Get inspired by some of the research already funded

As of December 2022, the LifeArc Philanthropic Fund has awarded £14.6 million to 45 research projects since 2017. Click on the items below to find out about the projects we have funded and which are making progress towards translating science into treatments or diagnostics for the following rare and ultra-rare diseases:

Amyotrophic lateral sclerosis and frontotemporal dementia

Project title: SRSF1-targeted gene therapy for C9ORF72-linked Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Principal investigator: Dr Guillaume Hautbergue, University of Sheffield

Co-investigators: Prof Mimoun Azzouz and Prof Dame Pamela Shaw, University of Sheffield

Start date: 18 September 2020

Duration: 36 months

Amount funded: £513,141

Partner funding: £50,000 co-funding contribution from the MND Association

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable and fatal adult-onset neurodegenerative diseases. Someone in the world is diagnosed with ALS or FTD every few minutes.

People with ALS lose nerve cells in the motor system – leading to progressive paralysis and death, usually within 2-5 years of the first symptoms.

In people with FTD, nerve cells in the frontal and temporal lobes of the brain die, affecting cognitive function and behaviour. A fault in a gene known as C9ORF72 is the most commonly known genetic cause of both conditions.

There is currently no treatment for FTD. The current treatment for ALS patients, riluzole, only marginally extends survival – typically by around three months – and does not relieve the symptoms of progressive paralysis.

In both conditions, the gene is copied into the cells by a protein, which the team identified as SRSF1.

In C9orf72-linked ALS and FTD, one the main drivers of disease is the transport of pathological, C9orf72 repeated RNA molecules from the nucleus to the cytoplasm where neurotoxic dipeptide repeat proteins (DPRs) are generated. The team identified a particular protein called SRSF1 which binds to the pathological repeated RNA molecules and transports them out of the cell centre, effectively overriding the gatekeeping machinery within the nucleus by opening a back door.

The team had already shown that, by using a gene therapy comprising interfering virus vehicles to reduce the levels of SRSF1 protein, there was a reduction in nuclear transport of pathological RNA molecules and generation of neurotoxic DPRs – addressing a root cause of the diseases.

In the laboratory, this gene therapy approach promotes the survival of patient-derived nerve cells and has no detrimental effects at the genome-wide level or in control cell cultures.

The team also demonstrated that SRSF1 depletion prevents paralysis in a fly model of C9ORF72-ALS/FTD, and also that this intervention is safe in healthy mice.

The purpose of this project is to conduct further studies to optimise the gene therapy treatment strategy ahead of developing a clinical trial application as follows:

  • Evaluate the best delivery route for gene therapy.
  • Define the dose of gene therapy needed to achieve the best reduction of SRSF1 in a mouse model of C9ORF72 disease.
  • Conduct a pilot study to assess the therapeutic efficacy and any potential long-term adverse effects of the therapeutic gene therapy.
  • Identify the biological processes which are modulated in the mouse brain after treatment and compare them to data available in patient-derived brain cells.
  • Seek advice from regulatory bodies for a pre-clinical package to facilitate future clinical development.

The Motor Neurone Disease Association (MND Association) contributed £50,000 to the project.

This new research will be conducted in collaboration with the Cell and Gene Therapy Catapult which will provide support with designing the clinical vector and a detailed non-clinical safety strategy as well as regulatory advice to guide the team at the University of Sheffield through interactions with the Medicines and Health Regulatory Agency (MHRA).

Find out more via this recent press release.

Congenital factor VII deficiency

Project title: Gene Therapy for Congenital Factor VII Deficiency; Final IMPd/IND Enabling Studies

Principal investigator: Amit C. Nathwani, UCL Cancer Institute, Department of Haematology


  • Prof Flora Peyvandi; Fondazione IRCCS Ca’ Granda, Italy
  • Dr Kaan Kavakli; EGE University Childrens Hospital, Turkey
  • Prof Johannes Oldenberg; University Clinic Bonn, Germany
  • Dr Mary Mathias; Royal Free Hospital & GOSH, UK
  • Prof Edward Tuddenham; UCL
  • Prof Guglielmo Mariani; Westminster University, UK
  • Prof Amy Shapiro; Indiana Hemophilia & Thrombosis Center, USA
  • Dr Ulrike Reiss; St Jude Children’s Research Hospital, Memphis, USA
  • Dr Andrew Davidoff; St Jude Children’s Research Hospital, Memphis, USA

Start date: 20 March 2019

Duration: 21 months

Amount funded: £811,582

Partner contribution: $2M from Hemophilia of Georgia to St Jude Children’s Research Hospital, Memphis, USA

This study aims to move forward the development of a cutting-edge gene therapy approach for severe factor VII deficiency (SF7D), a life-threatening bleeding condition characterised by a deficiency of clotting factor VII – a protein essential for the blood to clot normally. The condition is linked to a recessive chromosome and is thought to affect around 1 in 500,000 people.

