Transplantation of genetically modified haematopoietic stem cells for Friedreich's Ataxia

Lead Research Organisation: University of Bristol
Department Name: Bristol Medical School


Friedreich's ataxia (FA) is an incurable neurological disorder, typically presenting in late childhood. People with the condition experience progressive accumulation of neurological disability with impaired muscle coordination, weakness, imbalance and difficulties with speech, swallowing, hearing, vision and sensation. It is caused by a genetic mutation in the frataxin gene (FXN), which carries the genetic code for a protein called frataxin, resulting in low levels of frataxin within cells throughout the body causing them to malfunction and eventually die. There have numerous studies looking at possible new therapies for FA, but, as yet, people with FA remain without any treatment to limit disease progression.
Our research group have performed bone marrow (BM) stem cell transplantation experiments in mice that have the same genetic mutation as people with FA. When we transplant these FA mice with BM stem cells taken from donor mice with a normal version of the FXN gene, their indicators of disease improve significantly, with improvements in movement, balance, coordination and nerve cell survival. Interestingly, we can track the transplanted BM stem cells and find that large numbers of these cells have travelled into parts of the nervous system affected by FA and helped to protect and repair injured nerve cells.
We are currently developing BM stem cell treatments for FA, having recently performed a clinical trial in people with FA looking at how well BM cells can be activated and released into the blood stream with a hope they aid nerve cell repair. The results of this trial are very encouraging; we now want to move our research forward to a definitive treatment for people with FA.
Although experimental evidence demonstrates the feasibility of BM stem cell transplantation as an effective therapy for FA, when used clinically, transplanting healthy stem cells from the BM of one person and transferring them to another (called a allogeneic transplant) is associated with hugely significant risks; the challenge of finding an appropriately immune system matched BM donor, the use of powerful drugs to suppress the immune system (resulting in serious complications such as heart disease, neurological injury and infection/sepsis), the risk of severe anaemia and life-threatening complications arising from transplanted cells attacking other cells in the body all remain a possibility.
To avoid the major risks of allogeneic BM stem cell transplantation, we propose an alternative approach through removing stem cells from a person with FA and inserting a new FXN gene into the DNA of these cells using genetic engineering techniques. These stem cells, carrying a normal version of the FXN gene, can then be transplanted back into that person to enter the BM, blood and nervous system to then protect and repair to other cells.
A vital preliminary stage in the development of this treatment is to fully elucidate the biological mechanisms, safety and efficacy of the approach in an animal model of FA prior to clinical trials. This project will use state-of-the-art technology to insert a new FXN gene into BM stem cells prior to transplanting them into mice containing the same genetic abnormality as people with FA. These mice will be monitored to assess the impact transplantation has on FA disease progression. We will also develop a technique to deliver the FXN to human BM cells to ensure this can be done safely and efficiently in human cells.
Following on from this study, we will be in a position to develop new clinical trials in people with FA. Translation of BM stem cell transplantation therapy to clinical practice is realistic; the procedure has been successfully applied in humans for other diseases for over 50 years. We believe that our approach offers a significant advance in therapeutic options for people with this otherwise incurable and untreatable disease.

Technical Summary

Friedreich's ataxia (FA) is a neurodegenerative disease currently lacking any proven treatment. Experimental findings have provided robust evidence that allogeneic haematopoietic stem cell (HSC) transplantation may offer an effective treatment for the disease. When used in clinical practice, however, allogeneic transplantation is associated with significant morbidity and mortality. To mitigate this limitation, we propose to investigate whether genetic modification of endogenous HSCs (insertion of functional frataxin gene (FXN) ex vivo) and subsequent autologous HSC transplantation, is of therapeutic benefit. This approach offers the prospect of a significantly safer and rapidly translatable therapy which may have significant clinical impact on both symptoms and long-term disability for people with FA.

This project aims to produce a clinically relevant lentiviral transduction protocol for stable FXN delivery to isolated HSCs; to determine the efficacy of autologous FXN-corrected HSC transplantation to reverse neurological features of Friedreich's ataxia; and define mechanisms by which corrected cells prevent atrophy of large sensory dorsal root ganglion (DRG) neurons.

