Tevard Biosciences Announces Publication of Preclinical Research Supporting Engineered Suppressor tRNAs for Duchenne Muscular Dystrophy

Engineered AAV-delivered suppressor tRNA therapy restored physiological levels of full-length dystrophin, improved muscle function and demonstrated favorable tolerability in preclinical model

Study published in Science Advances

Tevard Biosciences, Inc., a biotechnology company pioneering tRNA-based therapies to cure a broad range of genetic diseases, today highlighted the publication of research conducted by scientists at Tevard Biosciences, Johns Hopkins University, MIT, and the Whitehead Institute for Biomedical Research in Science Advances. The paper, entitled “Engineering suppressor tRNAs for effective treatment of Duchenne Muscular Dystrophy,” describes the development of an engineered suppressor tRNA gene therapy to treat patients with Duchenne muscular dystrophy (DMD) caused by nonsense mutations in the dystrophin gene. The paper is available https://doi.org/10.1126/sciadv.aeg3466.

Key Takeaways

• In a preclinical DMD model, engineered suppressor tRNA therapy restored physiological levels of full-length dystrophin, improved muscle strength and motor coordination, and was well tolerated.
• Engineered suppressor tRNAs targeted disease-causing nonsense mutations while leaving normal stop codons intact, demonstrating exquisite selectivity.
• By targeting nonsense mutations as a class, the platform has potential beyond DMD and other muscular dystrophies.

READ THE PAPER HERE

Duchenne muscular dystrophy (DMD) is one of the most devastating genetic diseases affecting children. DMD is caused by mutations in the dystrophin gene, which encodes a protein essential for muscle health and structural stability. There is currently no cure, and no approved therapeutic can restore full-length dystrophin protein. Developing treatments to restore dystrophin has been particularly challenging because the gene is too large for conventional gene therapy approaches. Existing therapies produce shortened versions of dystrophin or are only applicable to certain mutations, leaving a significant unmet medical need. Tevard’s suppressor tRNA (“sup-tRNA”) platform represents a critical therapeutic avenue for DMD caused by nonsense mutations, which account for 15% of DMD patients and up to 40% of other muscular dystrophies.“People living with DMD caused by a nonsense mutation urgently need therapies that go beyond today’s limitations,” said Harvey Lodish, Ph.D., Whitehead Institute Founding Member, Tevard Biosciences Co-Founder, Chair of the Scientific Advisory Board, Board Member and senior author of the paper. “These findings demonstrate the potential of suppressor tRNAs to restore physiological levels of full-length dystrophin, and support further development of this technology for patients with nonsense mutations in genes causing other muscle disorders that currently have no or limited treatment options.”The study was conducted by scientists from Tevard Biosciences, the RNA Innovation Center at Johns Hopkins University, and the Massachusetts Institute of Technology (MIT) and Whitehead Institute for Biomedical Research. Together, the team identified highly potent engineered sup-tRNAs that selectively target UAA nonsense mutations and developed an optimized AAV expression system for efficient delivery to all impacted tissues.

“These tRNAs were engineered to act on the disease-causing stop codons while leaving normal stop codons intact. That precision is the whole point. And because premature stop codons contribute to a significant share of nearly every recessive genetic disease, this approach has potential well beyond dystrophin,” said Jeff Coller, Ph.D., Tevard Co-Founder, member of the Scientific Advisory Board, and co-corresponding author of the study.Among the key findings reported in the study:Systemic administration was well tolerated and restored full-length dystrophin across multiple muscle groups, including the heart, diaphragm, and skeletal muscle, and normalized muscle fiber size in cardiac muscle in the D2.mdx mouse model.

●     Significantly improved muscle strength and motor coordination, as measured by grip strength and rotarod performance.

●     Comprehensive proteomic analysis shows proteome-wide reversal of disease-associated molecular signatures, indicating true disease modification beyond just target protein rescue.

●     Demonstrated exquisite selectivity for disease-causing nonsense mutations over native stop codons that are found at the end of all protein coding genes.

Tevard’s sup-tRNA platform is designed to overcome nonsense mutations by enabling cells to bypass premature stop codons and produce full-length, functional proteins. Because it targets nonsense mutations as a class rather than a single gene, the approach has the potential to be applicable across multiple genetic diseases caused by premature stop codons.

“We’re pleased to share these findings with the scientific community and patient advocates. The publication marks an important step in the continued development of our suppressor tRNA platform and contributes to the growing body of evidence supporting this approach,” said Daniel Fischer, Co-Founder, President and CEO of Tevard Biosciences. “We continue to build on these exciting results and have improved the technology to achieve functional rescue up to undiseased levels. We are excited about these most recent results and look forward to bringing a novel, best-in-class therapeutic to individuals with Duchenne and other muscular dystrophies.”