Alnylam Testing New Molecular Therapy Candidates for ALS, Other Neurodegenerative Diseases

Newly developed molecular treatment candidates called small interfering RNAs (siRNAs) have been successfully delivered to the brain and spinal cord in a rat preclinical study, Alnylam Pharmaceuticals recently announced.

According to the company, the development of siRNAs may lead to the prevention or treatment of diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s, Parkinson’s, and Huntington’s.

Alnylam is now planning to advance a pipeline of these investigational therapeutics into clinical development. It expects to select its first central nervous system-targeted candidate in 2018 and to file its first investigational new drug application in late 2019 or early 2020.

The siRNA molecules mediate RNA interference (RNAi), a natural process that regulates gene expression. Specifically, siRNAs silence messenger RNAs (mRNAs), which are generated from DNA and contain the genetic information to produce proteins. A single siRNA molecule is able to silence a large number of selected mRNAs. According to Alnylam, this approach functions upstream of current medications.

“Over the past 15 years, Alnylam has advanced conjugate-based delivery of investigational RNAi therapeutics with multiple transformative discoveries, paving the way for development of a whole new class of innovative medicines,” Kevin Fitzgerald, PhD, Alnylam’s senior vice president of research, said in a press release.

“Initial efforts are focused on genetically validated CNS targets, use of biomarkers for initial proof-of-concept, and disease settings with high unmet need and a definable path to regulatory approval and patient access,” he said.

Fitzgerald also said that the company’s initial development of siRNAs for liver disease targets set a strong foundation for the development of RNAi therapeutics targeting the brain and spinal cord.

Initial results from the preclinical work in rats were presented at the TIDES: Oligonucleotide and Peptide Therapeutics 2018 Annual Meeting, taking place through May 10 in Boston. Alnylam’s presentation, “Delivering on RNAi Therapeutics: Patisiran and Beyond,” showed that a single injection of a novel siRNA into the spinal canal led to broad distribution across the brain and spinal cord.

The data also demonstrated sustained and specific mRNA silencing of a disease target in all relevant central nervous system regions. According to the company, the innovative siRNA molecules use Alnylam’s chemistry platform with additional changes to allow for broad central nervous system delivery and efficient uptake in neurons.

Besides these investigational RNAi treatments, Alnylam is developing siRNA therapeutics for various diseases such as familial amyloid polyneuropathy, hemophilia, hypercholesteremia, and complement-mediated diseases.