Dicerna’s GalXC-Plus™ RNAi Technology Delivers Target Knockdown Across CNS and to Specific CNS Cell Types in Preclinical Studies
Mar 30, 2021
“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
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
About RNAi and Dicerna’s GalXC RNAi Platform Technologies
Ribonucleic acid interference, or RNAi, provides a unique advantage to other disease inhibitor technologies, like small-molecule pharmaceuticals or monoclonal antibodies: instead of targeting proteins after they have been produced and released, RNAi silences the genes themselves via the targeted destruction of the messenger RNA (mRNA) made from the gene. Rather than seeking to inhibit a protein directly, the RNAi approach can prevent a disease-causing protein’s creation, directly impacting disease manifestation.
Dicerna’s proprietary GalXC™ RNAi platform aims to advance the development of next-generation RNAi-based therapies. Investigational therapeutics developed using our flagship GalXC technology utilize a proprietary N-acetyl-D-galactosamine (GalNAc)-mediated structure of double-stranded RNA molecules that are designed to bind specifically to receptors on liver cells, leading to selective hepatocyte internalization and access to the RNAi machinery within the cells. Dicerna is continuously innovating and exploring new applications for RNAi technology beyond GalNAc-mediated delivery to the liver, including alternative RNA structures and fully synthetic ligands that target other tissues and enable new therapeutic applications, referred to as GalXC-Plus™.
Cautionary Note on Forward-Looking Statements
This press release includes forward-looking statements pertaining to the Company’s GalXC-Plus technology and its clinical or commercial potentials, other discovery and development data presented at the
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