Refining haematopoietic stem cell populations and their gene modification as a therapy for rare inherited disorders

Developments from academic and biotech sectors have driven gene and stem cell therapy to the clinical setting, with data demonstrating an encouraging long-term safety profile and durable correction of several inherited genetic blood disorders such as ADA-SCID (Strimvelis) and X-CGD (OTL-102). Despite this progress, there is an urgent need to improve manufacturing processes for therapeutic gene modified cells in order to reduce the associated production costs, as this presents a major barrier to sustainability of access to patients. As production of sufficient quantities of viral vectors required to genetically modify a patients' stem cells incurs the most significant costs, this studentship project will focus on approaches to reduce vector use, with an emphasis on identifying optimal therapeutic stem cells, and increasing their susceptibility to lentiviral transduction.

Specific aims are:

i) To identify a refined population of true long-term repopulating haematopoietic stem cells from within peripheral blood stem cells, which are capable of delivering a therapeutic effect, and evaluate clinically applicable methods for their isolation (Years 1 & 2, industry placement).

ii) To examine the efficiency of gene transfer to stem cell subsets using lentiviral vectors and apply targeted approaches to improve cell transduction (Years 2 & 3).

iii) To demonstrate the function and therapeutic potential of optimally transduced and selected stem cell subsets in a preclinical model of stem cell transplantation (Years 3 & 4).

Candidates will develop core laboratory skills in immunological, vector, gene transfer and cell biology techniques, in addition to working with directly translational research methods, using preclinical models and clinical grade platforms.