis and his team also traced the extended family of two particular patients with FUS-related ALS — who share a family name and hometown — back to Lee County, Virginia, in the 1800s.
FUS encodes a protein known to regulate the levels of other genes and proteins. In particular, it can control the amount of the MnSOD enzyme available in motor nerve cells. Indeed, ALS patients with FUS mutations have low levels of MnSOD, which will contribute to increased oxidative stress and motor neuron death in the spinal cord.
Kasarskis, working with two colleagues at the university’s Markey Cancer Center — Daret St. Clair, a professor of toxicology and cancer biology, and Haining Zhu, a professor of molecular and cellular biochemistry — decided to investigate a way to target this particular form of ALS.
The team screened hundreds of FDA-approved medicines that could enhance the antioxidant capacity of cells and counteract the effects of low levels of MnSOD. With this strategy, they identified Celestone as a potential candidate.
“During the screening process, we found that one drug being used extensively is betamethasone. It’s used in all kinds of inflammatory diseases, it’s very non-toxic so you can give short-term, high doses without problems for patients, and it has a long history of use for other conditions,” St. Clair said. “And that’s how the TRANSLATE clinical trial began.”
The TRANSLATE study is designed to assess the therapeutic effect of Celestone for patients with FUS-driven ALS. The trial is being supported by the school’s UK Multidisciplinary Value Program.
The researchers are planning to enroll 10 people with a FUS mutation who either have ALS or are a family member of an ALS patient. Participants will receive injections of Celestone, and blood samples will be collected to measure changes in antioxidant levels.
“We think that this benefit may not be limited to this particularly focused group of ALS patients, but that it could also be applicable in the larger ALS population, which has a similar component of mitochondria damage from oxidative stress,” St. Clair said.