The liver is one of the prime targets for gene therapy to correct defects in a variety of clotting factor genes, but gene therapy for this condition has not been explored due to its rarity and the perceived difficulty in intervening early enough in life to prevent permanent organ damage and death.

This project is using the same virus vector platform technology that supported successful gene therapy in people with a related condition, haemophilia B, by mediating the continuous expression of a transgenic protein in these patients.

The team has developed a more potent form of the virus vector containing a codon optimised human FVII cDNA under the control of a small liver-specific promoter. The new virus vector has shown to greatly increase the transgene expression and preclinical data has enabled the potential therapy to be granted an orphan drug designation (ODD).

This study proposes/will undertake phase I/II clinical trials of the orphan drug in adults, potentially followed by trials in adolescents and children.

The team has established a wide-reaching clinical research network which, together with swift trial design and access to clusters of patients, improves the prospect of successful gene therapy for the condition.

Dravet syndrome

Title: AAV9-mediated gene targeting of natural antisense transcript as a novel treatment for Dravet Syndrome

Principal investigator: Dr Rajvinder Karda, University College London (UCL) Institute for Women’s Health


  • Simon N Waddington, UCL
  • Stephanie Schorge, UCL
  • Helen Cross, UCL

Start date: 1 May 2020

Duration: 36 months

Amount funded: £575,831

Dravet syndrome is a rare neurological condition that is often described as a complex form of epilepsy.

Children and adults with this lifelong condition will experience severe seizures that are difficult to control. Individuals with the condition may also suffer from varying degrees of intellectual disability and a spectrum of associated health conditions (known as ‘comorbidities’) – which may include autism, ADHD, challenging behaviours and difficulties affecting their speech, mobility, eating and sleep.

80% of patients with the condition carry a mutation in the SCN1A gene which encodes a sodium ion channel, NaV1.1, which functions to maintain normal firing patterns in neurons. Mutated NaV1.1 channels in Dravet syndrome patients do not function properly, which results in abnormal neuronal activity.

There is no cure and current treatments have limited benefit, as well as side-effects.

With this funding, Dr Karda aims to develop a gene therapy for Dravet syndrome. The approach involves delivering a gene element, using a viral vector, in order to increase healthy SCN1A expression and thereby restore the number of functional sodium ion channels, which in turn should normalise neuronal excitability.

The project will test the novel gene therapy in mice which have a deletion in the Scn1a gene (mouse equivalent gene) and therefore are a model of Dravet Syndrome. The Dravet mice, like the human Dravet patients, contain one functional gene and one non-functional gene and show seizures, cognitive impairment and premature death, which makes it a clinically relevant model of disease. Treatment is expected to upregulate the Scn1a gene, producing more functional sodium ion channels, which should restore normal neuronal activity.

The aim is to generate an optimised, clinically relevant gene therapy treatment which has demonstrated robust efficacy and safety in a clinically translatable model of the Dravet syndrome disease.

The gene therapy has the potential to treat all patients with an SCN1A mutation that causes loss of function, regardless of the specific mutation. It could potentially reduce or completely stop seizures, cognitive impairment, ataxia (an inability to coordinate muscle movements) and premature death.

Early-onset neurodegenerative disorder

Project title: Targeting autophagy as a shared mechanism in rare early-onset neurodegenerative disorder

Principal investigator: Sovan Sarkar, University of Birmingham


  • Timothy Barrett, University of Birmingham
  • Malgorzata Zatyka, University of Birmingham
  • Richard Tuxworth, University of Birmingham
  • Suresh Vijay, Birmingham Women and Children’s Hospital
  • Evangeline Wassmer, Birmingham Women and Children’s Hospital

Start date: 1 August 2019

Duration: 36 months

Amount funded: £420,746

There are over 600 rare neurodegenerative diseases, many childhood-onset, with devastating effects on children and families.

Finding new treatments is hampered by their rarity, a limited understanding of how they work and a low commercial incentive for investment. This research project targets a mechanism that many of these rare disorders have in common: deregulated autophagy.

