Identifying Novel Genes and Developing Treatments for Children with Inherited Neuromuscular Diseases
PhD or MPhil
About the Project
Summary
Inherited neuromuscular disorders are disabling, progressive, often fatal conditions, representing an enormous unmet medical need with devastating impacts on affected families, the healthcare system, and the economy. There are no cures and the limited therapies available treat symptoms without addressing the underlying disease.
Aims
Next-generation sequencing has facilitated a molecular diagnosis for many inherited neurological disorders, such as mitochondrial diseases and other neuromuscular diseases, which are the focus of this research. The development of targeted therapies requires detailed laboratory investigation of molecular and mutational mechanisms, and a systematic evaluation of well-chosen agents as well as gene and transcript directed strategies using standardized experimental systems. Our research is focusing on understanding the molecular pathogenesis of childhood onset inherited neuromuscular diseases, such as mitochondrial disease and other neuromuscular diseases to develop targeted therapies.
Using a translational approach, we aim to
- understand the clinical course of patients in relation to the underlying disease mechanism
- delineate the mutational and molecular mechanisms of the molecular defect in the appropriate cell types by developing model systems such as induced neuronal progenitor cells (in vitro) and zebrafish (in vivo)
- improve the treatment options for patients by developing novel therapies that are directed at these mechanisms, including directly at the genetic mutation or resulting transcript.
We use a combination of exome sequencing, genome sequencing, and other omics technologies to identify novel disease genes and disease mechanisms. By functional evaluation in vitro (iPSC-derived neuronal progenitor cells, brain organoids) and in vivo (zebrafish) we confirm pathogenicity and uncover molecular mechanisms of disease. To address the mutational mechanisms, we use gene transfer, splice modulation, allele silencing and CRISPR/cas systems.
Funding Notes
For academic year October 27/28; Gates US applications (round 1) close 14th October 26, further information available via Gates Website
Cambridge Trust, Gates Cambridge (round 2) deadline 8th December 26 to be eligible for funding. If you apply after the funding deadlines you will not be eligible for the Cambridge Funding competition, please indicate in your application all the funding you are eligible for. You can also check funding search
Funding is not available for Lent or Easter 27 places as the funding deadline for these has already passed, you will need to have other funding in place to support your studies
References
Application portal link; PhD https://www.postgraduate.study.cam.ac.uk/courses/directory/cvcnpdpcn/apply; Research MPhil https://www.postgraduate.study.cam.ac.uk/courses/directory/cvcnmpmds/apply Please do try to get in contact directly with the supervisor should you want to discuss the project further. If you do not hear back from the supervisor, you contact can still include their name on the application as this will be sent to them to review as well as our committee.
Further reading
- Thompson R, Spendiff S, Roos A, Bourque PR, Warman Chardon J, Kirschner J, Horvath R, Lochmüller H. Advances in the diagnosis of inherited neuromuscular diseases and implications for therapy development. Lancet Neurol. 2020 Jun;19(6):522-532.
- Olimpio C, Paramonov I, Matalonga L, Laurie S, Schon K, Polavarapu K, Kirschner J, Schara-Schmidt U, Lochmüller H, Chinnery PF, Horvath R. Increased Diagnostic Yield by Reanalysis of Whole Exome Sequencing Data in Mitochondrial Disease. J Neuromuscul Dis. 2024 May 13.
- Ferreira T, Polavarapu K, Olimpio C, Paramonov I, Lochmüller H, Horvath R. Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies. J Neurol. 2024 Jun;271(6):3546-3553.
- Van Haute L, O'Connor E, Díaz-Maldonado H, Munro B, Polavarapu K, Hock DH, Arunachal G, Athanasiou-Fragkouli A, Bardhan M, Barth M, Bonneau D, Brunetti-Pierri N, Cappuccio G, Caruana NJ, Dominik N, Goel H, Helman G, Houlden H, Lenaers G, Mention K, Murphy D, Nandeesh B, Olimpio C, Powell CA, Preethish-Kumar V, Procaccio V, Rius R, Rebelo-Guiomar P, Simons C, Vengalil S, Zaki MS, Ziegler A, Thorburn DR, Stroud DA, Maroofian R, Christodoulou J, Gustafsson C, Nalini A, Lochmüller H, Minczuk M, Horvath R. TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease. Nat Commun. 2023 Feb 23;14(1):1009.
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