Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy.
Loss-of-function mutations in the myotubularin gene (MTM1) cause X-linked myotubular myopathy (XLMTM), a fatal, congenital pediatric disease that affects the entire skeletal musculature. Systemic administration of a single dose of a recombinant serotype 8 adeno-associated virus (AAV8) vector expressing murine myotubularin to Mtm1-deficient knockout mice at the onset or at late stages of the disease resulted in robust improvement in motor activity and contractile force, corrected muscle pathology, and prolonged survival throughout a 6-month study. Similarly, single-dose intravascular delivery of a canine AAV8-MTM1 vector in XLMTM dogs markedly improved severe muscle weakness and respiratory impairment, and prolonged life span to more than 1 year in the absence of toxicity or a humoral or cell-mediated immune response. These results demonstrate the therapeutic efficacy of AAV-mediated gene therapy for myotubular myopathy in small- and large-animal models, and provide proof of concept for future clinical trials in XLMTM patients.
Department of Rehabilitation Medicine, School of Medicine, University of Washington, Campus Box 358056, Seattle, WA 98109, USA.
Martin K
MK
Childers
Romain
R
Joubert
Karine
K
Poulard
Christelle
C
Moal
Robert W
RW
Grange
Jonathan A
JA
Doering
Michael W
MW
Lawlor
Branden E
BE
Rider
Thibaud
T
Jamet
Nathalie
N
Danièle
Samia
S
Martin
Christel
C
Rivière
Thomas
T
Soker
Caroline
C
Hammer
Laetitia
L
Van Wittenberghe
Mandy
M
Lockard
Xuan
X
Guan
Melissa
M
Goddard
Erin
E
Mitchell
Jane
J
Barber
J Koudy
JK
Williams
David L
DL
Mack
Mark E
ME
Furth
Alban
A
Vignaud
Carole
C
Masurier
Fulvio
F
Mavilio
Philippe
P
Moullier
Alan H
AH
Beggs
Anna
A
Buj-Bello
D000818:Animals; D000229:Dependovirus / Q000235:genetics; D003964:Diaphragm; D004195:Disease Models, Animal; D004285:Dogs; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction; D018908:Muscle Weakness; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics
D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin