Gene Therapy for Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig's disease, is a chronic, neurodegenerative disease with no known cure. ALS is characterised by the loss of both upper and lower motor neurons. On becoming symptomatic, patients with ALS survive between 1–5 years. The aetiology and pathogenesis of ALS is complex and can vary among cases; however, some forms of ALS have been identified to be genetic in origin. In particular, 20% of familial ALS cases have been attributed to a gain‐of‐function mutation in the SOD1 gene. Thus, gene therapy has been an attractive method to potentially treat ALS. The intention of this article is to provide the reader a summary of common gene therapy strategies for ALS.

Key Concepts:

  • Amyotrophic lateral sclerosis is a progressive neurodegenerative disease with no known cure.

  • ALS exists in two forms: familial ALS and sporadic ALS.

  • Twenty per cent of fALS cases are due to a mutation in the SOD1 gene.

  • SOD1 murine models have been valuable in the advancement of gene therapy for ALS.

  • Gene therapy is a promising therapeutic option for ALS.

Keywords: amyotrophic lateral sclerosis; motor neuron disease; gene therapy; viral vectors; SOD1 model

References

Azzouz M and Mazarakis N (2004) Non‐primate eiav‐based lentiviral vectors as gene delivery system for motor neuron diseases. Current Gene Therapy 4(3): 277–286.

Azzouz M, Ralph GS, Storkebaum E et al. (2004) Vegf delivery with retrogradely transported lentivector prolongs survival in a mouse als model. Nature 429(6990): 413–417.

Calvo AC, Moreno‐Igoa M, Mancuso R et al. (2011) Lack of a synergistic effect of a non‐viral als gene therapy based on bdnf and a ttc fusion molecule. Orpahent Journal of Rare Diseases 6: 10.

Chian RJ, Li JH, Ay I et al. (2009) Igf‐1:tetanus toxin fragment c fusion protein improves delivery of igf‐1 to spinal cord but fails to prolong survival of als mice. Brain Research 1287: 1–19.

Dodge JC, Treleaven CM, Fidler JA et al. (2010) Aav4‐mediated expression of igf‐1 and vegf within cellular components of the ventricular system improves survival outcome in familial als mice. Molecular Therapy 18(12): 2075–2084.

Federici T and Boulis NM (2012) Gene therapy for amyotrophic lateral sclerosis. Neurobiology of Disease 48(2): 236–242.

Federici T, Kutner R, Zhang XY et al. (2009) Comparative analysis of hiv‐1‐based lentiviral vectors bearing lyssavirus glycoproteins for neuronal gene transfer. Genetic Vaccines and Therapy 7: 1

Franz CK, Federici T, Yang J et al. (2009) Intraspinal cord delivery of igf‐i mediated by adeno‐associated virus 2 is neuroprotective in a rat model of familial als. Neurobiology of Disease 33(3): 473–481.

Gurney ME, Pu HF, Chiu AY et al. (1994) Motor‐neuron degeneration in mice that express a human Cu, Zn superoxide‐dismutase mutation. Science 264(5166): 1772–1775.

Henriques A, Pitzer C, Dittgen T et al. (2011) Cns‐targeted viral delivery of g‐csf in an animal model for als: improved efficacy and preservation of the neuromuscular unit. Molecular Therapy 19(2): 284–292.

Kaspar BK, Llado J, Sherkat N, Rothstein JD and Gage FH (2003) Retrograde viral delivery of igf‐1 prolongs survival in a mouse als model. Science 301(5634): 839–842.

Knippenberg S, Thau N, Dengler R, Brinker T and Petri S (2012) Intracerebroventricular injection of encapsulated human mesenchymal cells producing glucagon‐like peptide 1 prolongs survival in a mouse model of als. PLoS One 7(6): e36857

Lentz TB, Gray SJ and Samulski RJ (2012) Viral vectors for gene delivery to the central nervous system. Neurobiology of Disease 48(2): 179–188.

