Dr. Rakesh Parekh was in his mid-40s when weakness in his left arm during workouts first signaled something was wrong. The emergency medicine physician from Orlando, Florida, initially dismissed the symptoms as overexertion, but genetic testing revealed a devastating truth: he carried the same CHCHD10 gene mutation that had killed his father from amyotrophic lateral sclerosis (ALS).
In April 2024, Parekh became the first person to receive a personalized antisense oligonucleotide (ASO) drug targeting CHCHD10 mutations. The treatment, developed by the n-Lorem Foundation, appears to have slowed his disease progression by more than half—a remarkable outcome for someone four years into an ALS diagnosis.
Targeting the Genetic Root of Disease
ALS, also known as Lou Gehrig's disease, is caused by faulty proteins that attack neurons in the brainstem and spinal cord, eventually causing patients to lose muscle control, including those needed to breathe. The antisense oligonucleotide works by silencing the mutated gene that produces these harmful proteins, effectively "putting out the match that starts the fire," according to Dr. Jeffrey Rothstein, director of the Robert Packard Center for ALS Research at Johns Hopkins Medicine.
"His disease has maybe even improved a little bit, he is not losing strength like he used to," said Dr. Bjorn Oskarsson, Parekh's neurologist and director of the ALS Center of Excellence at Mayo Clinic in Florida. This represents atypical progress for ALS patients, who typically have only about three years after diagnosis.
The Promise of Precision Medicine
The n-Lorem Foundation, founded by Dr. Stanley Crooke, specializes in creating individualized treatments for "nano-rare" diseases affecting fewer than 30 people at a time. Crooke established the nonprofit because patients with such rare conditions "have no hope, no place to go, no help," as commercial drug development isn't viable for such small populations.
Parekh's treatment took three years and $1.2 million to develop, but now that it exists, the foundation can adapt it more quickly for other patients with the same mutation. Approximately 10 people are now receiving treatment based on Parekh's drug formulation, with the foundation covering all costs.
Expanding the Genetic Treatment Landscape
The success builds on recent advances in ALS gene therapy. The FDA has approved four ALS drugs since 1995, including Qalsody from Ionis Pharmaceuticals—the first FDA-approved ALS drug targeting a specific genetic mutation (SOD1). This treatment addresses about 2% of ALS cases, roughly 500 people in the United States.
"Our success rates are much higher if we try to tailor therapies for individuals who carry [a] particular genetic mutation," said Dr. Suma Babu, co-director of the Neurological Clinical Research Institute at Massachusetts General Hospital. Studies have shown that gene-targeting drugs can slow disease progression and even improve symptoms.
Current Limitations and Future Potential
While promising, gene-targeting therapies face significant limitations. Scientists have identified genetic mutations in only 15-20% of ALS patients, leaving approximately 80% without known genetic causes. Among the 20% of ALS cases with genetic origins, about 70% of familial cases and 10% of sporadic cases have identified mutations.
However, geneticists continue discovering new mutations linked to ALS each year. Dr. Oskarsson expects inherited genes to eventually explain more than half of all ALS diagnoses, potentially opening doors to more targeted treatments.
Long-term Outlook
Parekh receives his treatment every three months through spinal injection directly into his cerebrospinal fluid. He has now lived longer with treatment than his father survived after diagnosis, remaining active enough to play with his children and recently climb steep stairs to the Acropolis during a trip to Greece.
The durability of these effects remains uncertain. "We don't have decades of experience with it. We are hopeful that it will hold for their lifetime, but we do not know that," Oskarsson acknowledged.
Despite limitations, researchers remain optimistic about the approach's transformative potential. "If we can make this a livable disease for 300 people who are potentially in the prime ages of their lives, I think that's success," Babu said. "If we can chip away gene by gene, subtype by subtype, I think we will see successes in ALS."
