. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nat Neurosci. 2005 Jan;8(1):85-92. PubMed.

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  1. Scaling-up growth factor therapy for ALS

    Amyotrophic lateral sclerosis (ALS) is the most aggressive of the major adult-onset neurodegenerative disorders. Despite important progress in the understanding of ALS pathogenesis, there is still no effective therapy, and patients with this disease typically die within only three to five years after onset of the first symptoms. The last couple of years have seen exciting progress in slowing down the disease in transgenic mouse models of ALS, but prognosis for patients with motor neuron disease has not changed. This study from Belgium has investigators revisiting old concepts, which might help to bridge the "therapeutic gap" between mouse and man.

    The group of Peter Carmeliet of the University Leuven has demonstrated that chronic delivery of a specific recombinant growth factor (vascular endothelial growth factor) directly into the intraventricular space of rats with motor neuron disease significantly delays onset and slows progression of paralysis. This is the first report to show conclusively that administering recombinant growth factors can have a beneficial effect in experimental ALS.

    Like all neurons, motor neurons depend on neurotrophic factors for their sustained survival. Providing trophic support to the ailing motor neurons of ALS patients has therefore been a compelling therapeutic concept for quite a while. However, serious practical issues have hampered the successful implementation of this strategy. Several clinical trials using intramuscular injections and even intrathecal application of a range of different growth factors have been profoundly disappointing. These setbacks have left investigators struggling to figure out whether their failure was a problem of the choice of growth factor, a problem of adequate delivery, or both.

    Somewhat unexpectedly, vascular endothelial growth factor (VEGF), better known for its effects on blood vessel growth, has emerged as a powerful and rather specific promoter of motor neuron survival. This surprising insight was quickly translated into a remarkably successful therapeutic mouse trial using intramuscular injections of lentiviral gene shuttles to deliver VEGF. Together with a similar study using viral vectors to deliver insulin-like growth factor 1 (IGF-1), this approach has put the spotlight on viral delivery of therapeutically effective growth factor genes. But successful clinical implementation of viral gene therapy is fraught with important safety concerns, so the finding of the Carmeliet group should be welcome news for all those hoping to start clinical trials quickly.