A new cell and gene therapy approach for Friedreich's ataxia

Friedreich's ataxia is a rare disease caused by mutation of the Frataxin gene (FXN). This results in dramatically reduced levels in the tissues of patients of a protein essential for life called Frataxin. Children born with the defective version of the FXN gene by the age of 5 to 10 years start to manifest the symptoms of the disease that include gradual loss of strength and sensation in the arms and legs; muscle stiffness (spasticity); and impaired speech, hearing, and vision. Individuals with Friedreich's ataxia develop muscle weakness and often have a form of heart disease called hypertrophic cardiomyopathy, which enlarges and weakens the heart muscle and can be life threatening. The average life expectancy is 37 years and there is still no definitive cure for the condition. Standard management is mainly symptomatic and based on physiotherapy, to alleviate difficulty on speech or swallowing, surgery, for severe cases of scoliosis or foot deformities, and medication to control hearth arrhythmias. The experimental approach that we are using in our laboratory to tackle the condition is based on cell and gene therapy. We aim to restore appropriate levels of the Frataxin protein by engineering a new version of the FXN gene that will be inserted in the DNA of blood forming (stem) cells. The blood stem cells will deliver the therapeutic protein to the heart, the brain and other tissues that are particularly sensitive to the loss of Frataxin. Since the therapeutic protein will be produced by stem cells that are permanently homed in the bone marrow of patients, the treatment should result in the cure of the condition. Before testing this strategy in patients, we need to demonstrate its efficacy in a mouse model of Friedrich's ataxia that was developed in our laboratory. We will conduct a clinical trial in mice using appropriately modified FXN genes that will be introduced into blood cells. The modified cells will be injected into mice and the progression of the disease will be compared between treated and control animals. If our strategy will be successful in the laboratory, this will justify the start of a clinical trial in patients with Friedrich's ataxia.

Friedreich's ataxia is a rare genetic disease affecting the nervous system, caused by mutations of the Frataxin gene (FXN). This results in dramatically reduced levels in the tissues of patients of a protein essential for life called Frataxin. Individuals with Friedreich's ataxia develop muscle weakness and often have a form of heart disease called hypertrophic cardiomyopathy, which enlarges and weakens the heart muscle and can be life-threatening. Affected individuals can die at a young age and there is still no definitive cure for the condition.
The idea at the base of this proposal is to restore the expression of the Frataxin protein in Friedreich's patients by engineering secreted, cell penetrating versions of the molecule that will be delivered by haematopietic stem cells (HSCs). Patient's blood stem cells will be modified to carry a virus that produces the cell-penetrating Frataxin. The Frataxin-producing stem cells will be reinfused into patients where they will permanently home into the bone marrow. Modified haematopoietic cells circulating in the blood stream will differentiate into macrophages, oligodendrocytes and other terminally differentiated cells which will deliver the therapeutic protein to the damaged tissues, hopefully resulting in a permanent cure. The main goal of the study is to validate this concept using a mouse model of Friedrich's ataxia established in our laboratory. YG8LR mice show reduced expression of FXN and symptoms similar to those of patients. We will use this mouse model to investigate whether intravenous injections of HSCs modified to express Frataxin fused to different cell penetrating peptides ameliorate symptoms and restore normal organ systems functions. In parallel, we will manipulate human HSCs in vitro to gain proof of principle that expression of the therapeutic gene does not affect normal haematopoietic differentiation. If completed, this study should lead to the first cell and gene therapy trial for Friedrich's ataxia.

-Who will benefit from this research?

The beneficiaries of the research are broadly divided in Academia, Skill Transfer, Industry and Public Health.

-How they might benefit from this research?

Development of ATMPs are probably going to have a solid effect over biotechnology industry and general wellbeing. The UK is in a one of a kind position for advancement of ATMPs as it has favourable lawmaking body that oversees the utilization of human tissue, a flourishing examination group which has been instrumental in the overall improvement of cell and quality therapeutics and a dynamic biotechnology industry which has possessed the capacity to catch both private and open investments. Development of the cell and gene therapy industry in the UK is vital to draw internal investments. A venture of this nature encourages the further advancement of this beginning industry. As far as financial advantages, the outcome of our project will increase the quality of gene and cell therapy projects that will lead to: i) expanded income for organizations in the UK that develop and supply viral products, cell culture media and reagents, ii) help in efficiency, work creation and private investments over the cell and gene therapy industry. Patients and health care providers (NHS) will profit by enhanced treatments and lower failure rates, reducing the budgetary weight on the NHS. The clinical benefits, thus, will have a social effect, as patients could have enhanced treatments, making their recuperation speedier, increasing their well being and their social and financial situations.
More short term impacts of the projects will be: a) The creation of animal and cellular models of Friedreich's ataxia that will be used to understand the pathophysiological causes of the disease and for preclinical validation studies b) The identification of molecular targets c) The establishment of links with other national and international laboratories interested in ataxia research. This global collaboration will generate knowledge and stimulate awareness and interest in Friedreich's ataxia research; d) Fostering the aggregation of patients, clinicians groups and stimulating the formation of charities specialised in neurodegenerative diseases research, with the opportunity for jobs creation. The basic research questions investigated in this grant application will benefit academia by enhancing the understanding of fundamental biological processes. Post doctoral fellows, undergraduate and graduate students will benefit from this research by learning new techniques, being involved in problem solving exercises and challenged intellectually during presentations in laboratory and conference meetings.