Summary
Making proteins is fundamental for energy production, fighting disease, growth and development. In a family of rare, neurodegenerative diseases, known as mitochondrial aminoacyl-tRNA synthetase (mt-aaRS) diseases, this process is disrupted at its most fundamental level: the attachment of amino acid ‘building blocks’ to the growing protein.
Mt-aaRS diseases affect the mitochondria of the cell, disrupting energy production. In each disease variant, it is the attachment of a different amino acid that is inhibited, resulting in a diverse array of problems affecting different organs in the body. For example, deficiency in the attachment of one amino acid might lead to heart failure, while deficiency in another to neurodegeneration, seizures, ataxia or spasticity. Research in mt-aaRS diseases has been largely focused on studying individual variants. This project will study neurodegenerative mt-aaRS diseases in the laboratory, to understand this disease family holistically.
Project aims
Our aim is to build a comprehensive database of mt-aaRS mutations including children afflicted worldwide and utilize cutting edge technologies including human brain organoids, single cell transcriptomics, zebrafish models, gene editing and advanced bioinformatics to identify the biological pathways and understand why the brain is more affected while other organs protected. The student will have the opportunity to establish 2D and 3D (brain organoids) neuronal models of mt-aaRS diseases to better understand tissue specific presentations.
Knowledge gained through each of these components will guide targeted therapies for patients with mt-aaRS and other neurodegenerative mitochondrial diseases affecting nearly 1.5 million worldwide.
References
Podmanicky O, Gao F, Munro B, Jennings MJ, Boczonadi V, Hathazi D, Mueller JS, Horvath R. Mitochondrial aminoacyl-tRNA synthetases trigger unique compensatory mechanisms in neurons. Hum Mol Genet. 2024 Feb 18;33(5):435-447.
Del Greco C, Antonellis A. The Role of Nuclear-Encoded Mitochondrial tRNA Charging Enzymes in Human Inherited Disease. Genes (Basel). 2022 Dec 9;13(12):2319.
Trial Readiness in Ataxia Telangiectasia (AT) (PhD & MPhil)
Supervisor: Prof Rita Horvath and Dr Anke Hensiek
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.
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.
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.
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. 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.
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.
Contact details
Professor Rita Horvath, rh732@medschl.cam.ac.uk - Neurology
Co-supervisor: Dr Denisa Hathazi
Opportunities
This opportunity is open to PhD applicants.