Perhaps the most promising treatment for ALS so far -- This presentation was given yesterday at the Society for Neuroscience 2004 in San Diego. Phase I Trials in Humans are slated for 1 or 2Q 2005 at Johns Hopkins and (possibly) Mass General.


B.K.Kaspar1*; J.L.Vich2; L.Christian1; L.Frost1; J.D.Rothstein2; F.H.Gage1
1. Salk Inst., La Jolla, CA, USA
2. Johns Hopkins Univ., Baltimore, MD, USA
Chronic delivery of molecules to the CNS, such as the spinal cord, for therapeutic purposes has proven difficult. We recently discovered that adeno-associated virus (AAV) can be retrogradely transported efficiently from muscle to motor neurons of the spinal cord allowing a feasible approach to deliver therapies to motor neurons. We have now characterized the extent of retrograde transport of the different AAV serotypes including AAV 1-6. All serotypes demonstrate retrograde transport ability with serotypes 1, 2, and 6 showing the highest levels of transport.

We utilized the transport properties of AAV-2 to deliver neurotrophic factor genes to muscles in a transgenic mouse model of Amyotrophic Lateral Sclerosis (ALS) and showed significant retrograde transport and expression in the spinal cord. Delivery of AAV-IGF-1 (Insulin-like growth factor-1) remarkably slowed the onset of disease progression and increased survival over 30 days in comparison to control, AAV-GFP treated animals. Furthermore, IGF-1 delayed the motor decline assessed by motor performance tasks. Recent dose-response studies have shown a dose-dependence for therapeutic benefit, with at least 4x10e9 viral particles/animal delivered for efficacy. In addition, we show the therapeutic benefits of IGF-1 toward motor neurons are mediated in part, by disrupting the apoptotic cascade.

Furthermore, we have recently shown that a combination of IGF-1 gene delivery and exercise has profound effects on survival and function, indicative of synergistic effects with exercise and IGF-1, in which animals live nearly twice as long. We have elucidated several molecular mechanisms that may result in the synergistic response.

This work provides a novel targeting approach for neurotrophic factor delivery by AAV mediated gene therapy in the development of therapeutics towards neurological disorders and demonstrates the beneficial effects of exercise in the nervous system.
Citation:B.K. Kaspar, J.L. Vich, L. Christian, L. Frost, J.D. Rothstein, F.H. Gage. VIRAL VECTORS AND EXERCISE FOR THERAPY IN ALS Program No. 134.3. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004. Online.
2004 Copyright by the Society for Neuroscience all rights reserved.