Alnylam’s small RNA interference (RNAi) therapies were delivered successfully to the brain and spinal cord of a rat model, bringing promise to the treatment of neurodegenerative diseases, including Parkinson’s.
The company says it now plans to advance its pipeline of RNAi therapeutics into clinical development.
The initial results of the preclinical study were presented at the TIDES: Oligonucleotide and Peptide Therapeutics 2018 Annual Meeting that took place May 7-10 in Boston, Massachusetts, in a talk titled “Delivering on RNAi Therapeutics: Patisiran and Beyond.”
RNAi is a natural process of gene silencing that regulates gene expression through small interfering RNA (siRNA) molecules. siRNA binds to a specific messenger RNA (mRNA) — a molecule generated from DNA that guides the production of a specific protein — targeting them for destruction, ultimately preventing the production of those proteins.
Since specific siRNA molecules can be designed for any given gene and a single siRNA molecule is able to silence many target mRNAs, RNAi therapy has the potential to prevent or reverse neurodegenerative diseases caused by dominantly inherited genes, including Parkinson’s, Alzheimer’s, Huntington’s and amyotrophic lateral sclerosis (ALS).
In diseases caused by mutations in only one copy of the gene (each person has two copies of a gene, one inherited from the mother, and one from the father), a specific siRNA can target the disease-causing mRNA and leave the normal mRNA intact.
Alnylam is developing and optimizing its RNAi therapeutic platform to improve siRNA molecules’ potency, durability, tolerability, and stability in the body.
Some of Alnylam’s investigational RNAi therapies have shown promising clinical data for the treatment of genetic diseases such as acute hepatic porphyrias (a liver disease) and hereditary ATTR amyloidosis (a multi-system disease).
The company’s experience and knowledge in RNAi therapeutics, along with additional advances in its Enhanced Stabilization Chemistry (ESC) platform, have now allowed the delivery of siRNA molecules to the central nervous system (CNS) — the spinal cord and the brain — and an efficient uptake in nerve cells.
A preclinical study performed in rats showed that a single injection of 0.9 mg of two different novel siRNA conjugates into the spinal canal achieved a robust and durable reduction of their disease target mRNAs in the relevant regions of the brain and spinal cord.
The positive preclinical data motivated Alnylam to advance the central nervous system pipeline of investigational RNAi therapeutics into clinical development.
“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,” Kevin Fitzgerald, PhD, Alnylam’s senior vice president of research, said in a press release.
The company 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.