RNA therapy shows encouraging results in CMT1A animal tests
Safety, efficacy measures show promise for TVR110
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TVR110, an experimental RNA therapy designed to treat Charcot-Marie-Tooth disease type 1A (CMT1A), showed promising signs of efficacy and an encouraging safety profile in tests done in animals, a study reported.
The preclinical work was funded by Armatus Bio, the company developing TVR110. Scientists at Armatus conducted the lab studies alongside researchers at other institutions.
Rachel Salzman, CEO of Armatus and the study’s co-author, said in a company press release that the study “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.”
The study, “Safety, efficacy, and distal nerve Schwann cell biodistribution in mice and NHPs to support translation of AAV9 RNAi therapy for CMT1A,” was published in Molecular Therapy Nucleic Acids.
Treatment targets gene activity
CMT1A is caused by a duplication of the PMP22 gene, resulting in too much PMP22 protein. Excess levels of this protein disrupt Schwann cell function, specialized cells that produce myelin, a fatty substance that wraps around nerve fibers to protect them and help them transmit electrical signals. This leads to problems in the peripheral nervous system (the nerves that run through the body outside the brain and spinal cord), ultimately resulting in CMT symptoms such as movement problems and abnormal sensations.
TVR110 is designed to reduce the activity of the PMP22 gene, lowering levels of PMP22 protein. The experimental therapy uses a so-called microRNA, which is designed to destroy intermediary molecules required for making PMP22 protein from the gene.
This microRNA is delivered with a viral vector, a virus that’s been engineered to deliver a therapeutic gene instead of causing infection. The virus used to make this vector, called adeno-associated virus (AAV), serves as a platform for several gene therapies approved for other diseases.
This platform “leverages AAV’s natural tropism to Schwann cells to potentially offer years of protection,” said Scott Harper, PhD, senior author of the study and chief scientific advisor to Armatus. Tropism refers to the ability of a virus to easily target a particular type of cell.
In a 2022 study, scientists published proof-of-concept data showing that TVR110 treatment reduced PMP22 protein levels in a mouse model of CMT1A. Building on those results, the researchers ran a detailed battery of preclinical tests to characterize the experimental therapy’s safety profile and determine the optimal dose for human testing. These tests included further studies in mice and cell models, as well as tests using monkeys.
No significant toxicities were reported, and detailed analyses of human cells indicated that TVR110 effectively targeted the PMP22 gene without substantially affecting the activity of other genes. The researchers also identified optimal doses that, in humans, are predicted to reduce protein levels to about 93% (near normal, which would be 100%).
One of the biggest questions the study needed to address was biodistribution — that is, how well the therapy moved through the body to Schwann cells. This is a major issue because TVR110 is designed to be delivered by injection into the spinal canal, then to travel to Schwann cells in the peripheral nervous system.
“Although intrathecal gene therapy has been previously tested in humans, no one had yet assessed the ability of an AAV9 vector to transduce Schwann cells of the longest distal nerves in humans,” the scientists wrote. “This is a critical question for translation of this approach, because if the vector cannot reach and transduce Schwann cells of the distal nerves, the therapy will simply not work.”
The researchers’ experiments in nonhuman primates indicated that TVR110 effectively targets distant Schwann cells, supporting the potential of the therapy in large animals such as humans.
“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 Harper, a principal investigator at the Nationwide Children’s Hospital Center in Columbus, Ohio.
Salzman said the 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,” Salzman said.