Autophagy is the process by which cells degrade and recycle their unwanted or damaged components. It is critical for maintaining a healthy cellular balance. Deregulated autophagy, when this process goes wrong, reduces the viability of cells and leads to neurodegeneration.

This project targets deregulated autophagy in two exemplar rare disorders: Niemann-Pick type C1 (NPC1) disease and Wolfram syndrome (WS). Induction of autophagy has been beneficial in various transgenic or animal-based disease models.

Although several chemical modulators of autophagy have been identified, some research has indicated that drugs identified in immortalized human cells or mouse cells may not be effective in human disease-affected cell types.

The research team will be using different models based on pluripotent human stem cells – stem cells that can become any other type of cell – to identify candidate drugs that induce autophagy and that work in relevant tissues such as human neurons.

The project’s overarching aim is to determine the most potent inducer of autophagy via drug repurposing that will have therapeutic benefits in patients’ brains and can also be used in other rare early-onset neurodegenerative disorders associated with defective autophagy.

The research project aims to provide a robust experimental platform showing that targeting a common disease mechanism such as autophagy can be generalized to more than one neurodegenerative disease; that this can be extended in future to related conditions such as Batten/CLN3 disease; and that the data will support a future proposal for an early phase proof of concept and safety study in children with neurodegenerative disorders.

Fragment-based antibiotic discovery

Project title: Genome-wide target discovery and validation for fragment-based antibiotic discovery

Principal investigator: Professor Andres Floto, University of Cambridge


  • Professor Julian Parkhill, University of Cambridge
  • Professor Sir Tom Blundell, University of Cambridge

Start date: 3 March 2021

Duration: 48 months

Amount funded: £235,212

Partner contributions: Cystic Fibrosis Trust; Rosetrees Trust

Lung health is an area of medical need for people with cystic fibrosis (CF).

Industry efforts are focused on developing new precision medicines to treat the underlying genetic mutations that cause cystic fibrosis. However, these medicines will not be able to reverse existing lung damage, or eliminate the risk of chronic infection with drug-resistant bacteria.

The failure of antibiotics limits life expectancy of people with CF. New antibiotics are needed to counter the growth of antimicrobial resistance, such as Mycobacterium abscessus.

Conventional screening of bacteria against chemical libraries is incredibly inefficient because a very large number of drugs are needed to screen all possible chemical shapes

One solution is to break drugs down into their basic building blocks, or fragments,  and use these to screen against a purified target – such as a protein that is closely associated with a particular disease process.

This method enables researchers to work out where the fragments are binding and ‘grow’ or ‘link’ the fragments to build a drug that fits together perfectly. The approach has been successful in developing drugs for cancer and inflammation, but not, as yet, antibiotics.

The main challenges with applying this approach to developing new antibiotics are:

  • Finding the best target to attack within the bacteria
  • Working out how to design the antibiotic so the bacteria cannot become resistant
  • Designing drugs that bind to their target well but can also get inside bacteria and stay there, as bacteria are adept at pumping out antibiotics.

For this project, the team is aiming to use this fragment based approach to develop novel antibiotics for the bacteria M. abscessus which presents a serious threat to people with CF. The team will systematically analyse all the genes in the bacteria to find those which are most vulnerable to chemical inhibition using advanced gene editing and silencing technologies. They will then use computational biology to discover how best to design antibiotics which are less prone to bacterial resistance.

Finally, they will use artificial intelligence to develop rules for building antibiotics that actually get into the bacteria. This approach could overcome the barriers to using rational drug discovery for antibiotics, making it more straightforward to create many new drugs.

Friedreich's ataxia

Project title: Preclinical development of novel histone methyltransferase Inhibitors for Friedreich’s ataxia

Principal investigator: Richard Wade-Martin, University of Oxford

Start date: 29 April 2019

Duration: 4 years

Amount funded: £395,962

Friedreich’s ataxia (FRDA) is a neurodegenerative disease which typically begins during childhood or adolescence and is fatal.

In FRDA the molecular mechanisms of disease are associated with making the frataxin gene (FXN) inactive. Molecular mechanisms are the individual actions of chemicals and proteins that play a part in orchestrating cellular processes.

The disease is caused by a fault in the FXN gene, which when healthy, provides instructions to cells via a sequence of DNA to produce a protein called frataxin, (whose exact function is unclear).

