Research published in Molecular Therapy Nucleic Acids demonstrates broad biodistribution and controlled PMP22 silencing, supporting advancement toward human trials
COLUMBUS, Ohio--(BUSINESS WIRE)--Armatus Bio, a late-preclinical stage biotech innovator developing vectorized RNAi medicines in neuromuscular disorders, today announced the publication of foundational data in Molecular Therapy Nucleic Acids describing the safety and biodistribution impact of TVR110, a first-in-class and potential best-in-class vectorized microRNA in development for Charcot-Marie-Tooth disease type 1A (CMT1A). Developed in partnership with scientific collaborators from the Nationwide Children’s Hospital Center for Gene Therapy and the Cyprus Institute of Neurology and Genetics, the study confirmed that a single intrathecal (IT) injection of AAV9-delivered miRNA successfully reached distal Schwann cells to correct the genetic driver of CMT1A.
CMT1A is caused by a duplication of the PMP22 gene, leading to protein overproduction and progressive nerve damage. TVR110 is designed to reduce this overproduction, restoring myelin structure and motor function. In a CMT1A mouse model, a single injection of TVR110 safely lowered PMP22 mRNA protein levels and reduced disease manifestations leading to improved nerve histology, myelin structure and functional behavior. With these data, a comprehensive study was conducted in large animals to define the biodistribution of the vector as well as target engagement throughout the peripheral nerves.
"These results provide compelling evidence that AAV9 can reach distal peripheral nerve Schwann cells in large animals following a single lumbar injection, and perhaps more importantly, that our precision engineered microRNA can deliver controlled silencing of PMP22 to reduce the effects of this debilitating disease," said Scott Harper, PhD, Principal Investigator at the Nationwide Children’s Hospital Center for Gene Therapy and Chief Scientific Advisor to Armatus. "Unlike non-viral approaches requiring frequent dosing, this platform leverages AAV’s natural tropism to Schwann cells to potentially offer years of protection."
The published data describe TVR110’s potential as a durable, highly-specific therapeutic candidate. Key findings included:
Defined PMP22 target engagement in mice and NHPs informing target dose selection for human trials
- TVR110 at the target doses (6x1013 vg and 1.2x1014 vg) achieved an average of 38% knockdown of PMP22 mRNA and protein across the sciatic nerve, predicted to reduce PMP22 levels in patients to 93%, near the 100% physiological norm while avoiding the risks of over-silencing.
Effective biodistribution to distal nerves in large animals with a single IT injection
- Demonstrated for the first time that lumbar IT delivery of AAV9 achieves broad distribution across peripheral nerves, including the sciatic and femoral nerves, reaching the distal Schwann cells critical for treatment in people living with CMT1A.
Established safety and specificity
- No significant toxicities were observed, including no evidence of dorsal root ganglia (DRG) inflammation.
- High specificity, as demonstrated by RNA sequencing of ~16,000 transcripts, which confirmed PMP22 was the only gene consistently downregulated to clinically acceptable levels without excessive silencing. TVR110 also demonstrated a 25x higher binding affinity for PMP22 versus any other genomic site.
“These data establish that we can overcome the primary hurdle in CMT1A: namely achieving broad, durable therapeutic-level biodistribution across the peripheral nervous system with a single administration. By demonstrating precise, titratable silencing of PMP22 without the toxicity seen in earlier-generation approaches, TVR110 is a highly differentiated product with a clear, de-risked path toward human clinical trials,” said Rachel Salzman, DVM, Chief Executive Officer of Armatus Bio. “This is a foundational milestone not just for CMT1A, which has no approved therapies, but also supports the use of gene-silencing medicines for a range of neuromuscular disorders with defined unmet needs today.”
About CMT1A
Charcot-Marie-Tooth disease type 1A is a peripheral nerve demyelination and axon degeneration disease caused by a duplication of the PMP22 gene, which leads to the production of an abnormal amount of peripheral myelin protein 22 (PMP22). The disease affects over 150,000 people in the U.S. and EU. It typically presents in the teenage or young adult years, and leads to progressive muscle weakness and sensory loss in the extremities that often results in severe disability, pain, and loss of independence. There are currently no approved disease-modifying therapies or curative interventions for CMT1A.
About Armatus
Armatus Bio is a late-preclinical stage, privately held biotech innovator developing advanced medicines that leverage vectorized RNAi (RNA interference). Armatus’ uniquely specific, engineered microRNAs are noncoding RNAs responsible for regulating gene expression by mirroring innate cellular biogenesis processes without altering the underlying genetic make-up. The company's two lead assets are designed to target neuromuscular disorders: TVR110 for Charcot-Marie-Tooth disease type 1A (CMT1A), and ARM-201 for Facioscapulohumeral Muscular Dystrophy (FSHD), which together affect more than 225,000 people in the U.S. and European Union. In preclinical studies, these investigational drugs demonstrated robust signals of target engagement and biomarker improvement, and both are advancing toward the clinic. For more information, visit www.ArmatusBio.com.
Contacts
Media contact:
Kellie Hotz
khotz@armatusbio.com
