Karyopharm Exports KPT-350 To Biogen’s ALS Pipeline

Seeing the ALS SINEs? Biogen licenses Karyopharm’s brain-penetrant nuclear export inhibitor (NEI), KPT-350. The drug candidate is to be evaluated as a potential treatment for neurological diseases including ALS. [Courtesy of Sun et al., 2016 under CC BY 4.0 license.]

Biogen added a new ALS drug candidate to its portfolio this month. The strategy, developed by Karyopharm Therapeutics in Newton, Massachusetts, aims to protect motor neurons in ALS by blocking nuclear export. The approach, which targets the exportin Xpo1/CRM1, may reduce motor neuron toxicity in ALS in part, by helping keep TDP-43 from building up in the cytoplasm (see January 2018 news).

The small molecule, known as KPT-350, is one of a group of compounds to be further developed by Biogen in Cambridge, Massachussetts as a potential therapy for neurological diseases including ALS. The strategy is at the preclinical stage.

The approach builds on previous preclinical studies led by Johns Hopkins University School of Medicine’s Jeffrey Rothstein and Thomas Lloyd, which suggest that this strategy may help reduce motor neuron loss in C9orf72 ALS/FTD and Huntington’s disease (Grima et al., 2017; Tamir et al, 2017).

The $217M USD milestone-based licensing deal, announced by Karyopharm Therapeutics on Jan 25, is announced less than a month after Mayo Clinic’s Wilfried Rossoll and colleagues in Jacksonville, Florida reported that cytoplasmic TDP-43 may disrupt nucleocytoplasmic transport of key proteins and RNAs by sequestering key structural components of nuclear pores (see January 2018 news; Chou et al., 2018). TDP-43 aggregates are estimated to clutter the cytoplasm of motor neurons in more than 95% of cases of ALS (Neumann et al., 2006).


To learn more about how a nuclear traffic tie-up may contribute to ALS, check out TDP-43 Snarls Nuclear Traffic.


Chou CC, Zhang Y, Umoh ME, Vaughan SW, Lorenzini I, Liu F, Sayegh M, Donlin-Asp PG, Chen YH, Duong DM, Seyfried NT, Powers MA, Kukar T, Hales CM, Gearing M, Cairns NJ, Boylan KB, Dickson DW, Rademakers R, Zhang YJ, Petrucelli L, Sattler R, Zarnescu DC, Glass JD, Rossoll W. TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat Neurosci. 2018 Jan 8. [PubMed].

Grima JC, Daigle JG, Arbez N, Cunningham KC, Zhang K, Ochaba J, Geater C, Morozko E, Stocksdale J, Glatzer JC, Pham JT, Ahmed I, Peng Q, Wadhwa H, Pletnikova O, Troncoso JC, Duan W, Snyder SH, Ranum LPW, Thompson LM, Lloyd TE, Ross CA, Rothstein JD. Mutant Huntingtin Disrupts the Nuclear Pore Complex. Neuron. 2017 Apr 5;94(1):93-107.e6. [PubMed].

Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006 Oct 6;314(5796):130-3. [PubMed].

Further Reading

Kim HJ, Taylor JP. Lost in Transportation: Nucleocytoplasmic Transport Defects in ALS and Other Neurodegenerative Diseases. Neuron. 2017 Oct 11;96(2):285-297. [PubMed].

Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):56-61 [PubMed].

Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, Petrucelli L, Kim HJ, Gao FB, Taylor JP. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):129-33. [PubMed]



Biogen c9orf72 CRM1 disease-als karyopharm KPT-350 nucleocytoplasmic transport tdp-43 topic-randd XPO1
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