Editors' ChoiceGene Therapy

Interfering in Charcot-Marie-Tooth disease 2D

See allHide authors and affiliations

Science Translational Medicine  09 Oct 2019:
Vol. 11, Issue 513, eaaz3712
DOI: 10.1126/scitranslmed.aaz3712


Patient-tailored RNA interference prevents the onset of Charcot-Marie-Tooth 2D disease.

Personalized medicine tailors treatments to the patient’s needs. In rare diseases, the development of targeted therapeutic approaches for subsets of patients may be due to either the specific medical needs or technical constraints of the therapeutic approach. Rarer are the cases in which the identification of a mutation in a single patient leads to the development of a patient-specific gene therapy approach, as seen in a recent work from Morelli and colleagues. Starting from an atypical case of early onset motor neuropathy, extensive targeted genetic screening identified a pathogenic deletion in the glycyl-tRNA-synthetase (GARS) gene. Dominant mutations in this gene are responsible for Charcot-Marie-Tooth disease type 2D (CMT2D). The authors developed an allele-specific RNA interference (RNAi) approach targeting the dominant four amino acid deletion. Adeno-associated viral vector-mediated, intracerebroventricular delivery of the vector in neonate animals prevented the onset of the neuropathy in a mouse model bearing the same deletion in the GARS gene. However, as observed in other neuropathies with axonal degeneration, post-onset RNAi treatment resulted in partial or even no benefit depending on the timing of intervention. A similar approach targeting the P278KY allele in a mouse model of CMT2D showed similar results.

This paper provides proof-of-concept allele-specific strategies for treating dominant mutations in CMT2D. Although this approach is intrinsically mutation-specific, the authors indicate the unspecific knockout of GARS transcripts and the reintroduction of a RNAi-resistant GARS gene copy by the same vector as a possible treatment strategy. The complexity of such a transgene expression cassette may represent a challenge from a translational point of view. However, the work described in this paper clearly summarizes the difficulty of the development of personalized treatments for rare diseases and highlights the arduous diagnostic journey of a patient with an ultra-rare mutation with an atypical manifestation.

Highlighted Article

Stay Connected to Science Translational Medicine

Navigate This Article