Targeting SOD1 ALS From Within

Looking inward. Emerging intrabodies aim to reduce motor neuron toxicity in ALS by lowering levels of key misfolded proteins from motor neurons including SOD1 and TDP-43. [Image: Pathophysiology of ALS. Courtesy of Hardiman et al., 2017, Nature Reviews Disease Primers].

A new strategy may help reduce motor neuron toxicity in SOD1 ALS. The approach, developed by a research team led by University of Chicago’s Raymond Roos in Illinois, uses single-chain intracellular antibody fragments, known as intrabodies, to target misfolded SOD1 for destruction. The intrabodies, which are encoded by a single gene, can be packaged into adeno-associated viruses (AAVs) including AAV9, enabling delivery into motor neurons and glia in the brain and spinal cord (see June 2017, July 2017 news).

The strategy increased the survival of a mouse model of the disease (SOD1 G93A) by up to 18% depending on the timing of administration. A significant reduction in motor neuron loss could also be detected at least when treated at the neonatal stage.

The approach, delivered intravenously, builds on previous studies led by Université Laval’s Jean-Pierre Julien in Quebec City, Canada, which found that a single intrathecal injection of a similar gene therapy delayed disease onset in the same mouse model of the disease (Patel et al., 2014). The strategy is one of a growing number of approaches that aims to treat SOD1 ALS by reducing levels of the misfolded SOD1 enzyme (see May 2017, May 2018 news).

The study appeared on August 31 in Neurobiology of Disease.


Check out Update: Targeting TDP-43 in ALS to learn how scientists aim to use a similar strategy to tackle other forms of ALS including sporadic disease.


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].

Patel P, Kriz J, Gravel M, Soucy G, Bareil C, Gravel C, Julien JP. Adeno-associated virus-mediated delivery of a recombinant single-chain antibody against misfolded superoxide dismutase for treatment of amyotrophic lateral sclerosis. Mol Ther. 2014 Mar;22(3):498-510. [PubMed].

Further Reading

Manoutcharian K, Perez-Garmendia R, Gevorkian G. Recombinant Antibody Fragments for Neurodegenerative Diseases. Curr Neuropharmacol. 2017;15(5):779-788. [PubMed].

Tamaki Y, Shodai A, Morimura T, Hikiami R, Minamiyama S, Ayaki T, Tooyama I, Furukawa Y, Takahashi R, Urushitani M. Elimination of TDP-43 inclusions linked to amyotrophic lateral sclerosis by a misfolding-specific intrabody with dual proteolytic signals. Sci Rep. 2018 Apr 16;8(1):6030. [PubMed].


disease-als intrabodies misfolded SOD1 SOD1 topic-preclinical
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