245. Delivery of IGF-1 in the Spinal Cord of a Mouse Model of ALS after Intraparenchymal Injection of an Adeno-Associated Vector
Authors: Christine Haenggeli, Angelo C. Lepore, Natalie Perez, Brian K. Kaspar, Jeffrey D. Rothstein
Journal: Molecular Therapy (2006)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease arising from a progressive loss of motor neurons in the motor cortex, brainstem and spinal cord, leading to atrophy of limb, axial and respiratory muscles. The cause of motor neuron degeneration remains largely unknown and to date there is no potent therapy. Some familial cases of ALS are caused by dominant mutations in the gene encoding superoxide dismutase (SOD1). Overexpression of SOD1 gene mutations in mice and rats recapitulates the clinical and pathological characteristics of ALS and therefore constitute useful models of ALS to screen therapeutical approaches. The potent neuroprotective activities of neurotrophic factors, such as Insulin-growth factor (IGF-1), make them promising candidates in the treatment of ALS. These compounds, however, to show any level of efficacy, must be continuously delivered and must be directly targeted to the affected cells to avoid undesirable side effects.Adeno-associated virus (AAV) vectors are attractive viral vectors as they mediate long-term stable expression in post-mitotic cells, such as muscle and neurons, with inducing minimal immune responses. Recently we have used AAV2 to retrogradelly deliver IGF-1 to spinal cord motor neurons. Intramuscular injection of AAV- IGF-1 in a transgenic SOD1 mouse significantly delayed disease progression. As this approach proved to be efficient in this paradigm, it might not be always the case. Indeed, the limitation of injecting viral vectors intramuscularly resides that only a small percentage of motor neurons get transduced. To achieve a higher rate of neuronal transduction and increased levels of gene expression, we injected viral vectors directly into the spinal cord. Preliminary experiments using AAV2-eGFP showed robust and broad eGFP expression in neurons beyond the injection site. We are in the process of evaluating the effects of intraparenchymal injections of AAV2-IGF-1 in ALS mutant mice. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease arising from a progressive loss of motor neurons in the motor cortex, brainstem and spinal cord, leading to atrophy of limb, axial and respiratory muscles. The cause of motor neuron degeneration remains largely unknown and to date there is no potent therapy. Some familial cases of ALS are caused by dominant mutations in the gene encoding superoxide dismutase (SOD1). Overexpression of SOD1 gene mutations in mice and rats recapitulates the clinical and pathological characteristics of ALS and therefore constitute useful models of ALS to screen therapeutical approaches. The potent neuroprotective activities of neurotrophic factors, such as Insulin-growth factor (IGF-1), make them promising candidates in the treatment of ALS. These compounds, however, to show any level of efficacy, must be continuously delivered and must be directly targeted to the affected cells to avoid undesirable side effects. Adeno-associated virus (AAV) vectors are attractive viral vectors as they mediate long-term stable expression in post-mitotic cells, such as muscle and neurons, with inducing minimal immune responses. Recently we have used AAV2 to retrogradelly deliver IGF-1 to spinal cord motor neurons. Intramuscular injection of AAV- IGF-1 in a transgenic SOD1 mouse significantly delayed disease progression. As this approach proved to be efficient in this paradigm, it might not be always the case. Indeed, the limitation of injecting viral vectors intramuscularly resides that only a small percentage of motor neurons get transduced. To achieve a higher rate of neuronal transduction and increased levels of gene expression, we injected viral vectors directly into the spinal cord. Preliminary experiments using AAV2-eGFP showed robust and broad eGFP expression in neurons beyond the injection site. We are in the process of evaluating the effects of intraparenchymal injections of AAV2-IGF-1 in ALS mutant mice.