2. Academic Validation
  3. Drug screening with human SMN2 reporter identifies SMN protein stabilizers to correct SMA pathology

Drug screening with human SMN2 reporter identifies SMN protein stabilizers to correct SMA pathology

  • Life Sci Alliance. 2019 Mar 25;2(2):e201800268. doi: 10.26508/lsa.201800268.
Yiran Wang 1,  Chongchong Xu 2 3,  Lin Ma 1 4 5,  Yongchao Mou 2 3,  Bowen Zhang 1,  Shanshan Zhou 1,  Yue Tian 1,  Jessica Trinh 2,  Xiaoqing Zhang 6 4 5 7 8 9,  Xue-Jun Li 10 3
Affiliations

Affiliations

  • 1 Brain and Spinal Cord Innovative Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
  • 2 Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL, USA.
  • 3 Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA.
  • 4 Key Laboratory of Reconstruction and Regeneration of Spine and Spinal Cord Injury, Ministry of Education, Shanghai, China.
  • 5 Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University, School of Medicine, Shanghai, China.
  • 6 Brain and Spinal Cord Innovative Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China xqzhang@tongji.edu.cn.
  • 7 Tsingtao Advanced Research Institute, Tongji University, Shanghai, China.
  • 8 Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China.
  • 9 Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 10 Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL, USA xjli23@uic.edu.
PMID: 30910806 DOI: 10.26508/lsa.201800268
Abstract

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by reduced levels of functional survival motor neuron (SMN) protein. To identify therapeutic agents for SMA, we established a versatile SMN2-GFP reporter line by targeting the human SMN2 gene. We then screened a compound library and identified Z-FA-FMK as a potent candidate. Z-FA-FMK, a cysteine protease inhibitor, increased functional SMN through inhibiting the protease-mediated degradation of both full-length and exon 7-deleted forms of SMN. Further studies reveal that CAPN1, CAPN7, CTSB, and CTSL mediate the degradation of SMN proteins, providing novel targets for SMA. Notably, Z-FA-FMK mitigated mitochondriopathy and neuropathy in SMA patient-derived motor neurons and showed protective effects in SMA animal model after intracerebroventricular injection. E64d, another cysteine protease inhibitor which can pass through the blood-brain barrier, showed even more potent therapeutic effects after subcutaneous delivery to SMA mice. Taken together, we have successfully established a human SMN2 reporter for future drug discovery and identified the potential therapeutic value of cysteine Protease Inhibitors in treating SMA via stabilizing SMN proteins.

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