It is shown that systemic delivery of these sup-tRNAs restores full-length dystrophin and recovers muscle strength and motor function in mice at lower doses than AAV microdystrophin therapies, establishing sup-tRNAs as a promising therapeutic platform for DMD and other disorders.
Abstract
Duchenne muscular dystrophy (DMD) is a fatal disorder caused by loss of dystrophin, a protein essential for muscle cell integrity. To date, no therapeutic has restored full-length dystrophin. Suppressor transfer RNAs (sup-tRNAs) have the potential to treat the ∼15% of patients with DMD and nonsense mutations. We have evolved highly potent UAA sup-tRNAs through an extensive mutagenesis screening campaign, optimized our adeno-associated virus (AAV) expression vectors, and developed efficient RNA polymerase III promoters. We show that systemic delivery of these sup-tRNAs restores full-length dystrophin and recovers muscle strength and motor function in mice at lower doses than AAV microdystrophin therapies. We see no adverse toxicology and observe proteome-wide reversion of molecular pathophysiology. These data establish sup-tRNAs as a promising therapeutic platform for DMD and other disorders.
Duchenne muscular dystrophy (DMD) is a fatal disorder caused by dystrophin mutations, leading to progressive muscle degeneration and cardiac failure. Although AAV-based DMD therapies with innovative designs to overcome the cargo limits of the virus are effective in animal models, these current systems may face clinical...
Ryan H. Hsu, Claire E. Williams, Geraldine Maier et al.· bioRxiv· 0 citations
It is suggested that even modest levels of base editing-mediated exon skipping may ameliorate the DMD cardiac phenotype toward a BMD-like state, supporting the translational potential of this dual rAAV base editing approach for DMD cardiomyopathy.
Ina Luksch, Christine M. Poch, Aylin Mayer et al.· Human Gene Therapy· 0 citations
A human skeletal muscle xenograft model is adapted, using 222 transplanted muscles from human donors, to use as a platform for AAV delivery and shows for the first time, that human muscles transplanted in immune-deficient mice are efficiently transduced by AAV vectors at following intravenous injection of the host mice...
Duchenne muscular dystrophy (DMD) remains, despite decades of careful clinical management, a relentless disease - and for a long time, medicine could only slow it down, not stop it. That may be changing. CRISPR-Cas genome editing now offers something earlier therapies could not: a route to permanent, DNA-level correcti...
Through multidisciplinary treatment and continuous scientific progress, individualized precision medicine that integrates therapies targeting secondary pathogenic pathways with dystrophin-restoration techniques can finally convert this devastating illness into a tolerable chronic ailment.
Shahjad Ansari, M. Saifi, Sarfaraz Ahmed et al.· Current pharmaceutical desig...· 0 citations
This work combined site-specific chemical modification of sup-tRNAs with cargo-tailored pulmonary lipid nanoparticle (LNP) engineering to overcome barriers and restore cystic fibrosis transmembrane conductance regulator (CFTR) expression and function.
