XLMTM is caused by mutations in the MTM1 gene that lead to a lack or dysfunction of myotubularin, a protein that is needed for normal development, maturation, and function of skeletal muscle cells. Gene replacement therapy candidate AT132 utilizes an AAV8 vector to deliver a functional copy of the MTM1 gene to transfect and express myotubularin in skeletal muscle cells.
Pompe is caused by mutations in the gene that encodes the enzyme GAA, which is responsible for metabolizing glycogen within the lysosome of the cell. Dysfunction or absence of functional GAA results in toxic accumulation of lysosomal glycogen. Gene replacement therapy candidate AT845 utilizes an AAV8 vector to deliver a functional copy of the gene to transfect and express GAA directly in tissues affected by the disease.
DMD is caused by mutations in the dystrophin gene, which encodes the protein dystrophin, a structural protein involved in maintaining muscle cell integrity. AAV-antisense candidates AT702, AT751 and AT753 utilize vectorized exon skipping to induce cells to skip over faulty or misaligned sections of the genetic code, which results in the expression of a more complete, functional protein.
DM1 is caused by a mutation called a CTG trinucleotide repeat in the DMPK gene, resulting in the accumulation of toxic DMPK RNA in affected cells. AT466 is an AAV-antisense candidate, and Audentes is evaluating vectorized RNA knockdown and vectorized exon skipping to treat DM1. Both approaches are designed to prevent the accumulation of toxic DMPK RNA, thereby restoring normal cellular function.