A single donation of umbilical cord blood could be engineered into an "off-the-shelf" supply of cancer-killing T cells for over ten children with leukaemia. This project tackles three major limitations of current gene therapies for children: the need for patient-specific cell engineering, the lack of effective treatments for inherited immune disorders like CD40 ligand deficiency, and the challenge of managing lifelong HIV infection in adolescents. Existing approaches rely on slow, custom-made cell products and leave many patients without options. The research uses precise DNA-cutting tools—TALENs and CRISPR-Cas9—to permanently edit T cells in three ways: disabling their original receptors and adding a leukaemia-targeting receptor for universal use; correcting the genetic mutation that causes CD40 ligand deficiency; and removing the CCR5 co-receptor while adding antiviral proteins to make T cells resistant to HIV. If successful, these therapies could transform chronic childhood conditions into single-intervention cures, reducing the need for lifelong medications, repeated hospital visits, and donor-matched transplants. For the NHS, this would mean fewer long-term care costs and better outcomes for children with otherwise debilitating or fatal diseases.
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Background Great Ormond Street Hospital undertakes the largest number of paediatric haematopoietic stem cell transplants (HSCT) in Europe, and is a nationally commissioned centre for children with immunodeficiencies, and also cares for children infected with HIV. This experience has brought us to the forefront of gene based therapies for conditions where it is possible to collect, engineer and return cells to patients. Paediatric disorders have been particularily suitable for these ex-vivo gene therapy approaches, partly because of their early presentation, but also because of reduced dosing requirements. I have led the translational development of T cells encoding suicide genes, anti-leukaemia receptors and anti-viral elements, and all these therapies have benefited from 'in-house' retroviral and lentiviral vector technology. However, I have recognised that existing approaches carry a number of limitations, and now propose deploying the next generation of DNA engineering techniques to address some of the key hurdles. New targeted DNA-nucleases, including transcription activator-like effector nucleases (TALENs) or clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR-Cas) nucleases, are capable of mediating highly efficient DNA scission at precisely defined genomic loci. In combination with our existing lentiviral and other vector technology, they offer burgeoning therapeutic possibilities and T cell therapies are an ideal arena for their early application. Aims My aim is to widen gene therapy applications with new reagents and to unlock approaches for otherwise chronic and disabling conditions of childhood. Three different T cell therapies have been selected, aiming to allow a broad exploration of emerging therapeutic possibilities:- Production of umblical cord blood T-cells that are available 'off the shelf' following permanent genetic disruption of their existing T-cell receptors and simultaneous engineering to express a new chimeric antigen receptor (CAR) against the B-cell leukeamia antigen, CD19. Correction of disease causing mutations in CD40 Ligand deficiency, an inherited immune disorder which results in debilitating immunodeficiency Engineering of T-cells to resist HIV by disruption of the HIV co-receptor CCR5, in combination with expression of innate, humanised antiviral restriction factors. Plan of Investigation Preclinical development (Years 1-2) of reagents and processes for ex-vivo T-cell modification using lentiviral vectors and nuclease reagents (TALENs and CRISPRs). Translational adaptation in our clean room facility will follow, ahead of submissions to the MHRA and ethics committees for clinical trials approvals. Clinical Phase testing (Years 2-5). (i) A bank of T-cells engineered to target CD19+B-cell leukaemia will be produced from healthy umbilical cord blood donations. These naive cells exhibit powerful effects in transplant patients, and sufficient T-cells could be produced from a single donation to treat over 10 children (ii) Pilot testing of CD40L gene-editing will be undertaken in children without suitable HLA-matched transplant donors, aiming to provide a pool of circulating T-cells with functional restoration of CD40L expression (iii) Clinical therapy with engineered T-cells in HIV infection will be offered to adolescents who have been on life-long antiretroviral therapy (ART) and require alternative treatment interventions. Subsequent larger phase studies (Years 5-10) will draw support from our clinical trials centre, and clinical research networks; successful approaches would then be selected for progression towards licencing and commercialisation where appropriate. Benefits to NHS This project will bring immediate access to cutting edge technology directly to NHS patients, and is designed to provide a first evaluation of a new generation of technologies. The selected treatments will, in the first instance, address areas of unmet need in children with chronic conditions. If successful, much larger numbers of patients stand to benefit from these approaches which are designed treat chronic conditions with a single intervention. This would have enormous resource saving implications for the NHS, as well as families, carers and wider society.
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