Potential SOD1 ALS Gene Therapy Right on Target Scientists Say

Silencing SOD1. Scientists at the University of Sheffield are developing a potential gene therapy for SOD1 ALS. The strategy, unlike existing approaches, is injected directly into the CNS intrathecally, to lower the dosage (viral load) needed to reduce the risk of unwanted side effects. [Image: National Human Genome Research Institute.]

Researchers are one step closer to developing a potential gene therapy for SOD1-ALS. The AAV9-based approach, developed by a research team led by University of Sheffield’s Pamela Shaw and Mimoun Azzouz in England, aims to reduce motor neuron toxicity in the disease by lowering levels of SOD1. The misfolded enzyme is thought to contribute to ALS by multiple mechanisms (for review, see Taylor et al., 2016).

The potential gene therapy, according to a new study, reduced neuronal loss in a mouse model of the disease up to 88% and increased its survival by up to 42% depending on treatment timing. No off-target effects could be detected.

The strategy uses a short hairpin RNA (shRNA) to silence the SOD1 gene. The approach is one of a growing number of strategies that aims to lower levels of the misfolded enzyme in motor neurons using RNA interference technologies (December 2017 news; Foust et al., 2013; see also May 2017 news).

The study appeared on September 7 in Molecular Therapy Nucleic Acids.

Meanwhile, a research team led by Timothy Miller at the Washington University-St. Louis in Missouri is using a different strategy to tackle SOD1 ALS. They developed a SOD1 antisense oligonucleotide to lower levels of the misfolded enzyme (see May 2018 news). The approach, according to preclinical studies, may also help reduce motor neuron toxicity mediated by cell non-autonomous mechanisms in the CNS (see August 2017 news; Hoye et al., 2017). The strategy is at the phase 1 stage (see May 2018 news). The approach is being developed in partnership with Biogen in Cambridge, Massachusetts and Ionis Pharmaceuticals in Carlsbad, California.

Featured Papers

Iannitti T, Scarrott JM, Likhite S, Coldicott IRP, Lewis KE, Heath PR, Higginbottom A, Myszczynska MA, Milo M, Hautbergue GM, Meyer K, Kaspar BK, Ferraiuolo L, Shaw PJ, Azzouz M. Translating SOD1 Gene Silencing toward the Clinic: A Highly Efficacious, Off-Target-free, and Biomarker-Supported Strategy for fALS. Mol Ther Nucleic Acids. 2018 Sep 7;12:75-88. PubMed.

Hoye ML, Regan MR, Jensen LA, Lake AM, Reddy LV, Vidensky S, Richard JP, Maragakis NJ, Rothstein JD, Dougherty JD, Miller TM. Motor neuron-derived microRNAs cause astrocyte dysfunction in amyotrophic lateral sclerosis. Brain. 2018 Sep 1;141(9):2561-2575. PubMed.


Foust KD, Salazar DL, Likhite S, Ferraiuolo L, Ditsworth D, Ilieva H, Meyer K, Schmelzer L, Braun L, Cleveland DW, Kaspar BK. Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. Mol Ther. 2013 Dec;21(12):2148-59. PubMed.

Miller TM, Pestronk A, David W, Rothstein J, Simpson E, Appel SH, Andres PL, Mahoney K, Allred P, Alexander K, Ostrow LW, Schoenfeld D, Macklin EA, Norris DA, Manousakis G, Crisp M, Smith R, Bennett CF, Bishop KM, Cudkowicz ME. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 2013 May;12(5):435-42. PubMed.

McCampbell A, Cole T, Wegener AJ, Tomassy GS, Setnicka A, Farley BJ, Schoch KM, Hoye ML, Shabsovich M, Sun L, Luo Y, Zhang M, Thankamony S, Salzman DW, Cudkowicz M, Graham DL, Bennett CF, Kordasiewicz HB, Swayze EE, Miller TM. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J Clin Invest. 2018 Aug 1;128(8):3558-3567. PubMed.

Hoye ML, Koval ED, Wegener AJ, Hyman TS, Yang C, O’Brien DR, Miller RL, Cole T, Schoch KM, Shen T, Kunikata T, Richard JP, Gutmann DH, Maragakis NJ, Kordasiewicz HB, Dougherty JD, Miller TM. MicroRNA Profiling Reveals Marker of Motor Neuron Disease in ALS Models. J Neurosci. 2017 May 31;37(22):5574-5586. PubMed.

Further Reading

Ly CV, Miller TM. Emerging antisense oligonucleotide and viral therapies for amyotrophic lateral sclerosis. Curr Opin Neurol. 2018 Oct;31(5):648-654. PubMed.

Biferi MG, Cohen-Tannoudji M, Cappelletto A, Giroux B, Roda M, Astord S, Marais T, Bos C, Voit T, Ferry A, Barkats M. A New AAV10-U7-Mediated Gene Therapy Prolongs Survival and Restores Function in an ALS Mouse Model. Mol Ther. 2017 Sep 6;25(9):2038-2052. PubMed.

Ghadge GD, Kay BK, Drigotas C, Roos RP. Single chain variable fragment antibodies directed against SOD1 ameliorate disease in mutant SOD1 transgenic mice. Neurobiol Dis. 2018 Aug 31. pii: S0969-9961(18)30520-5. PubMed.

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