Objective: This paper outlines current therapeutic options for HD, and ultimately suggests taking a combinatorial therapeutic approach to slow HD progression by simultaneously treating multiple factors that contribute to HD pathogenicity. Namely, this study proposes a combinatorial therapeutic approach that selectively targets the BDNF and extra-synaptic NMDA receptors.

Background: Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disorder caused by an expansion of a polyglutamine (polyQ) chain within the protein huntingtin (HTT). Pathology of the disease indicates extensive neurodegeneration occurs within the striatum resulting in the loss of cognitive abilities, motor function disorder, and psychiatric disorders. There are multiple factors contributing to neurodegeneration as a result of the mHTT. Specifically, two leading causes include: 1.) loss-of-function of mHTT reducing survival signaling via Brain-derived Neurotrophic Factor (BDNF) and 2.) a gain-of-function result of mHTT causing excitotoxicity via N-methyl D-aspartate (NMDA) receptors that ultimately results in Ca²⁺ mediated apoptotic signaling. Current research commonly targets these factors in proposed therapeutic options; however, no single agent has been identified to ameliorate all effects of mHTT.

Method: A review of literature was conducted to determine current therapeutic options and active clinical trials. This article proposes a theoretical multi-factorial therapeutic approach to treating HD. As such, general systematic review methods were not applicable.

Results: Currently, research to date has solely focused on therapeutically targeting one pathogenic mechanism of HD, which has not been shown to provide significant therapeutic benefit likely due to the continued progression of disease via non-targeted pathways. Active clinical trials including SAGE-718, like other proposed therapeutic options for HD, have been investigated independently. Our study differs in that we focus on two pathogenic pathways of HD using combinatorial therapies.

Conclusion: HD is not defined by a single pathogenic process and therefore a single therapeutic target is unlikely to alleviate all pathogenic processes of a diversely acting mutant protein. Our paper builds on the literature by proposing a multi-faceted approach to treating HD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/huntingtons-disease-pathogenesis-molecular-factors-and-potential-for-combinatorial-therapies-a-focus-on-bdnf-and-nmda-receptor-therapies/