Intramuscular viral delivery of paraplegin rescues peripheral axonopathy in a model of hereditary spastic paraplegia.
Degeneration of peripheral motor axons is a common feature of several debilitating diseases including complicated forms of hereditary spastic paraplegia. One such form is caused by loss of the mitochondrial energy-dependent protease paraplegin. Paraplegin-deficient mice display a progressive degeneration in several axonal tracts, characterized by the accumulation of morphological abnormal mitochondria. We show that adenoassociated virus-mediated (AAV-mediated) intramuscular delivery of paraplegin halted the progression of neuropathological changes and rescued mitochondrial morphology in the peripheral nerves of paraplegin-deficient mice. One single injection before onset of symptoms improved the motor performance of paraplegin-deficient mice for up to 10 months, indicating that the peripheral neuropathy contributes to the clinical phenotype. This study provides a proof of principle that gene transfer may be an effective therapeutic option for patients with paraplegin deficiency and demonstrates that AAV vectors can be successfully employed for retrograde delivery of an intracellular protein to spinal motor neurons, opening new perspectives for several hereditary axonal neuropathies of the peripheral nerves.
Pirozzi
Marinella
M
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
Quattrini
Angelo
A
Andolfi
Gennaro
G
Dina
Giorgia
G
Malaguti
Maria Chiara
MC
Auricchio
Alberto
A
Rugarli
Elena I
EI
D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D000229:Dependovirus; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D008666:Metalloendopeptidases / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics* / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D010264:Paraplegia / Q000188:drug therapy / Q000235:genetics*; D010525:Peripheral Nerves / Q000187:drug effects / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism
D008666:Metalloendopeptidases; C112889:SPG7 protein, human; C491813:Spg7 protein, mouse; D000074183:ATPases Associated with Diverse Cellular Activities