Disease rescue and increased lifespan in a model of cardiomyopathy and muscular dystrophy by combined AAV treatments.
BACKGROUND
The BIO14.6 hamster is an excellent animal model for inherited cardiomyopathy, because of its lethal and well-documented course, due to a spontaneous deletion of delta-sarcoglycan gene promoter and first exon. The muscle disease is progressive and average lifespan is 11 months, because heart slowly dilates towards heart failure.


RESULTS
Based on the ability of adeno-associated viral (AAV) vectors to transduce heart together with skeletal muscle following systemic administration, we delivered human delta-sarcoglycan cDNA into male BIO14.6 hamsters by testing different ages of injection, routes of administration and AAV serotypes. Body-wide restoration of delta-SG expression was associated with functional reconstitution of the sarcoglycan complex and with significant lowering of centralized nuclei and fibrosis in skeletal muscle. Motor ability and cardiac functions were completely rescued. However, BIO14.6 hamsters having less than 70% of fibers recovering sarcoglycan developed cardiomyopathy, even if the total rescued protein was normal. When we used serotype 2/8 in combination with serotype 2/1, lifespan was extended up to 22 months with sustained heart function improvement.


CONCLUSIONS
Our data support multiple systemic administrations of AAV as a general therapeutic strategy for clinical trials in cardiomyopathies and muscle disorders.
Vitiello
Carmen
C
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
Faraso
Stefania
S
Sorrentino
Nicolina Cristina
NC
Di Salvo
Giovanni
G
Nusco
Edoardo
E
Nigro
Gerardo
G
Cutillo
Luisa
L
Calabrò
Raffaele
R
Auricchio
Alberto
A
Nigro
Vincenzo
V