VEGF: multitasking in ALS

Abstract

Amyotrophic lateral sclerosis (ALS, often called Lou Gehrig’s disease) is a devastating disease characterized by progressive paralysis and inevitable death within 5 years of diagnosis in most patients. Unlike patients with other neurodegenerative disorders like Alzheimer or Parkinson disease, most ALS patients have minimal cognitive impairment. The disease often strikes healthy individuals in their prime, and more than 90% of ALS patients have no family history of the disease. ALS patients usually first notice muscle weakness in their extremities (limb-onset) or have difficulty in swallowing or breathing (bulbar-onset), all of which are a consequence of the preferential loss of motor neurons in the spinal cord and brainstem (Fig. 1). Once diagnosed, patients suffer knowing that there is no cure and that there are very few therapeutic options available to improve their quality of life. Indeed, since the first description of ALS by Charcot in 1869, there has only been one therapeutic approved for ALS (Riluzole, which probably acts to limit synaptic release of the neurotransmitter glutamate), and this extends survival by only a few months. Although the etiology of most cases of ALS remains unknown, the discovery that a proportion of familial ALS is caused by mutations in the ubiquitously expressed enzyme superoxide dismutase 1 (SOD1) has allowed the creation of transgenes that produce ALS-like disease in rodents—an essential tool for preclinical therapeutic development. Despite more than a decade of active research using these transgenic models, however, the pathogenic mechanisms of the disease remain elusive. In this issue, Storkebaum and colleagues1 offer impressive new evidence demonstrating that delivery of the predominant isoform of the neurotrophin, vascular endothelial growth factor (VEGF165, called VEGF here) directly into the cerebral spinal fluid (CSF) has significant therapeutic benefit in mutant SOD1 transgenic models of ALS (Fig. 1). Motor neurons require neurotrophic support during development and for postnatal maintenance. Therefore, insufficient trophic support has long been an appealing hypothesis of ALS pathogenesis—and thus the premise for many therapeutic strategies. What Storkebaum et al.1 have now done is to stereotactically position a catheter, connected to a tiny osmotic pump (implanted under the skin) containing purified recombinant VEGF protein, into the lateral ventricle of rats expressing a familial ALS-causing transgene encoding mutant SOD1G93A. The authors convincingly demonstrate that not only does biologically active VEGF protein perfuse throughout brain regions adjacent to the delivery site, but it also is distributed (presumably via natural CSF flow) to the brainstem and cervical spinal cord, with lower levels in thoracic and lumbar cords. Most importantly, SOD1 mutant animals receiving this intracerebroventricular (i.c.v.) treatment remained spontaneously active at an older age compared to untreated symptomatic animals. When animals were treated at day 60, before the development of symptoms, VEGF delayed the onset of paralysis and extended survival for 22 days without the serious side effects associated with systemic VEGF treatment, namely edema, vascular growth and leakage and immunogenic response. VEGF treatment, when started at the onset of paralysis, improved survival by 10 days. Analysis of ventral motor roots, the axonal projections of motor neurons in the spinal cord, confirmed the positive benefit of VEGF i.c.v treatment. Although VEGF had previously been shown to be effective when delivered intraperitoneally2 or through indirect delivery of a VEGF gene (using pseudocoated lentivirus) to motor neurons using intramuscular injections3, this is the first effective demonstration of a therapy for mutant SOD1-mediated ALS through direct delivery of a recombinant protein into the nervous system. The authors also demonstrate that i.c.v. delivery of VEGF—and thus elevated local concentrations of the growth factor—provided the most significant protection to cervical motor neurons. The prolonged survival of this subset of motor neurons is of considerable interest because they are critically required for respiration and thus are generally those lost in the final stages of human disease. To do this, the authors exploited a phenotypic variation in this SOD1G93A rat line in which, in a proportion of

DOI: 10.1038/nn0105-5

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@article{Velde2005VEGFMI, title={VEGF: multitasking in ALS}, author={Christine Vande Velde and Don W Cleveland}, journal={Nature Neuroscience}, year={2005}, volume={8}, pages={5-7} }