The defective gene causes a part of the DNA instructions – a triplet sequence known as GAA – to repeat over and over again, hundreds of times. This error greatly reduces the amount of frataxin protein produced by the cell.

The team at Oxford, led by Dr Richard Wade Martins, screened for chemical probes that restore FXN expression and found a group of compounds which significantly increased frataxin protein. With funding from LifeArc, the team aims to:

  • Generate a series of compounds of suitable stability and potency to test target hypotheses in vitro and in vivo
  • Test the efficacy and safety of the compounds in types of stem cells derived from FRDA patients and differentiate these into the specific cell types most affected by reduced frataxin
  • Study the in vivo expression of FXN after treatment in a novel FRDA mouse disease model developed by the team.
Idiopathic intracranial hypertension

Project title: Non-invasive MRI of Blood-Cerebrospinal Fluid Barrier Function: A Breakthrough Translational Method to Improve Treatment for Idiopathic Intracranial Hypertension

Principal investigator: Dr Jack Wells, University College London

Co-investigator: Prof Alexander Gourine, University College London

Start date: 18 September 2020

Duration: 24 months

Amount funded: £146,781

Idiopathic intracranial hypertension (IIH) is a rare disease that most commonly affects women of childbearing age. Patients experience extremely painful headaches and can suffer loss of vision that, for many, leads to permanent damage to their eyesight.

The condition causes fluid pressure to build up in the brain. The primary source of this fluid pressure is a structure in the brain called the choroid plexus. While drugs can control the function of the choroid plexus, research has revealed that the benefits of these drugs are highly unpredictable.

This reflects a lack of data measuring how effectively the drugs affect the function of the choroid plexus and the resulting change to brain fluid pressure.

The team’s laboratory had previously invented the first non-invasive technique, using MRI, to measure the function of the choroid plexus – the part of the brain that these drugs seek to target.

In this study, the team is using the new, non-invasive technique in combination with intra-cranial pressure monitoring techniques to see how a range of drugs already approved for IIH affect choroid plexus function and brain fluid pressure in anaesthetised mice. This will allow the team to define how drugs affect choroid plexus function and brain fluid pressure for the first time.

The resulting data will fill a gap in knowledge about the mechanisms that underlie drug treatment strategies for IIH and provide a strong foundation for improving drug treatment for patients.

The technique has potential as an enabling technology and further development through this project could enable better drug assessment in other indications linked with raised ICP and ChP dysfunction.

Junctional epidermolysis bullosa (JEB)

Title: Repairing the skin barrier in Junctional Epidermolysis Bullosa (JEB)

Principal investigator: Dr Matthew Caley, Queen Mary University of London (QMUL)

Co-investigator: Professor Edel O’Toole, QMUL

Start date: 1 September 2020

Duration: 24 months

Amount funded: £152,122

Partner funding: DEBRA Austria, £21,600

Junctional epidermolysis bullosa (JEB) is a rare genetic skin disorder leading to severe skin fragility from birth, caused by the loss of skin basement membrane proteins that anchor the outer layer of the skin to the rest of the body. The most severe form, JEB generalised severe, is caused by complete loss of one of the parts of laminin 332, which is a key component of the basement membrane.

Babies diagnosed with this form of JEB do not survive beyond their first birthday. Current treatment for JEB is focused on palliative care, such as treating poor wound healing and infection, but this does not treat the underlying cause of disease. JEB patients therefore suffer from severe unmet need and require better, inexpensive treatments that can be made widely available and are more effective targeting disease mechanisms to improve on the treatment of disease symptoms.

Dr Caley’s team had discovered a previously unreported characteristic of JEB skin, a loss of cholesterol from the skin of JEB patients.

Within the skin, cholesterol plays an important role in maintaining the skin barrier preventing water loss, skin infection and dry skin-related itch. The team believes that the loss of skin cholesterol in JEB patients increases the severity of this disease. A restoration of skin cholesterol would not cure these patients but would improve their quality of life.

The approach is to use QMUL’s simple model of JEB to identify drugs that can restore cholesterol in JEB, testing positive hits in more complex 3D JEB skin models and finally use a JEB mouse model to identify future treatments for JEB patients.The team aims to identify novel drugs for the treatment of JEB patients and validate them in preclinical models of the disease. Restoring cholesterol to the patient’s skin could improve both their quality of life and survival.

The Epidermolysis Bullosa charity, DEBRA Austria, contributed €25,000 to the project.

