Identifying Novel Genes and Developing Treatments for Children with Inherited Neuromuscular Diseases

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. 

Project 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. 

References

1. 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. 

2. 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. 

3. 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. 

4. 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. 

Contact details

Professor Rita Horvath, rh732@medschl.cam.ac.uk - Neurology 

Opportunities

This project is open to applicants who want to do a:

  • PhD
  • MPhil