Gene Editing approach as treatment for neurodevelopmental disorders

Background

Patients with neurodegenerative and neurodevelopmental disorders are currently offered in efficient therapeutic options that fails to slow down disease progression. This highlights the unmet need for innovative therapies that act directly on the causative origins of these devastating diseases. New opportunities are arising fast with the advent of gene-editing technologies such as zinc-finger nucleases (ZFNs) and the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas. Indeed, these technologies are now significantly complementing the gene therapy toolkit by offering unprecedented access to directly correct disease-causing genomic mutations. Base editing for instance delivered by adeno-associated virus serotype 9 (AAV9) led to remarkable pre-clinical efficacy in disease models 1 . Another evidence for the significant progress in gene editing technology is the recent approval by regulators of the first genome editing therapy for blood disorders.

Objectives

Our ultimate goal is to progress AAV9 base genome editing therapeutic strategies for genetic disorders affecting the central nervous system (CNS). Specific aims of the current PhD project are: i) Design and establish base editing therapeutic technology at our centre;

ii) Evaluate the in vitro efficacy of the therapeutic vector system in iPSC derived neurons;

iii) complete a proof-of-concept efficacy stydy in pre-clinical in vivo model of disease.

Novelty

The plan is to develop this gene editing technology for patients currently have no treatment options. Our proposed base editing strategy is an attractive solution since it is targeting the causative gene. Experimental Approach

1) Base editing design: Currently, the adeno-associated (AAV)-based system is one of the most refined and effective gene delivery systems. Remarkable safety and efficacy data were reported from 2 separate phase I/II clinical trials in patients with rare diseases 2,4 . We plan to design AAV expressing base editors to convert recessive mutations reported in patients.

2) In vitro validation of the therapeutic vector using iPS-derived neurons from patients. A number of readouts will be used as demonstrated in a recent study utilising this cell model.

3) Pre-clinical proof-of concept using in vivo disease model. The efficacy of the selected AAV will then be tested in vivo using a mouse model carrying mutation causing the disease in patients.

Training opportunities

The student will join a team of several postdocs, PhD students and technicians. They will benefit from their support and expertise. The student will use/learn cell culture, basic molecular biology techniques, genome editing, viral vector design, disease modelling, immunostaining, microscopy and in vivo pre-clinical expertise. Base editors’ delivery to the cell models will be achieved using lentiviral or adeno-associated vectors. The student will use the assays to characterise the therapeutic vectors generated under this project. They will generate data key to establish future partnerships with industry. The successful candidate will work closely with the GTIMC and SITraN teams to progress this project towards achieving the objectives of the project.

Website links

Link 1: http://sitran.org/people/azzouz/

Link 2: https://www.sheffield.ac.uk/smph/people/neuroscience/arshad-majid

Link 3: https://www.sheffield.ac.uk/smph/people/neuroscience/guillaume-hautbergue

Link 4: https://uk.linkedin.com/in/mimoun-azzouz-9b7221a4