Innovative methods for gene therapy in Ataxia-Telangiectasia

Research Project information

Principal researcher: Professor Ignacio Molina & Dr García-Pérez
Institute:  University of Granada
Cost: £100,000 over 36 months
Start Date: 15th of November 2019 (Extension to 31st August 2023 granted in October 2020)

What are the researchers proposing to do?
Gene therapy is a technique for correcting genetic defect by inserting a healthy copy of a gene into cells (replacing a faulty gene).  To deliver a gene into cells, scientists use delivery systems called vectors. Gene therapy has cured a significant number of children suffering from primary immunodeficiencies. In a previous study, Professor Molina’s team demonstrated that this technique also cures A-T cells. However, the extremely large size of the ATM gene (the gene missing or not functioning completely in A-T) means most delivery systems are inefficient.  Therefore, applying this therapy to A-T patients is currently not possible. To overcome this, the team now plan to study whether a new type of vector called transposons are suitable. Transposons may carry large genes and deliver them into target cells very efficiently, and thus represent an innovative approach to introduce a healthy ATM gene into A-T patient cells.

There is no cure for A-T and therapeutic options are limited therefore it is vital to develop innovative approaches to design new treatments for the disease. Transposons are a new type of gene-delivery vector that have demonstrated their capacity for carrying large DNA fragments. In addition, they are very safe and efficient, and are becoming a sound alternative to traditional vectors, whose efficiency is severely limited with large genes. Transposons could be an ideal tool to introduce a healthy ATM gene into A-T patient cells. With this procedure, the team hope to reverse the functional defects found in A-T patient cells.

How will the research be done?
Professor Molina and Dr García-Pérez will introduce a healthy ATM gene, into patient cells by chemical or electrical means using an in vitro (controlled environment in the lab) experimental system. Once the gene is integrated into the host cell DNA, they will analyse whether the modified deficient cells fully recover from the defects associated to the disease. If they can demonstrate the system is efficient, they will obtain human haematopoitic stem cells (cells that can develop into all types of blood cells) to attempt their reconstitution by using a similar strategy. This is particularly important because future clinical trials will target these cells, which are capable of restoring the immune system. Demonstrating an in vitro cure of A-T haemotopoitic stem cells is one of the main objectives of the project and a key preclinical requirement prior advancing into human trials.

How could it make a difference to the lives of those affected by A-T?
This therapeutic approach could be, in theory, very beneficial to A-T patients. Although the team demonstrated a proof-of-concept that gene therapy repairs A-T patient cells, the large size of the healthy gene makes most delivery systems not efficient enough for clinical application in A-T patients. By exploring whether transposons are useful tools, the team hope to open the idea of using gene therapy for A-T patients. The research proposal is ambitious and complex, but the fact that no other treatment is currently available, nor will be in the foreseeable future, means that it is essential to explore any sound alternative that may increase both the chances of survival and quality of life of A-T patients.