AUTHOR=Nair Malavika A. , Niu Zhiyv , Madigan Nicholas N. , Shin Alexander Y. , Brault Jeffrey S. , Staff Nathan P. , Klein Christopher J. 

TITLE=Clinical trials in Charcot-Marie-Tooth disorders: a retrospective and preclinical assessment

JOURNAL=Frontiers in Neurology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2023.1251885

DOI=10.3389/fneur.2023.1251885

ISSN=1664-2295

ABSTRACT=Background: CMT has historically been managed symptomatically and with genetic counseling. Evolution of molecular and pathologic understanding holds therapeutic promise in gene targeted therapies. Methods: ClinicalTrials.gov from December 1999 to June 2022 was data extracted for CMT with preclinical animal gene therapy trials also reviewed by PubMed search.The number of active trials was 1 in 1999 and 286 in 2022. Academic settings accounted for 91% and pharmaceutical companies 9%. Of the pharmaceutical and academic trials, 38% and 28%, respectively, were controlled, randomized and double-blinded. Thirty-two countries participated: United States accounted for 26% (75/286). 86% of the trials were classified as therapeutic: 50% procedural (21% wrist/elbow surgery; 22% shock wave and hydrodissection therapy), 23% investigational drugs, 15% devices, 11% physical therapy. Sixtyseven therapeutic trials (49%) were designated phase 1-2, and 51%, phase 3-4. The remaining 14% represent nontherapeutic trials: diagnostic testing (3%), functional outcomes (4%), natural history (4%), standard of care (3%). One-hundred and three (36%) resulted in publications.Phase I human pharmaceutical trials are focusing on safety of small molecule therapies (n=8) and AAV and nonviral gene therapy (n=3). Preclinical animal gene therapy studies include 11 different CMT forms including viral, CRISPR-Cas9 and nanoparticle delivery.Current CMT trials are exploring procedural and molecular therapeutic options with substantial participation of the pharmaceutical industry worldwide. Emerging drug therapies directed at molecular pathogenesis are being advanced in human clinical trials, however, the majority remain within animal investigations.