Late-onset retinal degeneration (L-ORD)

Project title: Towards a therapy for late-onset retinal degeneration (L-ORD)

Principal investigator: Prof. Baljean Dhillon (BD), Dept. of Ophthalmology, University of Edinburgh


  • Prof. Baljean Dhillon, Dept. of Ophthalmology, University of Edinburgh
  • Prof. Caroline Hayward and Prof. Alan Wright, Institute of Genetics and Molecular Medicine, University of Edinburgh;
  • Prof. Siddharthan Chandran, MRC Institute for Stem Cell Research, University of Edinburgh
  • Prof. Robin Ali and Dr Alexander Smith, Institute of Ophthalmology, University College London, UK
  • Prof. Samuel Jacobson and Prof. Artur Cideciyan, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, USA
  • Dr. Andrew Browning, Department of Ophthalmology, Newcastle University, Newcastle

Start date: April 2021

Duration: 36 months

Amount funded: £497,971

Late-onset retinal degeneration (L-ORD) is a rare inherited eye disease that leads to blindness in older people. Sadly, there are currently no treatments that can help prevent sight loss.

L-ORD is caused by faults in a gene called C1QTNF5, which is highly active in the retinal pigment epithelium (RPE) – the thin layer of pigmented cells that supports and nourishes the retina at the back of the eye. In people with this faulty gene, the specialised light-sensing cells (rods and cones) in their retina stop working and eventually die, causing sight loss.

The Edinburgh research team is aiming to develop a new cutting-edge treatment that can correct the most common C1QTNF5 gene fault in RPE cells – offering the hope of preventing sight loss in these patients. They will carry out laboratory experiments to establish a suitable ‘gene-editing’ strategy that can correct the gene fault in RPE cells – and then test its effectiveness in stem cells and other RPE cell models of L-ORD.

The researchers will also study L-ORD patients with this gene fault to gain a better understanding of how the disease progresses over time. This will help them to determine the most appropriate timing for the treatment (delivered by an injection under the retina) and how to measure its effectiveness – laying the foundations for future clinical trials of this novel technology.

Natural killer-cell and gamma delta T-cell cancers

Project title: Novel Immunotherapeutics for Natural Killer-cell and Gamma Delta T-cell cancers

Principal investigator: Claire Roddie UCL Cancer Institute

Co-investigator: Martin Pule, UCL Cancer Institute

Start date:1 June 2021

Amount funded: £255,974

Most patients with lymphoma can receive treatment which effectively cures or controls their disease. However, certain rare types of lymphoma such as Natural Killer cell (NK-cell) lymphoma/leukaemia (NKL) and hepatosplenic gamma-delta (γδ) T-cell lymphoma (HGDTCL), can be very difficult to treat.

New treatments are urgently required because very few patients with advanced stage NKL or HGDTCL are cured. The overall survival of patients with HGDTCL is only 10 months and in patients with relapsed, advanced stage NKL, overall survival is only 4.9 months.

The research team believes that CAR-T therapy has a potential role in NKL and HGDTCL lymphomas.

CAR-T therapy is a powerful immunotherapy treatment which takes T-cells – key immune cells – and re-programmes them through gene therapy, giving them a ‘chimeric antigen receptor’ (CAR) which can recognise a specific protein on the surface of cancer cells. These engineered T-cells are then returned to the patient.

The therapy already works well in common forms of lymphoma, such as Diffuse large B-cell lymphoma (DLBCL) and those which are resistant to chemotherapy. Moreover, most patients with DLBCL who go into remission after CAR T-cell therapy stay in remission. This is unusual since most treatments for patients with resistant cancers extend life, but do not cure the disease.

The team has identified in laboratory work a cell surface protein called CD160 which is present on the surface of NKL and HGDTCL lymphomas. Having made CAR T-cells which recognise CD160, the team’s early laboratory experiments show these cells can kill NKL and HGDTCL cells.

The team is using LifeArc funding to:

  • Make the best possible chimeric antigen receptor (CAR) for the CD160 protein
  • Test the CAR in the laboratory and in mice with lymphoma
  • Study as many cases of NKL and HGDTCL as possible to measure how much CD160 protein they express on the cell surface.

It is hoped this laboratory work will demonstrate that CAR T-cells that target CD160 can eliminate NKL and HGDTCL lymphomas.

