Refinement of gene and cell therapies for inherited immunodeficiencies based on human interventions and developing technologies . (360G-Wellcome-104807_Z_14_Z)

Significant recent advances in gene transfer technology together with improved understanding of basic disease biology have led to remarkable clinical successes in several inherited immunodeficiencies and metabolic disorders, and the realisation that advanced gene and cell therapies can eventually be applied more widely. However, clinical studies have also revealed some initially surprising limitations of technology both generic and specific to individual disease targets. The objectives of this a pplication are to use knowledge gained through experimental studies and first generation clinical trials to acclerate the implementation of more refined approaches. The specific goals are: 1. to examine the efficacy and safety of ongoing first-into-man clinical trials of gene therapy in primary immunodeficiency through detailed molecular and immunological analysis of treated patients. 2. to translate knowledge gained from relevant animal modelling and clinical trials into more refined strate gies in terms of gene delivery and expression. 3. to develop state-of-the-art vector technologies including retroviral gene addition, gene editing, and regulated transgene expression. 4. to explore the feasibility of gene therapy in other disease targets. 5. to understand disease-specific limitations to successful and safe application of gene transfer technology through modelling in relevant laboratory model systems of disease. 7. to establish a streamlined pipeline from concept to clinical application, and thereby to accelerate the adoption of novel cell and gene therapies as standards-of-care for patients with primary immunodeficiencies and other tractable rare diseases.