Haematopoietic stem cell therapies: gene addition, editing, and molecular analysis (360G-Wellcome-217112_Z_19_Z)

We are pioneering the development and application of haematopoietic stem cell (HSC) gene therapy for rare disease, including primary immunodeficiency and inborn errors of metabolism. Remarkable progress has been made over the last two decades, with notable clinical success in a number of different diseases, and transfer of some into the commercial biotechnology sector. Our overall research aim is to create a flexible pipeline of research from gene discovery through disease biology to translation of novel gene and cell therapies. We will address the following areas. 1) enhancement of therapeutic translation for increased numbers of tractable disease targets 2) development of state-of- the-art manufacturing processes to ensure reliability of effect and safety, alongside use of novel technologies to increase efficiency 3) interrogation of haematological and immunological reconstitution in patients as a platform for understanding efficacy and underlying biological mechanisms 4) development of gene editing platforms for HSC modification where semi-random gene addition may be undesirable or ineffective 5) Development of new tools to enhance gene editing in HSC 6) evaluation of novel technologies for detecting on and off- target gene editing aberrations and pre-clinical/clinical assessment of safety 7) application of novel reduced toxicity conditioning strategies for HSC engraftment in gene therapy protocols.