title: IGF-1 delivery to CNS attenuates motor neuron cell death but does not improve motor function in type III SMA mice.
abstract: The efficacy of administering a recombinant adeno-associated virus (AAV) vector encoding human IGF-1 (AAV2/1-hIGF-1) into the deep cerebellar nucleus (DCN) of a type III SMA mouse model was evaluated. High levels of IGF-1 transcripts and protein were detected in the spinal cord at 2 months post-injection demonstrating that axonal connections between the cerebellum and spinal cord were able to act as conduits for the viral vector and protein to the spinal cord. Mice treated with AAV2/1-hIGF-1 and analyzed 8 months later showed changes in endogenous Bax and Bcl-xl levels in spinal cord motor neurons that were consistent with IGF-1-mediated anti-apoptotic effects on motor neurons. However, although AAV2/1-hIGF-1 treatment reduced the extent of motor neuron cell death, the majority of rescued motor neurons were non-functional, as they lacked axons that innervated the muscles. Furthermore, treated SMA mice exhibited abnormal muscle fibers, aberrant neuromuscular junction structure, and impaired performance on motor function tests. These data indicate that although CNS-directed expression of IGF-1 could reduce motor neuron cell death, this did not translate to improvements in motor function in an adult mouse model of type III SMA.
authors: Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan. milikai@ntuh.gov.tw
authors: Li-Kai
authors: LK
authors: Tsai
authors: Yi-Chun
authors: YC
authors: Chen
authors: Wei-Cheng
authors: WC
authors: Cheng
authors: Chen-Hung
authors: CH
authors: Ting
authors: James C
authors: JC
authors: Dodge
authors: Wuh-Liang
authors: WL
authors: Hwu
authors: Seng H
authors: SH
authors: Cheng
authors: Marco A
authors: MA
authors: Passini
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D015316:Genetic Therapy; D005822:Genetic Vectors; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
chemical_list: D007334:Insulin-Like Growth Factor I