Dicerna’s GalXC-Plus™ RNAi Technology Delivers Target Knockdown Across CNS and to Specific CNS Cell Types in Preclinical Studies
LEXINGTON, Mass -- Dicerna Pharmaceuticals, Inc. (Nasdaq: DRNA) (the “Company” or “Dicerna”), a leading developer of investigational ribonucleic acid interference (RNAi) therapeutics, today announced new data from preclinical studies of its GalXC-Plus™ RNAi technology demonstrating its potential to deliver deep and sustained messenger RNA (mRNA) knockdown against prespecified gene targets across the central nervous system (CNS) and to specific CNS cell types. By interfering with mRNA of a target gene, Dicerna’s proprietary GalXC-Plus RNAi technology is designed to silence disease-causing genes across multiple therapeutic areas and expands on the functionality and application of the Company’s flagship liver-targeted GalXC™ RNAi technology.
“The results from these preclinical applications of our GalXC-Plus technology demonstrate its flexibility and clear ability to target mRNA knockdown across the CNS as well as to specific, specialized cells within the CNS,” said Bob D. Brown, Ph.D., Chief Scientific Officer and Executive Vice President of Research and Development at Dicerna. “The depth and distribution across the brain and spinal cord in each of these trials reinforce the degrees of saturation and specificity that customizable GalXC-Plus structures can deliver to multiple CNS cell types. We are excited about the potential broad applicability of Dicerna’s GalXC-Plus technology to treat a broad range of CNS and other diseases.”
Data from a preclinical mouse study showed that a single dose of an unconjugated GalXC-Plus molecule engineered to silence mRNA produced by the ALDH2 gene, a widely occurring and common genetic test target, resulted in dose-dependent reductions of up to 92% knockdown in target mRNA across the CNS that lasted through the trial conclusion at 28 days. GalXC-Plus delivered similar mRNA reductions in non-human primate (NHP) studies after a single dose, resulting in up to 90% target mRNA silencing after 28 days. There were no adverse observations for any GalXC-Plus cohort in these trials.
Additional preclinical data demonstrated the degree and distribution of GalXC-Plus silencing of β-tubulin III (TUBB3 gene; expressed in neurons and associated with various cancers) and two undisclosed gene targets expressed by astrocytes and oligodendrocytes, respectively, using unconjugated and various conjugated GalXC-Plus payloads.
- Oligodendrocytes: There was a clear reduction of target mRNA in oligodendrocytes across the brain and spinal cord of rodents following a single, lumbar intrathecal or intracisternal GalXC-Plus dose with up to 80% target mRNA silencing after seven days. In NHPs, there was a clear dose-related relationship between GalXC-Plus intracisternal administration and target mRNA reduction with up to 85% target mRNA reduction maintained for approximately three months. There were no adverse observations for any GalXC-Plus cohort in these trials.
- Astrocytes: GalXC-Plus demonstrated a clear reduction in target mRNA in mouse astrocytes after a single lumbar intrathecal injection. An ongoing preclinical study also shows durable control of target mRNA expression, with up to 80% target mRNA reduction maintained for at least 160 days. The durability in rodents was independent of the initial magnitude of target knockdown.
- Neurons: The flexibility of the GalXC-Plus technology enabled additional conjugations to optimize delivery to neuronal cells, resulting in clear, CNS-wide reductions (up to 95%) in neuronal-specific Tubb3 mRNA after a single lumbar intrathecal dose in mice. Comparisons of target knockdown potency across astrocyte and neuronal cells using multiple GalXC-Plus conjugate modifications indicated the potential for complementary and tunable knockdown across multiple CNS cell types.
The data were presented as part of the sixth annual Oligonucleotide and Precision Therapeutics (OPT) Virtual Congress. “GalXC-Plus: Cell-Type Targeted Therapeutic Oligonucleotide Delivery in the CNS,” was presented by Maire Osborn, Ph.D., Associate Director of Neuro Discovery at Dicerna. The slide presentation will be made available on the Events & Presentations page of Dicerna’s corporate website.