Drug discovery for Charcot-Marie-Tooth Disease Using Patient-Derived iPS Cell Lines

Technical Summary

For CMT1A, SCAD has developed a protocol to produce high-quality Schwann cells from human iPS cells. They first examined Schwann cells from normal iPS cells (Fig.1A). Subsequently, they derived two iPS cell lines from CMT1A patients and managed to produce Schwann-like cells. Examination of animal models of CMT1A indicate impaired Schwann cell differentiation(Fredrich et al.,Nature Medicine, 2014),which may explain the difficulty faced by SCAD in producing mature Schwann cells from the patient-derived iPSCs. This observation suggests that impaired Schwann cell differentiation is an important phenotype of the disease and could be a target for therapy development. SCAD confirmed that Schwann-like cells generated from patient-derived iPS cells had increased expression ofPMP22, recapitulating the disease mechanism (Fig.1B).

Figure 1. CMT1A disease modeling with Schwann cells.

For CMT2A,SCAD has developed a protocol to produce high-quality motor neurons from patient-derived iPS cells. They established three iPSC lines and utilized the derived neurons for drug screening (Fig.2A). Through this process, they successfully identified several drug candidates which demonstrated efficacy in improving axonal and mitochondrial defects in the cells (Fig.2B), as well as showing efficacy in CMT2A model mice.

Figure 2. CMT2A patient-derived iPSCs for disease modeling and drug development.

SCAD is currently seeking collaborators and/or strategic business partners to investigate the pathophysiology of CMT and conduct drug discovery research using patient-derived iPS cell lines. Additionally, SCAD is endeavoring to develop cell therapy for CMT1A using Schwann cells produced from pluripotent stem cell lines.

Technology Readiness Level

3

Drug screening has been validated in patient-derived iPS cells and a mouse model of CMT2A

Potential Applications

CMT1A and 2A disease modeling

CMT1A and 2A drug screening

Possible Collaboration Mode(s)

R&D collaboration

Licensing

Patent No

Patent pending (for CMT2A)

Inventor(s)

Norio Nakatsuji, Ph.D.,

Emeritus Prof. Kyoto Univ.

Takayuki Kiboku

Haruka Sato