Lepore AC, Haenggeli C, Gasmi M et al. (2007) Intraparenchymal spinal cord delivery of adeno‐associated virus igf‐1 is protective in the sod1g93a model of als. Brain Research 1185: 256–265.

Moreno‐Igoa M, Calvo AC, Ciriza J et al. (2012) Non‐viral gene delivery of the gdnf, either alone or fused to the c‐fragment of tetanus toxin protein, prolongs survival in a mouse als model. Restorative Neurology and Neuroscience 30(1): 69–80.

Moreno‐Igoa M, Calvo AC, Penas C et al. (2010) Fragment c of tetanus toxin, more than a carrier. Novel perspectives in non‐viral als gene therapy. Journal of Molecular Medicine 88(3): 297–308.

Perez‐Martinez FC, Guerra J, Posadas I and Cena V (2011) Barriers to non‐viral vector‐mediated gene delivery in the nervous system. Pharmaceutical Research 28(8): 1843–1858.

Ralph GS, Radcliffe PA, Day DM et al. (2005) (S)ilencing mutant sod1 using rnai protects against neurodegeneration and extends survival in an als model. Nature Medicine 11(4): 429–433.

Raoul C, Abbas‐Terki T, Bensadoun JC et al. (2005) Lentiviral‐mediated silencing of sod1 through rna interference retards disease onset and progression in a mouse model of als. Nature Medicine 11(4): 423–428.

Rogers M‐L and Rush RA (2012) Non‐viral gene therapy for neurological diseases, with an emphasis on targeted gene delivery. Journal of Controlled Release 157(2): 183–189.

Sah DWY (2006) Therapeutic potential of RNA interference for neurological disorders. Life Sciences 79(19): 1773–1780.

Suzuki M, McHugh J, Tork C et al. (2007) Gdnf secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial als. PLoS One 2(8): e689

Suzuki M, McHugh J, Tork C et al. (2008) Direct muscle delivery of gdnf with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial als. Molecular Therapy 16(12): 2002–2010.

Towne C, Raoul C, Schneider BL and Aebischer P (2008) Systemic aav6 delivery mediating RNA interference against sod1: neuromuscular transduction does not alter disease progression in fals mice. Molecular Therapy 16(6): 1018–1025.

Towne C, Setola V, Schneider BL and Aebischer P (2011) Neuroprotection by gene therapy targeting mutant sod1 in individual pools of motor neurons does not translate into therapeutic benefit in fals mice. Molecular Therapy 19(2): 274–283.

Wang LJ, Lu YY, Muramatsu S et al. (2002) Neuroprotective effects of glial cell line‐derived neurotrophic factor mediated by an adeno‐associated virus vector in a transgenic animal model of amyotrophic lateral sclerosis. Journal of Neuroscience 22(16): 6920–6928.

Yuen EC and Mobley WC (1996) Therapeutic potential of neurotrophic factors for neurological disorders. Annals of Neurology 40(3): 346–354.

Further Reading

Nizzardo M, Simone C, Falcone M et al. (2012) Research advances in gene therapy approaches for the treatment of amyotrophic lateral sclerosis. Cellular and Molecular Life Sciences 69: 1641–1650.

O'Connor DM and Boulis NM (2012) Cellular and molecular approaches to motor neuron therapy in amyotrophic lateral sclerosis and spinal muscular atrophy. Neuroscience Letters 527: 78–84.

Steinmetz MP, Liu JK and Boulis NM (2005) Cellular and gene therapy approaches to spinal cord injury. In: Freese A, Simeone FA, Janson C and Leone P (eds) Principles of Molecular Neurosurgery, pp. 65–103. Basel, Switzerland: Karger Publishers.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
McEachin, Zachary, O'Connor, Deirdre, and Boulis, Nicholas(Sep 2013) Gene Therapy for Amyotrophic Lateral Sclerosis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025022]