Project team: Denisa Hathazi, PhD; Alexandria Risbeck
Summary
Ataxia-telangiectasia (AT) is a rare incurable disorder caused by variants in the AT-mutated (ATM) gene. Early loss of ambulation due to neurodegeneration, immunodeficiency and malignancy, with average survival <30 years is seen in classic AT; individuals with the variant form have milder, more variable presentations. Current obstacles to evaluate novel treatments include the lack of validated outcome and progression disease biomarkers and a suitable disease model to assess therapeutic targets.
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Antisense oligonucleotide (ASO) therapies present a promising disease-modifying treatment (e.g. SMA), and were recently applied to target single variants (“n-of-1” ASO trials). A deep intronic ATM splice-variant c.5763-1050A>G (present in 13 patients in our cohort) among others is an excellent ASO target, but the lack of validated outcome measures and biomarkers hampers clinical trial evaluation.
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To evaluate therapeutic interventions, we will retrospectively and prospectively study AT patients to identify robust clinical outcome measures and biomarkers supporting clinical trials. Retrospective analysis will define clinical progression in 100 AT patients over 10 years, followed by 2 years of prospective, quantified run-in data in a trial-ready AT subpopulation carrying c.5763-1050A>G, amenable to splice modifying ASO therapy. Collection of biomaterials from a subpopulation of AT patients enables preclinical studies of novel therapeutics.
Project aims
This project will establish a comprehensive set of molecular biomarkers capturing treatment effects on neuronal cells and patient samples, ultimately tailoring it to capture of treatment effects on single patient level.
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We will perform targeted and untargeted assays and validate their treatment-responsivity of variant specific ASOs (1) in vitro in induced pluripotent stem cell (iPSCs) derived neurons; complemented by (2) a patient fluid-based biomarker discovery and validation approach in the selected nano-rare condition – Ataxia Telangiectasia (AT) with ASO targetable mutations.
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The ultimate goal is to go even beyond the latest genetic medicine approaches, implementing a novel paradigm of treatment development: the field of single patient tailored antisense oligonucleotide (ASO) treatments for patients with nano-rare disease mutations.
References
1. Kim J, Woo S, de Gusmao CM, Zhao B, Chin DH, et al., Yu TW. A framework for individualized splice-switching oligonucleotide therapy. Nature. 2023 Jul;619(7971):828-836
2. Schon K, van Os NJH, Oscroft N, Baxendale H, Scoffings D, Ray J, et al. Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia. Ann Neurol. 2019;85(2):170–80.
3. Jennings MJ, Kagiava A, Vendredy L, Spaulding EL, Stavrou M, et al. Horvath R. NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice. Brain. 2022;145(11):3999-4015.
