Acamprosate, prescribed for alcohol use disorder, demonstrated a neuroprotective effect in cell studies
Repeat expansions in the C9orf72 gene are the most common genetic cause of ALS and FTD, accounting for 1 in 10 cases of these neurodegenerative diseases among people of European descent. Many carriers of the genetic variant will develop symptoms of ALS or FTD during their lifetime. The exact processes by which this repeat expansion leads to neuronal death are not fully understood, making it difficult to develop treatments. A research team led by Bryan J. Traynor, M.D., Ph.D., of the National Institute on Aging, with support from colleagues at the National Institute of Neurological Disorders and Stroke (NINDS), analyzed a large genomic dataset to identify existing medications that could potentially be repurposed to treat patients carrying C9orf72 repeat expansions.
The team assessed genetic data from 1,516 C9orf72 carriers and 41,273 ALS patients/healthy controls to identify the genetic variants influencing age at onset among patients carrying the C9orf72 repeat expansion. Age at symptom onset ranges widely with this mutation, providing a natural experiment within the population. They then leveraged gene-pattern and expression-pattern matching and pathway modeling to identify drugs that could potentially be repurposed to treat C9orf72-related ALS/FTD.
Their pipeline identified acamprosate, an oral medication used to manage alcohol use disorder, as a potential repurposable drug for slowing progression among symptomatic individuals and delaying disease onset among C9orf72 carriers. Further experiments validated a neuroprotective effect of acamprosate in motor neurons derived from these patients. In this model of cultured cells in a dish, acamprosate was shown to be at least as effective in reducing cell death as riluzole, the most widely prescribed drug for ALS. Tests of acamprosate, alone or in combination with riluzole, exceeded the neuroprotective properties of riluzole by 30% in the cell-based model. These findings were published in Cell Genomics.
The study authors note that molecular complexity underlying neurodegenerative diseases hampers drug discovery. Using genomic and transcriptomic data offers a potential solution, as these data types capture the multifaceted nature of neurological diseases. The computation pipeline was made publicly available so that other researchers could apply it to their particular neurological disease of interest. Importantly, this work highlights the potential value of genomics in repurposing drugs in situations where the underlying disease mechanisms are inherently complex. It is not clear at present whether acamprosate produces clinical benefit or is safe in people with ALS. A clinical trial of acamprosate in patients with ALS due to the C9orf72 repeat expansion is being planned for the NIH Clinical Center to help answer this question.
Article:
Saez-Atienzar S, et al. Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data. Cell Genomics. Oct 21, 2024.