GENE TARGET: A framework for evaluating Mendelian neurodevelopmental disorders for gene therapy.

Interest in gene-based therapies for neurodevelopmental disorders is increasing exponentially, driven by the rise in recognition of underlying genetic etiology, progress in genomic technology, and recent proof of concept in several disorders. The current prioritization of one genetic disorder over another for development of therapies is driven by competing interests of pharmaceutical companies, advocacy groups, and academic scientists. Although these are all valid perspectives, a consolidated framework will facilitate more efficient and rational gene therapy development. Here we outline features of Mendelian neurodevelopmental disorders that warrant consideration when determining suitability for gene therapy. These features fit into four broad domains: genetics, preclinical validation, clinical considerations, and ethics. We propose a simple mnemonic, GENE TARGET, to remember these features and illustrate how they could be scored using a preliminary scoring rubric. In this suggested rubric, for a given disorder, scores for each feature may be added up to a composite GENE TARGET suitability (GTS) score. In addition to proposing a systematic method to evaluate and compare disorders, our framework helps identify gaps in the translational pipeline for a given disorder, which can inform prioritization of future research efforts.

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© 2022 The Author(s).

Déclaration de conflit d'intérêts

M.S. reports grant support from Novartis, Biogen, Astellas, Aeovian, Bridgebio, and Aucta. He has served on scientific advisory boards for Novartis, Roche, Regenxbio, SpringWorks Therapeutics, Jaguar Therapeutics, and Alkermes. During the substantive drafting of this manuscript, M.M. received grant support from Bridge Bio and the PTEN research fund. Although M.M. is currently an employee of Takeda, this was not the case during the substantive drafting of this manuscript.