A New Drug Discovery Approach May Help Tackle ALS Heterogeneity

Reducing the noise. A new drug discovery platform may help scientists identify potential treatments for a wide range of cases of ALS, including sporadic disease. The approach uses a panel of iPSC-derived sporadic ALS motor neurons, which can be clustered by molecular phenotypes, to reduce heterogeneity (see August 2018 news). [Courtesy of Fujimori et al., 2018, Nature Medicine.]

A new strategy may help researchers discover potential therapies that protect motor neurons against ALS. The high-content high-throughput approach, developed by a research team led by Keio University School of Medicine’s Hideyuki Okano in Tokyo, Japan, aims to identify potential treatments for ALS by screening for drugs that promote the survival of motor neurons and reduce tell tale signs of the disease.

First, motor neurons in vitro are imaged that originate from cases of inherited forms of ALS, including TDP-43-linked disease. Then, the generalizability of these potential treatment approaches is evaluated by determining their ability to reduce at least some of these same phenotypes in motor neurons derived from people with sporadic disease.

The molecular pathologies detected include increased number of stress granules and TDP-43 aggregates, and key signs of neurodegeneration including neurite shrinkage.

The multi-phenotypic clustering approach capitalizes on a panel of induced pluripotent stem cell (iPSC) lines, developed by Okano’s team, derived from 32 cases of sporadic ALS that aims to help capture and control for the heterogeneity of the disease. The strategy is one of a growing number of approaches that aims to use ALS-patient derived motor neurons to identify existing FDA-approved medicines that can be repurposed as therapies for the disease (see May 2017 news).

The study is published on August 20 in Nature Medicine.


To learn more about this approach and its potential to identify treatments for ALS, check out Treating ALS in a Dish? Models Point to Drug Candidate for Sporadic Disease.

Featured Paper

Fujimori K, Ishikawa M, Otomo A, Atsuta N, Nakamura R, Akiyama T, Hadano S, Aoki M, Saya  H, Sobue G, Okano H. Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent. Nat Med. 2018 Aug 20. [PubMed].

Further Reading

Imamura K, Izumi Y, Watanabe A, Tsukita K, Woltjen K, Yamamoto T, Hotta A, Kondo T, Kitaoka S, Ohta A, Tanaka A, Watanabe D, Morita M, Takuma H, Tamaoka A, Kunath T, Wray S, Furuya H, Era T, Makioka K, Okamoto K, Fujisawa T, Nishitoh H, Homma K, Ichijo H, Julien JP, Obata N, Hosokawa M, Akiyama H, Kaneko S, Ayaki T, Ito H, Kaji R, Takahashi R, Yamanaka S, Inoue H. The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis. Sci Transl Med. 2017 May 24;9(391). [PubMed].

Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SS, Sandoe J, Perez NP, Williams LA, Lee S, Boulting G, Berry JD, Brown RH Jr, Cudkowicz ME, Bean BP, Eggan K, Woolf CJ. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 2014 Apr 10;7(1):1-11. [PubMed].

Egawa N, Kitaoka S, Tsukita K, Naitoh M, Takahashi K, Yamamoto T, Adachi F, Kondo T, Okita K, Asaka I, Aoi T, Watanabe A, Yamada Y, Morizane A, Takahashi J, Ayaki T, Ito H, Yoshikawa K, Yamawaki S, Suzuki S, Watanabe D, Hioki H, Kaneko T, Makioka K, Okamoto K, Takuma H, Tamaoka A, Hasegawa K, Nonaka T, Hasegawa M, Kawata A, Yoshida M, Nakahata T, Takahashi R, Marchetto MC, Gage FH, Yamanaka S, Inoue H. Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci Transl Med. 2012 Aug 1;4(145):145ra104. [PubMed].

Bilican B, Serio A, Barmada SJ, Nishimura AL, Sullivan GJ, Carrasco M, Phatnani HP, Puddifoot CA, Story D, Fletcher J, Park IH, Friedman BA, Daley GQ, Wyllie DJ, Hardingham GE, Wilmut I, Finkbeiner S, Maniatis T, Shaw CE, Chandran S. Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5803-8. [PubMed].


disease-als drug discovery FUS heterogeneity iPSCs tdp-43 topic-randd topic-researchmodels
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