ALS Immunotherapy: Vaccination Delays Disease in Mice

With a few shots of the protein that normally ails them, mouse models of amyotrophic lateral sclerosis stay healthy longer and gain an extra month of life once they do sicken, according to a paper in the June 27 Journal of Neuroscience. Researchers from the University of Toronto report an immunization strategy based on superoxide dismutase 1 (SOD1), which is mutated in one-fifth of people with familial amyotrophic lateral sclerosis (ALS) and drives many animal models of the disease. Importantly, the immunotherapy approach did not cause inflammation. SOD1 immunization might form part of a multipronged therapeutic scheme for people carrying SOD1 mutations, suggested senior author Janice Robertson.

Wild-type, properly folded SOD1 dimers neutralize oxygen radicals, but the mutant version fails to dimerize correctly and instead makes toxic, high-molecular-weight conglomerates. To focus the body’s immune attack only on the undesirable SOD1, Robertson and colleagues used a peptide antigen called SOD1 exposed dimer interface (SEDI). This hydrophobic peptide, corresponding to amino acids 145-151, usually sits hidden between the two units of a dimer, but is exposed in malformed SOD1. The SEDI peptide and antibodies were first developed by coauthor Avijit Chakrabartty, also at the University of Toronto, in collaboration with Robertson and Neil Cashman, since moved to the University of British Columbia in Vancouver (Rakhit et al., 2007). SEDI antibodies bind a range of SOD1 mutant proteins, as the researchers have shown by testing them in three different mouse models and a handful of human cases with different SOD1 mutations (Liu et al., 2009).

In the current work, first author Hsueh-Ning Liu used the SEDI peptide to immunize two different SOD1 mouse models, one with relatively slow-moving disease due to the glycine-37-arginine mutation and another, faster ALS model harboring the glycine-93-alanine mutation. She started the therapy at six weeks of age, before symptom onset. The SOD1-G37R mice received a booster two weeks later, then again one, two, and three months after that. The G93A mice got two booster shots.

For the G37R mice, the vaccine delayed disease onset from an average of 326 to 353 days, and extended lifespan from 352 days to 393 days. The treated G93A mice also enjoyed a longer healthy time leading up to symptoms—130 days before onset instead of 117—but no significant improvement in survival times.

Moreover, the researchers showed that the vaccination decreased the amount of misfolded SOD1 present in spinal cord lysates from the mice. When the team used a SEDI antibody to immunoprecipitate misfolded SOD1 monomers from spinal cord extracts, it picked up one-third less malformed dismutase in the vaccinated animals than in the control group. The treatment impacted oligomers more strongly, the researchers found, via Western blotting of the extracts. Vaccination diminished the number of SOD1 oligomers by more than 90 percent.

Robertson’s paper confirms the results seen in other SOD1 immunization studies, wrote Jean-Pierre Julien of Laval University in Québec City, Canada, in an e-mail to Alzforum. Julien and collaborators have also vaccinated ALS mice with different forms of SOD1 to augment lifespan (Urushitani et al., 2007; Takeuchi et al., 2010). Those experiments used the entire SOD1 protein, wild-type or mutant, as an antigen, Robertson noted. “The immune response generated in our mice only targeted misfolded forms of SOD1, whereas the [whole] protein will drive antibodies that target many, undefined forms of SOD1,” she told Alzforum. “That may or may not be good.”

Some researchers are wary of using active immunization in people, after an Alzheimer’s vaccine led to neuroinflammation in a clinical trial (see ARF related news story). “Passive immunization can be better controlled,” wrote Julien, who has found that antibodies to misfolded SOD1 prolong life in ALS mice (Gros-Louis et al., 2010). Robertson noted that in the AD trial, it was a Th1, cellular immune response that produced inflammatory cytokines and caused side effects (reviewed in Menéndez-González et al., 2011). Liu found that the SEDI-immunized mice elicited a Th2-mediated non-inflammatory response. There was no sign of a negative immune reaction, Robertson said.

