Validating a clinical candidate lentiviral vector for human haematopoietic stem cell gene therapy trials in people with Friedreich’s ataxia

Friedreich’s Ataxia (FA) is a complex and currently incurable genetic disorder, that typically appears in late childhood. People with the condition experience progressive accumulation of neurological disability. The disorder also affects multiple other organs, with over half of FA patients also presenting with cardiomyopathy, and a third with diabetes. Currently, FA treatment is symptomatic and supportive only, and there is a significant unmet need for treatments to prevent disease progression. FA is caused by a genetic mutation in the FXN gene, which carries the genetic code for a life-essential protein called frataxin. This mutation leads to low levels of frataxin within cells, causing them to malfunction and die. Our research, along with studies conducted by other scientists, has shown a promising therapeutic strategy for FA. It involves replacing a patient's blood stem cells harbouring the mutated FXN gene with cells from that of a healthy donor. When transplanted into individuals with FA, the donor stem cells, containing a normal FXN gene, have the capability to distribute and restore frataxin levels throughout the body. However, in clinical practice, transplanting cells from another person does carry several problems, including the challenge of finding an appropriately matched donor. There is also a significant risk of life-threatening complications related to the use of cytotoxic and immunosuppressive drugs to prevent donor cell rejection. Our research team are exploring an innovative approach to overcome the challenges associated with transplanting donor stem cells. This involves isolating a patient's own blood stem cells, inserting a new normal FXN gene using a modified non-pathogenic virus, and then transplanting them back into the individual. We have tested this approach in mice with FA and have shown extremely promising outcomes. These include improvements in blood stem cell function, restorations in body mass, and enhancements in the way the mice can move and walk. To obtain regulatory approval for the clinical use of genetically modified blood stem cells in humans, extensive preclinical studies are required. These studies must adhere to strict guidelines set by regulatory bodies, such as the European Medicines Agency (EMA), to ensure the safety and efficacy of the proposed therapy. As part of the preparations for securing the substantial funding required to initiate this pre-clinical work, it is vital to provide robust data demonstrating both the feasibility and scientific validity of the therapy in human blood stem cells. To bridge the gap between our current findings in FA mice and the planned pre-clinical safety and toxicology studies, we propose a focused, single-step study to validate the use of our non-pathogenic virus for delivering a healthy FXN gene into blood stem cells derived from individuals with FA. This represents a critical and high-risk step, essential for generating experimental, human-specific data on FXN gene addition and expression. This data will be key in rapidly de-risking the subsequent development of our approach and advancing towards a clinical trial application. Overall, through this study our focus is to develop a safe and easily applicable one-time treatment for people with FA that can slow or prevent disease progression.