Viral VEGF Treats Mouse ALS

Currently, there are no cures for amyotrophic lateral sclerosis (ALS), the late-onset neurodegenerative disease that claims most victims within three to five years of onset. But among the potential cures, gene therapy looks fairly attractive. Last year, Fred Gage and colleagues at The Salk Institute for Biological Studies, La Jolla, and Johns Hopkins University, Baltimore, slowed down ALS in mice by transfecting neurons with viruses expressing insulin-like growth factor (see ARF related news story). In last week’s Nature, Nicholas Mazarakis and colleagues at Oxford BioMedica, England, and Flanders Interuniversity, Leuven, Belgium, report that doing the same with vascular endothelial growth factor (VEGF) also delays onset of disease and extends lifespan.

The present collaboration grew out of earlier research by Peter Carmeliet’s lab implicating VEGF in ALS (see ARF related news story, Lambrechts et al., 2003), and efforts by Mazarakis to design viral vectors that are retrogradely transported inside neurons and can thus be injected into peripheral muscles (see Mazarakis section in ARF related news story). It also highlights a renewed trend in academia and industry of trying to exploit growth factors to treat neurodegenerative diseases.

First author Mimoun Azzouz and colleagues tested their therapy in a mouse model of ALS. The mice they used have a point mutation in the gene for superoxide dismutase 1 (SOD1). The authors tested their chosen retrovirus, the rabies-G pseudotyped equine infectious anaemia virus (EIAV), by engineering it with the traceable reporter gene, LacZ. Azzouz found that injecting a billion particles of virus into the leg and facial muscles of the mice led to expression of LacZ throughout the CNS motor neurons, indicating that the virus was distributed by retrograde transport back up the axons of motor neurons.

Next, Azzouz tested viruses expressing VEGF. When injected into SOD1 mutant animals at three weeks, before onset of symptoms, the first signs of disease were delayed until about day 128, whereas in control animals disease onset occurred at around day 93. The viral therapy also increased the mice’s lifespan by an average of 38 days, or 30 percent.

Any future treatment for humans, of course, would begin at disease onset. To simulate this the authors injected virus at 90 days, the average time of disease onset in mice. Under this regimen, lifespan increased from 127 days to 146. The authors also found that VEGF therapy increased the number of viable motor neurons by up to 44 percent. It is not yet known whether these data would translate into a slowing of disease progression and increased survival in humans. The treated mice performed better and longer at a variety of motor skills, Azzouz and colleagues found, raising hopes for functional improvements in human trials, as well.

“We believe that this approach may have potential as a safe and practical treatment for many of the motor symptoms of human ALS,” write the authors. For caution, it is worth noting, however, that despite the successes of IGF therapy in mice, human trials did not deliver a statistically significant improvement. This may be partly due to a weak delivery system (see Mitchell et al., 2002). Moreover, recent evidence has shown that when SOD is mutated only in glia, the disease progresses apace (see ARF related news story).—Tom Fagan

Comments

  1. This article provides further evidence of the promise of gene therapy to treat amyotrophic lateral sclerosis. In this work, Azzouz and colleagues utilized the ability of a lentivirus for remote delivery of a therapy to target the spinal cord, an area of the nervous system that has been difficult to target with standard drug therapies. This further supports the utility of retrograde viral gene delivery.

    This work stems from a recent article showing that mice in which VEGF (vascular endothelial growth factor) levels were reduced by stress conditions developed ALS-like neuropathology. This suggested that VEGF might be a useful molecule to treat ALS, given evidence on VEGF’s ability to promote vascularization as well as neuroprotection.

    Azzouz et al. used a lentivirus capable of retrograde transport that encoded the VEGF gene and they delivered this virus to different muscles of the SOD 1 mouse model of ALS. The results were quite dramatic: VEGF gene therapy slowed neurodegeneration of motor neurons and delayed the decline of motor function even when administered at the time of overt disease symptoms. These results are quite similar to those obtained using a similar approach for retrograde gene delivery of insulin-like growth factor-1 (IGF-1) in the same ALS animal model (Kaspar et al., 2003), suggesting that delivery of trophic or neuroprotective factors is a viable approach for the treatment of ALS.

    Indeed, these results are encouraging for clinical development. The EIAV vectors utilized for gene therapy have shown tremendous promise in preclinical studies. However, these particular vectors are in the earliest stages of development for the clinic. Clinical studies will require an assessment of safety in expanded animal studies and eventually patients. Nonetheless, this study provides additional evidence of the progress being made toward applying gene therapy research to the treatment of ALS and other neurodegenerative disorders.

    References:

    Kaspar BK, Lladó J, Sherkat N, Rothstein JD, Gage FH. Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science. 2003 Aug 8;301(5634):839-42. PubMed.

    View all comments by Fred Gage

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References

News Citations

  1. Repairing Damaged Tissues—Viruses Get into the Akt
  2. New Gene Suspect for ALS
  3. Budding RNAi Therapies, APP Protein Interaction Map Impress at Meeting
  4. ALS—Is It the Neurons or the Glia?

Paper Citations

  1. Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al-Chalabi A, Bornes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermeire S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang-Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R, Morrison KE, Robberecht W, Van Broeckhoven C, Collen D, Andersen PM, Carmeliet P. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet. 2003 Aug;34(4):383-94. PubMed.
  2. Mitchell JD, Wokke JH, Borasio GD. Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev. 2002;(3):CD002064. PubMed.

Further Reading

Papers

  1. Azzouz M, Ralph S, Wong LF, Day D, Askham Z, Barber RD, Mitrophanous KA, Kingsman SM, Mazarakis ND. Neuroprotection in a rat Parkinson model by GDNF gene therapy using EIAV vector. Neuroreport. 2004 Apr 29;15(6):985-90. PubMed.

Primary Papers

  1. Azzouz M, Ralph GS, Storkebaum E, Walmsley LE, Mitrophanous KA, Kingsman SM, Carmeliet P, Mazarakis ND. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature. 2004 May 27;429(6990):413-7. PubMed.

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