The dystrophin protein, which is a structural component of muscle fibers, is one of the largest proteins made in the human body. And the gene that produces dystrophin is the largest gene in the human genome, spanning 2.4 million base pairs on the X chromosome. Peter Eimon, director of research at Tevard and an author on the new research, says the large size of the dystrophin protein helps it act like a shock absorber in muscles. But the gene that encodes the protein is \u201ctoo big to fit into the standard vectors that are used to deliver gene therapies.\u201d That\u2019s why alternative approaches are needed instead of trying to deliver a whole functional gene.<\/p>\n
Elisabeth Gardiner, chief scientific officer at Tevard, says suppressor tRNAs are an ideal approach for the subset of individuals with DMD-causing nonsense mutations. Suppressor tRNAs \u201ccan go anywhere that a stop codon is aberrantly placed throughout the gene,\u201d she says.<\/p>\n
The new study reports the development of suppressor tRNAs that have been optimized to target UAA stop codons, which arise when a glutamine CAA is mutated. The suppressor tRNA reads UAA as glutamine and adds it to the growing dystrophin protein, instead of translation halting prematurely.<\/p>\n
The best-performing suppressor tRNAs in vitro were then validated by injecting into mice DMD models adeno-associated virus (AAV) vectors containing a gene that makes the suppressor tRNA.<\/p>\n
The most-efficient suppressor tRNAs improved the levels of full-length dystrophin to nearly 70% of wild-type levels. And functional metrics including muscle strength and motor coordination also showed improvement, with no adverse toxicity. \u201cNot only are we not seeing a negative effect, either in the liver or the muscle or the heart of these animals that have been treated with our therapy, but we’re now seeing huge benefits,\u201d Gardiner says.<\/p>\n
Bowen Li<\/a>, a biomedical engineer at the University of Toronto who works on suppressor tRNAs but wasn\u2019t involved in this research, is encouraged by the results, saying that the researchers \u201cwere able to show a broad distribution of the dystrophin in the skeletal muscles, the diaphragm, and the heart.\u201d<\/p>\n Li says broad distribution is an advantage of AAV vectors compared with lipid nanoparticles, another delivery system for suppressor tRNAs. But he also says AAV comes with disadvantages too, like greater risk of toxicity, which is why Li would like to see longer-term and more-comprehensive testing in nonhuman primates to validate the safety of the therapy. Li says he is also working on his own suppressor tRNA therapies for DMD but using non-AAV vectors.<\/p>\n Gardiner says Tevard has plans to do a lot more work to validate its therapy before moving to humans. She says the company is working to finalize the capsid it will use to deliver a suppressor tRNA in humans, do some potency trials, and complete work currently being done in nonhuman primates.<\/p>\n Ultimately, suppressor tRNA therapies have the capability to be somewhat disease agnostic, correcting nonsense mutations across genes. That\u2019s why Eimon says Tevard\u2019s goal is to develop a mature suppressor tRNA platform that the company can use to \u201cexpand to other muscular dystrophies or other therapeutic indications.\u201d<\/p>\n
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