A New ALS Therapeutic Strategy Sets Sail in Hopes to Stabilize NMJs

Out of dry dock. An emerging gene therapy, developed by Yuji Yamanishi’s team in Japan, delays the denervation of key muscles in a SOD1 mouse model of ALS including in the diaphragm. The strategy, which involves the delivery of the DOK7 gene using an AAV9-based vehicle, aims to stabilize neuromuscular junctions by increasing MuSK activation. [Miyoshi et al., 2017 under CC BY 3.0 license]

An emerging therapeutic strategy may help motor neurons and muscle fibers stay connected in ALS according to a new study led by University of Tokyo’s Yuji Yamanishi in Japan. The approach, which involves the upregulation of DOK7, aims to stabilize neuromuscular junctions by activating MuSK, a key receptor tyrosine kinase involved in the formation and maintenance of these connections. (Perez-Garcia and Burden, 2012).

The results build on a previous study, which demonstrated that this potential treatment strategy may be of benefit to at least some forms of neuromuscular disease (Arimura et al., 2014).

The strategy is based on previous work led by New York University School of Medicine’s Steven Burden which found that increasing MuSK activity helps keep muscle fibers and motor neurons connected longer in ALS – at least in mice (Kong et al., 2004; Punga et al., 2011). The approach is one of a growing number of gene therapies being developed for the disease (see May 2017 news).

A spoonful of sugar? In 2012, Justin Fallon’s team in Rhode Island discovered that biglycan is required for the stabilization of neuromuscular junctions – at least in mice (NMJs in wild-type (top), biglycan null (bottom) muscle). Now, they are developing a recombinant form of this extracellular matrix protein as a potential treatment for ALS. [Courtesy of Justin Fallon, Brown University].

The study is published on May 10 in EMBO Molecular Medicine.

The potential therapy, upon administration at disease onset, improved motor function and increased survival of a mouse model of SOD1 ALS by nearly 30% after exhibiting symptoms (64.2 ± 3.3 days; 50.3 ± 3.1 days) according to the study. The approach, however, did not curb motor neuron loss. The results are consistent with previous preclinical studies that suggest that a second therapy may be needed to protect motor neurons from ALS in part, by preventing their degeneration (Gould et al., 2006; Rouaux et al., 2007).

Meanwhile, Justin Fallon of Brown University is developing a different approach to help motor neurons and muscle fibers stay connected in people with ALS. The potential treatment strategy, which involves the injection of the extracellular matrix protein biglyan, also aims to stabilize neuromuscular junctions by increasing MuSK activation. The approach is based on previous studies which found that biglycan stabilizes these synapses in part, by regulating the localization and levels of MuSK at motor nerve terminals (Amenta et al., 2012).

The strategy, known as TVN-102, is being developed by Providence startup Tivorsan Pharmaceuticals in Rhode Island, which is co-founded by Fallon. The approach can be administered safely and systemically according to preclinical studies without the need to be targeted or delivered to muscles affected by the disease (Amenta et al., 2011).

Biglycan is now approaching the clinic. The potential therapy is going to be evaluated as a treatment for Duchenne muscular dystrophy at the phase 1 stage. The strategy is based on previous preclinical studies which found that biglycan improved muscle function in DMD by recruiting utrophin, a protein related to dystrophin (Amenta et al., 2011).

Testing of this approach in a mouse model of SOD1 ALS is expected to begin soon. Stay tuned.

Featured Papers

Miyoshi S, Tezuka T, Arimura S, Tomono T, Okada T, Yamanashi Y. DOK7 gene therapy enhances motor activity and life span in ALS model mice. EMBO Mol Med. 2017 May 10. [PubMed].

Amenta AR, Creely HE, Mercado ML, Hagiwara H, McKechnie BA, Lechner BE, Rossi SG, Wang Q, Owens RT, Marrero E, Mei L, Hoch W, Young MF, McQuillan DJ, Rotundo RL, Fallon JR. Biglycan is an extracellular MuSK binding protein important for synapse stability. J Neurosci. 2012 Feb 15;32(7):2324-34. [PubMed].


Arimura S, Okada T, Tezuka T, Chiyo T, Kasahara Y, Yoshimura T, Motomura M, Yoshida N, Beeson D, Takeda S, Yamanashi Y. Neuromuscular disease. DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction. Science. 2014 Sep 19;345(6203):1505-8. [PubMed].

Kong XC, Barzaghi P, Ruegg MA Inhibition of synapse assembly in mammalian muscle in vivo by RNA interference. EMBO Rep. 2004 Feb;5(2):183-8. [PubMed].

Punga AR, Maj M, Lin S, Meinen S, Rüegg MA. MuSK levels differ between adult skeletal muscles and influence postsynaptic plasticity. Eur J Neurosci. 2011 Mar;33(5):890-8. [PubMed].

Gould TW, Buss RR, Vinsant S, Prevette D, Sun W, Knudson CM, Milligan CE, Oppenheim RW Complete dissociation of motor neuron death from motor dysfunction by Bax deletion in a mouse model of ALS. J Neurosci. 2006 Aug 23;26(34):8774-86. [PubMed].

Rouaux C, Panteleeva I, René F, Gonzalez de Aguilar JL, Echaniz-Laguna A, Dupuis L, Menger Y, Boutillier AL, Loeffler JP. Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model. J Neurosci. 2007 May 23;27(21):5535-45. [PubMed]

Amenta AR, Yilmaz A, Bogdanovich S, McKechnie BA, Abedi M, Khurana TS, Fallon JR. Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice. Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):762-7. [PubMed].



disease-als muscle neuromuscular junction SOD1 topic-preclinical topic-randd
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