Objective: To review the progress made towards the development of a huntingtin (HTT) lowering strategy based on RNA and DNA and also to assess the hurdles for a commercially available treatment.

Background: There is a great need for a disease modifying therapy for Huntington’s disease (HD) and being a monogenic disease with complete penetrance when the number of CAG repeats are above 39 makes it a good candidate for therapies targeting DNA and RNA.

Method: Literature search was done in PubMed for papers published between 2017 and 2022 with keywords and combinations related to HD therapies targeting DNA and RNA. Titles and abstracts were shortlisted, reviewed, and used for the references.

Results: There were 621 articles that matched the keywords. Only articles about huntingtin lowering strategies based on RNA or DNA were selected. Four main techniques were identified: antisense oligonucleotides (ASOs), RNA interference (RNAi), zinc finger proteins and CRISPR/Cas9. Therapies based on ASOs were the only analyzed in phase 3 clinical trials. Tominersen was able to reduce mHTT levels significantly but patients had poorer clinical performance than controls and one of the possible causes is the concomitant lowering of wild type HTT (wtHTT). Despite the negative overall outcome, benefit was observed in a subgroup of patients so a new study will be conducted. Allele-specific ASOs are also being developed. Two different medications were being tested, however both of them did not show a significant reduction in mHTT. RNAi are triggers for a gene silencing pathway and there is currently a phase I/II study in recruitment process for administration of a microRNA via magnetic resonance-guided surgery, in contrast to ASOs which are administered intrathecally. To overcome the drug administration issues, exosomes are being studied as a way to transport the RNAi into the central nervous system in a different study[1].  CRISPR and Zinc finger proteins are gene editing tools, the latter has a substantially higher cost. There are already mouse models treated with CRISPR technology showing better motor function[2].

Conclusion: One of the most important issues now is to lower mHTT levels while maintaining wtHTT. Significant advances were made with different techniques and we are closer to develop a commercially available medication. Efforts are also being made to improve the administration techniques.

References: 1. Zhang, L., Wu, T., Shan, Y., Li, G., Ni, X., Chen, X. et al. (2021). Therapeutic reversal of Huntington’s disease by in vivo self-assembled siRNAs. Brain : a journal of neurology, 144(11), 3421–3435. https://doi.org/10.1093/brain/awab354

2. Ekman, F. K., Ojala, D. S., Adil, M. M., Lopez, P. A., Schaffer, D. V., & Gaj, T. (2019). CRISPR-Cas9-mediated genome editing increases lifespan and improves motor deficits in a Huntington’s disease mouse model. Molecular Therapy – Nucleic Acids, 17. https://doi.org/10.1016/j.omtn.2019.07.009

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MDS Abstracts - https://www.mdsabstracts.org/abstract/emerging-treatments-targeting-dna-and-rna-in-huntingtons-disease-a-review-of-future-perspectives-and-current-challenges/