VEGF & AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is characterized by a progressive degeneration of spinal cord and cerebral cortex motor neurons, leading to muscular atrophy, paralysis, respiratory failure, and death. While ALS is relatively rare, it is particularly devastating as patients typically succumb within 3 to 5 years of diagnosis. Further, there is currently no cure, very little to offer in the way of treatment, and relatively few clues as to its etiology.¹

Over the past several years, hypotheses regarding the pathology of ALS have focused on oxidative damage, protein aggregation, neurofilament disorganization, and excitotoxicity.¹ However, surprising evidence emerged three years ago from an unlikely source and has enticed some investigators to examine a different possibility. Researchers investigating VEGF-stimulated angiogenesis have found that homozygous vegf gene 'knock-in' (VEGF^d/d) mice, in which the hypoxia-response element of the promoter is disrupted, display reduced brain and spinal cord VEGF protein levels and develop unexpected symptoms that strongly resemble ALS.² In light of other evidence supporting a role for VEGF in neuroprotective mechanisms,³ these data implicate a failure of VEGF neuroprotection in the molecular pathology of ALS.

Since this initial finding, additional data supporting a role for VEGF in ALS have been presented. Individuals homozygous for a variety of mutations in the VEGF promotor region, resulting in lower VEGF protein expression, are at almost two times greater risk for developing ALS.⁴ Baseline VEGF levels in human cerebral spinal fluid are reduced in ALS patients compared to controls.⁵ Further, SOD1^G93A/VEGF^&detla;/d double mutant mice, in which both the Cu/Zn superoxide dismutase associated with human familial ALS and VEGF are dysfunctional or dysregulated, display more severe symptoms and decreased life expectancy.⁴

As a result of these developments, enthusiasm for the potential of VEGF as a therapeutic target Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is characterized by a progressive degeneration of spinal cord and cerebral cortex motor neurons, leading to muscular atrophy, paralysis, respiratory failure, and death. While ALS is relatively rare, it is particularly devastating as patients typically succumb within 3 to 5 years of diagnosis. Further, there is currently no cure, very little to offer in the way of treatment, and relatively few clues as to its etiology.¹

Over the past several years, hypotheses regarding the pathology of ALS have focused on oxidative damage, protein aggregation, neurofilament disorganization, and excitotoxicity.¹ However, surprising evidence emerged three years ago from an unlikely source and has enticed some investigators to examine a different possibility. Researchers investigating VEGF-stimulated angiogenesis have found that homozygous vegf gene 'knock-in' (VEGF^&detla;/d) mice, in which the hypoxia-response element of the promoter is disrupted, display reduced brain and spinal cord VEGF protein levels and develop unexpected symptoms that strongly resemble ALS.² In light of other evidence supporting a role for VEGF in neuroprotective mechanisms,³ these data implicate a failure of VEGF neuroprotection in the molecular pathology of ALS.

Since this initial finding, additional data supporting a role for VEGF in ALS have been presented. Individuals homozygous for a variety of mutations in the VEGF promotor region, resulting in lower VEGF protein expression, are at almost two times greater risk for developing ALS.⁴ Baseline VEGF levels in human cerebral spinal fluid are reduced in ALS patients compared to controls.⁵ Further, SOD1G93A/VEGF^d/d double mutant mice, in which both the Cu/Zn superoxide dismutase associated with human familial ALS and VEGF are dysfunctional or dysregulated, display more severe symptoms and decreased life expectancy.⁴

Figure 1. EIAV lentiviral vector delivery of the human VEGF gene to the gastrocnemius muscle of an ALS-like SOD1G93A-mutant mouse elicits stable expression of VEGF in the spinal cord, thereby preventing motor neuron death, delaying disease onset, reducing motor dysfunction, and increasing life expectancy.

As a result of these developments, enthusiasm for the potential of VEGF as a therapeutic target for ALS has been mounting. The first attempt at VEGF gene therapy in the SOD1^G93A ALS-like mouse model appears to be successful and may represent a long-awaited step forward for ALS research.⁶ Azzouz et al. found that single intramuscular injections of lentiviral vector carrying vegf are capable of elevating spinal cord VEGF levels, increasing motor neuron survival, delaying disease onset, decreasing motor dysfunction, and prolonging life (Figure 1). This was possible even when injections were given after mice began displaying ALS-like symptoms. While these findings are clearly remarkable, excitement for the arrival of approved human therapies must be tempered by the understanding that there is still very little known about the etiology of ALS much less the details of its molecular mechanisms and how these relate to mouse models of the disease.

References

1. Bruijn, L.I. et al. (2004) Annu. Rev. Neurosci. 27:723.
2. Oosthuyse, B. et al. (2001) Nat. Genet. 28:131.
3. Rosenstein, J.M. & J.M. Krum (2004) Exp. Neurol. 187:246.
4. Lambrechts, D. et al. (2003) Nat. Genet. 34:383.
5. Devos, D. et al. (2004) Neurology 62:2127.
6. Azzouz, M. et al. (2004) Nature 429:413.