Lentivirus vector-mediated genome editing and transplantation techniques will be employed to demonstrate the efficacy of HSC gene therapy in models of FA. Neurobehavioural, neurophysiological and biochemical changes will be assessed to measure the impact treatment has on protecting or repairing nervous system function. Single cell RNA-sequencing will be employed to explore mechanisms of the DRG neuroprotection. Super-resolution confocal and transmission electron microscopy will provide further in-depth histological assessment.

Developing autologous FXN-corrected HSC transplantation as a disease-modifying treatment for people with FA may lead to major therapeutic advances in the foreseeable future.

Planned Impact

In addition to the Academic Beneficiaries, outlined separately, we have identified the following groups who will benefit from the proposed research and in the following ways.
Patients and carers
Friedreich's ataxia is the commonest hereditary ataxia, affecting at least 1 in every 50,000 people. Symptoms generally begin in childhood and affected individuals experience insidious accumulation of neurological disability, as well as cardiac and endocrine disease. Neurological diseases such as Friedreich's ataxia invariably have devastating consequences for the individual concerned (people with neurological conditions have the lowest health-related quality of life (EQ-5D) of any long-term condition [NHS England]); and their treatment and care often imposes a large emotional and financial burden on families, carers and society as a whole. This project will immediately impact upon people with Friedreich's ataxia and their carers through facilitating discussions on therapeutic requirements and unmet clinical needs as well as influencing the development and planning of this project and future research studies. Our research has recently led to a novel phase II trial of an investigational medicinal product (G-CSF) in patients with Friedreich's ataxia. With an estimated 2 years of project completion, we hope this Project Grant will also impact upon individuals with Friedreich's ataxia by facilitating future funding streams for urgently needed clinical trials of potential disease-modifying therapies.

National Health Service and social care
The NHS spends £3.3 billion per year on neurological services, representing 3.5% of total spending. A significant proportion of neurological diseases such as Friedreich's ataxia are untreatable and therefore present a significant socioeconomic burden; 14% of the social care budget is spent on people living with neurological conditions [NHS England]. This project, which seeks to accelerate progress and expansion in the development of new disease-modifying therapies, will therefore not only impact on long-term disability and improve quality of life for individuals but also expand working lives and productivity. Thus, a successful therapeutic intervention arising from the proposed work (anticipated within 5 years of project completion) has the potential to significantly reduce costs for both the NHS and social care.

Pharmaceutical and biomedical industries
The UK has the potential to build a world-leading regenerative medicine industry. This work will benefit commercial industries, within the time span of the project, by providing new and deeper insights into the potential of autologous HSCT in the treatment of progressive neurological disorders. Moreover, understanding the precise role of dysfunctional or ineffectual myeloid lineage cells in driving the pathophysiology of neurodegenerative diseases will help facilitate the discovery of new avenues for regenerative therapeutics, guiding industries in the development of therapies for people with otherwise untreatable progressive neurological disease.

Medical Research Charities
This project will provide evidence for the critical input and contributions medical research charities make towards supporting scientists and accelerating progress in health research. Dissemination and communication of this research will promote the importance of such charities thereby further raising public awareness and potential for long-term fundraising.

This project will enhance and support researchers in developing excellence in leadership, professional skills, research and teaching. Staff will have access to development training opportunities, whilst gaining skills in research techniques, scientific communication and supervision. The skills and experience gained by staff involved in the project will be applicable to diverse employment sectors opening up potential career opportunities in academia, industry, or other related endeavours.


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Title Lentiviral- FXN transduction of mouse and human mesenchymal stem cells 
Description We have constructed lentiviral vectors expressing the FXN gene and are developing the method for optimal transduction of mesenchymal stem cells. We are exploring with the our Research and Enterprise Development (RED) department the possibility of establishing IP to cover this procedure. 
Type Of Material Technology assay or reagent 
Year Produced 2021 
Provided To Others? No  
Impact Non at present