Intravenous Administration of a MTMR2-Encoding AAV Vector Ameliorates the Phenotype of Myotubular Myopathy in Mice. J Neuropathol Exp Neurol 2018 Apr 01;77(4):282-295
Date
02/07/2018Pubmed ID
29408998Pubmed Central ID
PMC5939852DOI
10.1093/jnen/nly002Scopus ID
2-s2.0-85045070041 (requires institutional sign-in at Scopus site) 14 CitationsAbstract
X-linked myotubular myopathy (XLMTM) is a severe congenital disorder in male infants that leads to generalized skeletal muscle weakness and is frequently associated with fatal respiratory failure. XLMTM is caused by loss-of-function mutations in the MTM1 gene, which encodes myotubularin, the founder member of a family of 15 homologous proteins in mammals. We recently demonstrated the therapeutic efficacy of intravenous delivery of rAAV vectors expressing MTM1 in animal models of myotubular myopathy. Here, we tested whether the closest homologues of MTM1, MTMR1, and MTMR2 (the latter being implicated in Charcot-Marie-Tooth neuropathy type 4B1) are functionally redundant and could represent a therapeutic target for XLMTM. Serotype 9 recombinant AAV vectors encoding either MTM1, MTMR1, or MTMR2 were injected into the tibialis anterior muscle of Mtm1-deficient knockout mice. Two weeks after vector delivery, a therapeutic effect was observed with Mtm1 and Mtmr2, but not Mtmr1; with Mtm1 being the most efficacious transgene. Furthermore, intravenous administration of a single dose of the rAAV9-Mtmr2 vector in XLMTM mice improved the motor activity and muscle strength and prolonged survival throughout a 3-month study. These results indicate that strategies aiming at increasing MTMR2 expression levels in skeletal muscle may be beneficial in the treatment of myotubular myopathy.
Author List
Danièle N, Moal C, Julien L, Marinello M, Jamet T, Martin S, Vignaud A, Lawlor MW, Buj-Bello AAuthor
Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Administration, IntravenousAnimals
Disease Models, Animal
Escape Reaction
HEK293 Cells
Humans
Locomotion
Mice
Muscle Contraction
Muscle Strength
Muscle, Skeletal
Mutation
Myopathies, Structural, Congenital
PAX7 Transcription Factor
Phenotype
Protein Tyrosine Phosphatases, Non-Receptor
RNA, Messenger
Transduction, Genetic
Transfection
