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Québec: Transporters, Antibodies Offer Potential ALS Therapies

Series - Fondation André-Delambre, 2009 Symposium on Amyotrophic Lateral Sclerosis:

The doctor’s toolkit for amyotrophic lateral sclerosis is pathetically small—only one drug, riluzole, is approved for the disease, and its effects are hardly blockbuster. However, researchers are constantly coming up with new strategies to rescue motor neurons from degeneration. At the André-Delambre Symposium in Québec City, held September 25-26, 2009, two scientists presented ideas, still in the early stages, which might lead to new therapeutics down the line.

Brett Morrison of Johns Hopkins University in Baltimore, Maryland, discussed a strategy aimed at a monocarboxylate transporter, MCT1, which shuttles lactate out of the cell. Previous work in the laboratory of collaborator Jeff Rothstein, also at Johns Hopkins University, suggested MCT1 was reduced in animals with mSOD1. The transporter is particularly important in astrocytes, the motor neurons’ support cells which have been implicated in the disease (Yamanaka et al., 2008). Astrocytes have long, thin processes where mitochondria cannot fit; those tentacles must rely solely on glycolysis for energy. Lactate is a byproduct of this process, and MCT1 pumps it out of the cell.

Neurons express another transporter, MCT2, which is able to take up lactate into the cell. A longstanding theory says that motor neurons may then extract energy from the lactate via oxidative respiration (Aubert et al., 2005). Using lactate might be important, Morrison suggested, if the cells were low on glucose. “There are not many cells in the body that would be more metabolically active than a motor neuron,” he said.

Morrison showed that MCT1 levels were reduced in spinal cord astrocytes of people with ALS and in the same cells in a rat model of the disease. In cultured spinal cord slices, RNA inhibition of MCT1 expression caused motor neuron degeneration. To further study the importance of these transporters, Morrison used a specific small molecule inhibitor of MCT1 (Murray et al., 2005). The inhibitor’s effects on cultured spinal cord cells mirrored that of the RNAi: up to one-third of motor neurons died after three weeks. Under glucose starvation, the effect was even more dramatic, with inhibitor-treated motor neuron numbers dropping by more than half after two hours of glucose deprivation. When the researchers added extracellular lactate—to compensate for loss of MCT1-driven export of lactate from astrocytes—the motor neurons survived in the presence of the inhibitor. The results suggest that motor neurons depend on lactate, normally supplied by astrocytes via MCT1, for survival.

In vivo, the story was similar. RNA inhibition of MCT1 in the spinal cords of wild-type mice caused motor neuron numbers to drop by approximately one-half by four weeks after the RNAi treatment. The next step will be to augment MCT1 activity and look for a positive effect on motor neuron survival and disease progression. Collaborators are performing those experiments now, Morrison said. Simply injecting lactate would not work, Morrison noted, because the molecule is broken down too quickly.

François Gros-Louis of Laval University in Québec City presented another therapeutic possibility aimed at people with ALS mutations in superoxide dismutase 1. If too much aggregated SOD1 is the problem, Gros-Louis reasoned, then antibodies to the protein might induce the immune system to get rid of them. Similar strategies are being pursued for other neurodegenerative diseases, including Alzheimer disease, where both active and passive immunotherapies are in clinical trials (see ARF related news story). In previous work, immunizing mice with SOD1 protein delayed disease by a month in one model of the disease, although mice expressing the highest levels of mutant SOD1 were not helped. However, passive immunization by infusing mSOD1 antibodies was effective in the mice with the most severe disease (Urushitani et al., 2007). “We believe that passive immunization would be safer” for eventual use in people, Gros-Louis said.

Gros-Louis tested two antibodies, specific for only the mutant form of SOD1, as well as control IgG in 65 mSOD1 mice. The animals received antibody infusions from external pumps for 25 or 40 days. One antibody failed to give any benefit, but the other extended lifespan by up to nine days. Those treated animals had 25 percent less misfolded SOD1 than did control mice.

Gros-Louis also found that Fab fragments of the antibody extended survival. This suggests that smaller, single-chain fragments, which offer advantages such as ease of optimization and very little immunogenicity in the host, might work in the case of mSOD1. Gros-Louis is currently testing single-chain fragments in animals.

“For patients with the SOD1 mutation, there are very interesting approaches,” Morrison said of Gros-Louis’s work. But there is a caveat: “You are only going to help the 1 to 2 percent of patients with ALS with that mutation in SOD1.”—Amber Dance.

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References

News Citations

  1. Piping in Passive Immunization Spares Blood Vessels

Paper Citations

  1. Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci. 2008 Mar;11(3):251-3. PubMed.
  2. Aubert A, Costalat R, Magistretti PJ, Pellerin L. Brain lactate kinetics: Modeling evidence for neuronal lactate uptake upon activation. Proc Natl Acad Sci U S A. 2005 Nov 8;102(45):16448-53. PubMed.
  3. Murray CM, Hutchinson R, Bantick JR, Belfield GP, Benjamin AD, Brazma D, Bundick RV, Cook ID, Craggs RI, Edwards S, Evans LR, Harrison R, Holness E, Jackson AP, Jackson CG, Kingston LP, Perry MW, Ross AR, Rugman PA, Sidhu SS, Sullivan M, Taylor-Fishwick DA, Walker PC, Whitehead YM, Wilkinson DJ, Wright A, Donald DK. Monocarboxylate transporter MCT1 is a target for immunosuppression. Nat Chem Biol. 2005 Dec;1(7):371-6. PubMed.
  4. 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.

Further Reading

Papers

  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. Smith RA, Miller TM, Yamanaka K, Monia BP, Condon TP, Hung G, Lobsiger CS, Ward CM, McAlonis-Downes M, Wei H, Wancewicz EV, Bennett CF, Cleveland DW. Antisense oligonucleotide therapy for neurodegenerative disease. J Clin Invest. 2006 Aug;116(8):2290-6. PubMed.
  3. Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005 Jan 6;433(7021):73-7. PubMed.
  4. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med. 1994 Mar 3;330(9):585-91. PubMed.
  5. Lepore AC, Rauck B, Dejea C, Pardo AC, Rao MS, Rothstein JD, Maragakis NJ. Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nat Neurosci. 2008 Nov;11(11):1294-301. PubMed.

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