As a therapeutic, active immunization consisting of a few shots would be more convenient than long-term treatment with passive antibodies, Robertson noted. She is pursuing further experiments to test the SEDI treatment, which would likely be specific for the subset of people with ALS who bear SOD1 mutations. Researchers are also testing an antisense oligonucleotide strategy to block the translation of mutant SOD1, and adding the vaccine might train the immune system to mop up any protein that escapes the antisense block, Robertson suggested. Biogen Idec, headquartered in Weston, Massachusetts, holds a license to the SEDI epitope, among many other potential SOD1 antibodies it is exploring. Neurimmune of Schlieren, Switzerland, is also pursuing SOD immunotherapy (see ARF related news story).—Amber Dance

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References

News Citations

  1. Human Aβ Vaccine Snagged by CNS Inflammation
  2. Stockholm: New Strategies for Immunotherapy

Paper Citations

  1. Rakhit R, Robertson J, Vande Velde C, Horne P, Ruth DM, Griffin J, Cleveland DW, Cashman NR, Chakrabartty A. An immunological epitope selective for pathological monomer-misfolded SOD1 in ALS. Nat Med. 2007 Jun;13(6):754-9. PubMed.
  2. Liu HN, Sanelli T, Horne P, Pioro EP, Strong MJ, Rogaeva E, Bilbao J, Zinman L, Robertson J. Lack of evidence of monomer/misfolded superoxide dismutase-1 in sporadic amyotrophic lateral sclerosis. Ann Neurol. 2009 Jul;66(1):75-80. PubMed.
  3. Urushitani M, Ezzi SA, Julien JP. Therapeutic effects of immunization with mutant superoxide dismutase in mice models of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2495-500. PubMed.
  4. Takeuchi S, Fujiwara N, Ido A, Oono M, Takeuchi Y, Tateno M, Suzuki K, Takahashi R, Tooyama I, Taniguchi N, Julien JP, Urushitani M. Induction of protective immunity by vaccination with wild-type apo superoxide dismutase 1 in mutant SOD1 transgenic mice. J Neuropathol Exp Neurol. 2010 Oct;69(10):1044-56. PubMed.
  5. Gros-Louis F, Soucy G, Larivière R, Julien JP. Intracerebroventricular infusion of monoclonal antibody or its derived Fab fragment against misfolded forms of SOD1 mutant delays mortality in a mouse model of ALS. J Neurochem. 2010 Jun;113(5):1188-99. PubMed.
  6. Menéndez-González M, Pérez-Piñera P, Martínez-Rivera M, Muñiz AL, Vega JA. Immunotherapy for Alzheimer's disease: rational basis in ongoing clinical trials. Curr Pharm Des. 2011;17(5):508-20. PubMed.

External Citations

  1. antisense oligonucleotide strategy

Further Reading

Papers

  1. Luo Z, Li J, Nabar NR, Lin X, Bai G, Cai J, Zhou SF, Cao C, Wang J. Efficacy of a Therapeutic Vaccine Using Mutated β-amyloid Sensitized Dendritic Cells in Alzheimer's Mice. J Neuroimmune Pharmacol. 2012 Sep;7(3):640-55. PubMed.
  2. Solomon A, Akenine U, Andreasen N, Mangialasche F, Wimo A, Jelic V, Kivipelto M, Winblad B. Practical Lessons From Amyloid Immunotherapy Trials in Alzheimer Disease. Curr Alzheimer Res. 2012 May 21; PubMed.
  3. Morales-Corraliza J, Schmidt SD, Mazzella MJ, Berger JD, Wilson DA, Wesson DW, Jucker M, Levy E, Nixon RA, Mathews PM. Immunization targeting a minor plaque constituent clears β-amyloid and rescues behavioral deficits in an Alzheimer's disease mouse model. Neurobiol Aging. 2012 May 17; PubMed.
  4. Delrieu J, Ousset PJ, Vellas B. Gantenerumab for the treatment of Alzheimer's disease. Expert Opin Biol Ther. 2012 Aug;12(8):1077-86. PubMed.
  5. Robert R, Wark KL. Engineered antibody approaches for Alzheimer's disease immunotherapy. Arch Biochem Biophys. 2012 Mar 27; PubMed.
  6. Panza F, Frisardi V, Solfrizzi V, Imbimbo BP, Logroscino G, Santamato A, Greco A, Seripa D, Pilotto A. Immunotherapy for Alzheimer's disease: from anti-β-amyloid to tau-based immunization strategies. Immunotherapy. 2012 Feb;4(2):213-38. PubMed.

Primary Papers

  1. Liu HN, Tjostheim S, DaSilva K, Taylor D, Zhao B, Rakhit R, Brown M, Chakrabartty A, McLaurin J, Robertson J. Targeting of monomer/misfolded SOD1 as a therapeutic strategy for amyotrophic lateral sclerosis. J Neurosci. 2012 Jun 27;32(26):8791-9. PubMed.

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