Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a fatal, rapidly progressive neurodegenerative disorder characterized by weakness, muscle atrophy and spasticity due to the selective loss of both upper and lower motor neurons. ALS is the most common motor neuron disease, affecting more than 86,000 people worldwide, and with an average life expectancy of 3 to 5 years from onset. There is currently no cure for ALS, while most treatments, such as Sanofi-Aventis’s Rilutek (riluzole), only succeed in prolonging life by a moderate extent. Hence, given the great unmet need, novel treatments with improved efficacy are needed.
An important recent discovery may greatly aid the search towards a cure for ALS. Backed by funding from the ALS Therapy Alliance and CVS/Pharmacy, research led by Dr. Wim Robberecht found that suppression of EphA4, a gene involved in controlling output of motor nerve terminals, significantly extended the lifespan in worm and mouse models of ALS. Subsequently, investigators at the University of Massachusetts documented that rare defects in the same gene also promoted significant survival in human ALS patients, whereas Profilin-1 (PFN1), another gene within the same pathway as EphA4, was identified as an additional modulator of survival in ALS. Collectively, these findings highlight the potential for future ALS treatments involving the suppression of target genes such as EphA4.
The development of new treatments for ALS that fall under suppression therapy could be feasible based on previous research on other diseases. For example, scientists at the Israel Institute of Technology have developed and are testing compounds with the potential to treat genetic diseases such as cystic fibrosis, Usher syndrome and Rett syndrome. Based on the pre-clinical findings, aminoglycosides, which are clinically available antibiotic amine-modified sugars, have demonstrated efficacy in suppressing nonsense mutations in genes that account for more than 1800 human diseases. More recently, Alnylam Pharmaceuticals, a leading RNAi therapeutics company has also published promising pre-clinical results in Huntington’s disease, where small interfering RNA (siRNA) was able to target the causal Huntington gene and significantly silence the expression of mutant huntingtin mRNA throughout the striatum. To date, there are approximately 20 siRNA agents that have reached the clinical trials stage for different conditions, including Age-Related Macular Degeneration (AMD). Taken together, this provides initial proof of principle that suppression therapy could be a viable option for future ALS treatment. Indeed, RXi Pharmaceuticals Corporation has already taken the initiative and is at the product discovery phrase with their RNAi-based therapeutics for ALS.
In addition to the need to provide significant clinical improvements over current options, drug delivery methods for gene suppression therapy would also require careful consideration. Researchers at the University of Illinois are currently investigating the delivery of gene-suppressing medication using nanoparticles that can be administered transdermally. If successful, this would surely be an attractive proposition for patients who are unable to tolerate more invasive delivery channels such as intravenous injection.
Overall, genes such as EphA4 could be valuable targets for gene suppression therapy in ALS, and potentially provide much needed future treatment for this devastating and fatal disease.
Date: September 5, 2012