A test may help veterinarians confirm the diagnosis of degenerative myelopathy (DM) in dogs, an emerging large animal model of SOD1 ALS. The test, developed by a University of Missouri research team led by veterinary neurologist and neurosurgeon Joan Coates in Columbia, involves the measurement of phosphorylated neurofilament protein H (pNfH) in the cerebrospinal fluid (Toedebusch et al., 2017). The strategy builds on previous studies led by VIB’s Philip Van Damme in Belgium, which found that this approach may enable clinicians to confirm diagnosis of ALS by facilitating the exclusion of key disease mimics. The test is now being further validated (see January 2017, May 2017 news; Poesen et al., 2017).
Dog In the ALS Hunt
In 2008, scientists at the University of Missouri and the Broad Institute in Massachusetts discovered a genetic link between DM and ALS. The study, led by Coates, found that dogs with DM harbored mutations in the SOD1 gene. The dogs exhibit key signs of ALS, including progressive muscle weakness and paralysis beginning in the hind legs and spinal cord pathology (Awano et al., 2009; Katz et al., 2017).
DM occurs in older dogs typically at the age of at least 8. The disease is naturally occurring and according to the Orthopedic Foundation of Animals, may be most common in Pembroke Welsh Corgis. DM, however, has been detected in more than 50% of dog breeds (124/222) tested to date (Zeng et al., 2014).
Now, researchers at the University of Massachusetts Medical Center in Worcester are turning to these dogs to evaluate a potential gene therapy for SOD1 ALS (see May 2017 news). The strategy, developed by Robert Brown and Christian Mueller, aims to promote the survival of motor neurons by reducing levels of misfolded SOD1 in key tissues affected by the disease including the brain and spinal cord (Borel et al., 2016). A clinical trial, led by Tufts University veterinary neurologist and neurosurgeon Dominik Faissler in Massachusetts, launched in December 2016 and remains ongoing.
Meanwhile, Joan Coates is looking to some of the same strategies being developed for SOD1 ALS as potential treatments for DM in dogs. In collaboration with Washington University of St. Louis’ Tim Miller in Missouri, Coates is evaluating Ionis’ SOD1-lowering antisense oligonucleotide (ASO), currently being tested in the ALS clinic at the phase 1 stage (see May 2013 news; Miller et al., 2013). A clinical trial of Voyager Therapeutics’ potential SOD1 gene therapy is also ongoing. The results may help facilitate the development of these potential treatments for SOD1 ALS. Stay tuned.
Toedebusch CM, Bachrach MD, Garcia VB, Johnson GC, Katz ML, Shaw G, Coates JR, Garcia ML. Cerebrospinal Fluid Levels of Phosphorylated Neurofilament Heavy as a Diagnostic Marker of Canine Degenerative Myelopathy. J Vet Intern Med. 2017 Mar;31(2):513-520. [PubMed]
Katz ML, Jensen CA, Student JT, Johnson GC, Coates JR. Cervical spinal cord and motor unit pathology in a canine model of SOD1-associated amyotrophic lateral sclerosis. J Neurol Sci. 2017 Jul 15;378:193-203. [PubMed]
Awano T, Johnson GS, Wade CM, Katz ML, Johnson GC, Taylor JF, Perloski M, Biagi T, Baranowska I, Long S, March PA, Olby NJ, Shelton GD, Khan S, O’Brien DP, Lindblad-Toh K, Coates JR. Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2794-9. [PubMed]
Poesen K, De Schaepdryver M, Stubendorff B, Gille B, Muckova P, Wendler S, Prell T, Ringer TM, Rhode H, Stevens O, Claeys KG, Couwelier G, D’Hondt A, Lamaire N, Tilkin P, Van Reijen D, Gourmaud S, Fedtke N, Heiling B, Rumpel M, Rödiger A, Gunkel A, Witte OW, Paquet C, Vandenberghe R, Grosskreutz J, Van Damme P. Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease. Neurology. 2017 Jun 13;88(24):2302-2309. [PubMed].