Project title

Precision gene regulation as a novel therapeutic approach for neurodevelopmental disorders

Supervisors


Background

Neurodevelopmental disorders (NDDs) such as epilepsy, autism spectrum disorder, and intellectual disability are among the most prevalent paediatric conditions linked to rare genetic mutations. These disorders often share a common molecular feature: haploinsufficiency, where a single functional gene copy cannot support normal development [1]. Many of these disorders lack effective treatments and can cause life-long disability. 

Haploinsufficient genes are dosage-sensitive and tightly regulated, which presents major challenges for therapeutic intervention [1]. Many clinically important haploinsufficient genes, including those involved in epilepsy and intellectual disability, are too large or complex for conventional gene replacement approaches. As a result, there is a growing need for therapeutic strategies that can safely and precisely upregulate endogenous gene expression rather than relying on overexpression.

This project aims to develop a novel gene therapy strategy for the treatment of NDDs caused by haploinsufficiency through genomic targeting. The project will use state-of-the-art genome editing technologies to functionally validate novel genomic targets and assess whether restoration of gene expression can be achieved at the molecular level [2]. The project will also use human, patient-derived iPSC models of NDDs to investigate whether we can rescue disease phenotypes [3]. This PhD project would be foundational for the development of the next-generation of gene therapies for NDDs, transforming the treatment of these otherwise life-limiting disorders.  

Aims and objectives

  • Aim 1: Identify and characterise genomic targets associated with candidate disease genes.
  • Aim 2: Develop quantitative cellular assays to assess how changes in gene expression influence early neurodevelopmental processes.
  • Aim 3: Functionally evaluate candidate genomic targets in models of NDDs using genome editing.


Methods

  • Computational discovery: Genomic targets will be identified using multi-omics datasets through collaboration.
  • Experimental validation: Targets will be validated using scalable reporter systems and human cellular models (E.g. CRISPR-based perturbation assays, sequencing, RNA and protein analysis).
  • Functional assays: Quantitative phenotypic readouts will evaluate cellular consequences of altered gene regulation, with a focus on early neurodevelopmental processes. (E.g. live cell imaging, immunohistochemistry, electrophysiology).
  • Therapeutic Refinement: The most promising genomic targets will be further validated using disease-relevant human models. (E.g. organoids, multi-omics, next-generation sequencing).

 

Impact and innovation

This project will:

  • Develop a novel gene therapy approach applicable to several NDDs caused by haploinsufficiency.
  • Combine computational methods and genome editing to accelerate discovery.
  • Provide fundamental insight into the regulation of important disease genes in human neurodevelopment.


Timeline

  • Months 1-4: Computational discovery.
  • Months 4-18: Experimental validation and functional assays.
  • Months 18-33: Therapeutic Refinement.
  • Months 33-36: Thesis writing and submission.


References

  1. Veitia RA., Zschocke J., Birchler JA. Gene Dosage Sensitivity and Human Genetic Diseases. J Inherit Metab Dis. 2025; 48(4):e70058. DOI: 10.1002/jimd.70058.
  2. Kim, H.S., Kweon, J. & Kim, Y. Recent advances in CRISPR-based functional genomics for the study of disease-associated genetic variants. Exp Mol Med. 2024; 56, 861–869. DOI: 10.1038/s12276-024-01212-3.
  3. Birtele, M., Lancaster, M. & Quadrato, G. Modelling human brain development and disease with organoids. Nat Rev Mol Cell Biol. 2025; 26, 389–412 DOI: 10.1038/s41580-024-00804-1.


Who should students contact?

Dr Jenna Carpenter (jenna.carpenter.14@ucl.ac.uk)

Research topic

Epilepsy, Genetics, Development