Personalized RNA drug shows a year of stability in rare inherited ALS

A Florida emergency physician with an ultra-rare, inherited form of amyotrophic lateral sclerosis has gone a year on a drug custom-built for his specific genetic mutation without serious side effects, and with biomarkers and lung and cognitive function that have held steady rather than declined, according to a case report published this week in the journal Med. The patient, Dr. Rakesh Parekh of Orlando, was diagnosed in 2021 with ALS caused by a mutation in the gene CHCHD10, a variant so rare that fewer than 30 people carrying it have been identified worldwide.

Parekh's drug, an antisense oligonucleotide called nL-CHCHD-001, was designed and manufactured for him individually by the nonprofit n-Lorem Foundation, which builds one-patient medicines for diseases too rare to attract commercial drug development. He received it through a clinical protocol run out of Mayo Clinic in Jacksonville, where neurologist Bjorn Oskarsson serves as principal investigator. Nature's news desk covered the case Friday, describing it as the first time a therapy targeting the CHCHD10 mutation specifically has been given to a person with ALS.

ALS, also known as Lou Gehrig's disease, progressively destroys the nerve cells that control voluntary muscle movement, typically killing patients within two to five years of diagnosis as they lose the ability to walk, speak, swallow and eventually breathe unaided. Roughly 10 percent of cases are inherited, tied to mutations in one of more than two dozen identified genes, and CHCHD10 accounts for only a small sliver of that inherited fraction. Because so few people carry any single rare ALS mutation, pharmaceutical companies have historically had little financial incentive to develop drugs for them, leaving patients such as Parekh with few options beyond the handful of ALS treatments approved for the broader patient population.

The numbers

• CHCHD10 mutations cause well under 1 percent of inherited ALS cases, making Parekh's form of the disease what researchers call "nano-rare."
• n-Lorem's chemists synthesized and screened more than 320 candidate antisense oligonucleotides before settling on the lead compound now known as nL-CHCHD-001.
• The drug went from design to first dose in about three years, compared with a decade or more for earlier antisense drugs aimed at more common ALS mutations.
• Parekh received six spinal injections between April 2024 and April 2025, three 50-milligram doses followed by three 75-milligram doses, according to the Med report.
• After a year, his plasma neurofilament light chain — a blood biomarker that rises as motor neurons die — had fallen back into the normal range, while pulmonary function, cognitive testing and physical strength measures remained stable.

Those numbers matter because CHCHD10-linked ALS, while variable, has historically progressed steadily; stabilization rather than continued decline is what investigators were watching for.

How the drug was built

CHCHD10 encodes a small protein that helps maintain the structure of mitochondria, the energy-producing compartments inside cells; the mutant version is toxic to motor neurons, the nerve cells that control muscle movement and progressively die off in ALS. Antisense oligonucleotides work by binding to the RNA copied from a faulty gene and marking it for destruction before it can be translated into harmful protein, a mechanism already validated in ALS by tofersen, an antisense drug the Food and Drug Administration approved in 2023 for ALS caused by mutations in a different gene, SOD1.

Parekh's treatment came out of Silence ALS, a program run jointly by n-Lorem and the Eleanor and Lou Gehrig ALS Center at Columbia University, which develops individualized antisense drugs for patients whose ALS is caused by mutations too rare for a pharmaceutical company to pursue on its own. The National Institute of Neurological Disorders and Stroke awarded the program $15 million over three years through its URGenT Network to expand the approach to more patients. As of the program's most recent public accounting, nine of eleven enrolled CHCHD10-ALS patients had begun treatment, one of them at Mayo Clinic and eight through Columbia.

The approach builds on a personalized-medicine template that n-Lorem's founder helped pioneer during a long career at the antisense-drug company Ionis Pharmaceuticals, and that first drew wide attention in 2018 when researchers built a one-patient antisense drug for a child with a different fatal neurological disease. n-Lorem was created two years later to turn that kind of bespoke drug-making into a repeatable, charitable service for patients whose mutations are found in only a handful of people worldwide, rather than a one-off scientific feat; the foundation says it does not charge patients for the drugs it develops. Parekh's treatment is delivered by intrathecal injection, a spinal procedure that places the drug directly into the cerebrospinal fluid bathing the brain and spinal cord so it can reach motor neurons more efficiently than a drug taken orally or by vein.

Reaction and what happens next

Parekh, who watched his own father die of ALS before his diagnosis, had not expected an intervention to arrive in time.

"I really didn't think that there was something out there that could prolong my life or improve my life," Parekh told NBC News.

Stanley Crooke, n-Lorem's founder and chief executive, has pointed to the pace of enrollment as evidence the model can scale beyond a single patient. "Being able to dose nine patients in the first year of the funding is evidence of the importance of this grant and the benefit it can bring to patients who had little to no therapeutic options," Crooke said when the NIH grant was announced. Neil Shneider, the Columbia neurologist who directs the Gehrig ALS Center, framed the broader goal similarly: "The goal of Silence ALS is to design and develop individualized ASOs for patients with ultra-rare genetic forms of ALS."

The case report's authors, led by Mayo Clinic genomics researcher Margot Cousin, caution that a single patient's one-year course cannot establish that the drug works; CHCHD10-ALS itself progresses at variable speed, and a placebo-controlled trial is not feasible when a disease affects only a few dozen people worldwide. The clinical protocol remains open but is no longer recruiting new participants for this specific compound, according to its registration on ClinicalTrials.gov, while Silence ALS continues enrolling additional CHCHD10 carriers and n-Lorem pursues similarly personalized drugs for other single-digit-prevalence ALS mutations. Researchers involved in the program say the real test of the approach will be whether the three-year development timeline, sharply faster than earlier antisense programs, can be repeated for the next ultra-rare mutation in line.