This would allow the team to seek funding for a Phase I clinical study of CD160 CAR-T in patients with NKL and HGDTCL lymphomas. The team has a large programme of Phase I CAR-T studies running at their centre already and is confident it has the infrastructure and expertise to bring new CAR-T therapy projects swiftly from bench to bedside.

Non-ketotic hyperglycinemia

Project title: Gene therapy for Non-Ketotic Hyperglycinemia

Principal investigator: Prof. Nick Greene

Institution: UCL Great Ormond Street Institute of Child Health


  • Prof. Simon Waddington
  • Prof. Stephanie Schorge
  • Prof. Andrew Copp

Start date: 1 October 2019

Amount funded: £373,597

Non-Ketotic Hyperglycinemia (NKH) is a life-limiting inherited metabolic disease that affects the chemical changes in cells of the brain and liver. It is marked by a build-up of glycine (an amino acid) in the body because of a mutation in genes that encode parts of the glycine cleavage system (GCS).

Most patients carry mutations in glycine decarboxylase, an enzyme that is part of the GCS. NKH becomes apparent in babies soon after birth with lethargy, breathing difficulties and neurological problems, including epilepsy and developmental delay. Current treatments for NKH have limited effect and there is no cure.

The project aims to develop gene therapy for NKH using a virus-based vector, to restore the activity of GLDC in the brain. This strategy has the potential to treat any patient with a loss-of-function mutation in GLDC and could be used for the other main NKH-causing gene, AMT.

In this project, the team will test novel gene therapy vectors in a GLDC-deficient mouse model that displays key features of NKH. It will evaluate whether treatment restores GCS activity and whether this can reduce metabolic defects in the brain, normalise gene expression and improve neurological features. As a step towards clinical implementation, the team will also test whether the impact lasts over time and is safe. This will support development towards the final stages of pre-clinical testing – including the start of GMP manufacture and pre-clinical studies to support application for a clinical trial.

Oculopharyngeal muscular dystrophy

Project title: Optimisation of a gene therapy for Oculopharyngeal muscular dystrophy

Principal investigator: Linda Popplewell, Royal Holloway University of London

Co-investigator: Alberto Malerba, Royal Holloway University of London

Start date: 3 August 2021

Duration: 36 months

Amount funded: £224,925

Around 1 in 100,000 people globally are diagnosed with the genetic condition Oculopharyngeal muscular dystrophy (OPMD) – although rates are higher in some populations.

The condition is caused by defects in a gene that makes PABPN1, a protein that plays a part in several important biological processes. The genetic defects cause the protein to form clumps in cells in the muscles important for lifting the eyelids and for swallowing. It can also affect some arm muscles.

The team has collaboratively been optimising a gene therapy approach based on injecting modified viruses that can act as very efficient carriers (vectors) of DNA into skeletal muscle. The vectors carry information that inhibits the production of all PABPN1 made in the cell and makes new protein without the mutation.

Currently a number of gene therapies are being tested clinically for the systemic whole-body treatment of rare genetic muscle diseases. While the vector the team has collaboratively developed for OPMD works well when injected directly into the muscle, for long term benefit clinicians would need to treat many muscles in each patient. The team is therefore looking to design a new vector to allow whole-body bloodstream delivery to treat multiple skeletal muscles in the body.

The project is using a different vector type with several modifications to the DNA it contains so that it is suitable for skeletal muscle, with the ultimate aim of treating patients with a single injection. This would improve patients’ treatment options, clinical outlook and quality of life.

The team will optimise the DNA that encodes the normal protein that is missing in affected cells and screen cells to find the best performing sequence to include in the final gene therapy product.

They will also screen other regulatory DNA sequences to minimise the expression of the vector in tissues other than skeletal muscle. These new features will be enclosed in a single vector that will be tested by bloodstream delivery in a mouse model of OPMD, allowing researchers to examine improvement in the function of affected muscles.

Primary sclerosing cholangitis

Project title: FAecal microbiota transplantation in primaRy sclerosinG chOlangitis: The FARGO trial

Principal investigator: Palak Trivedi; NIHR Birmingham BRC, Centre for Liver and Gastrointestinal Research, University of Birmingham, UK


  • Nabil Quraishi; Univ. Hosp. Birmingham, UK
  • Tariq Iqbal; Univ. Hosp. Birmingham, UK
  • Andrew Beggs; Institute of Cancer and Genomic Sciences, Univ. of Birmingham, UK
  • Rachel Cooney; Univ. Hosp. Birmingham, UK
  • Simon Gates, Biostatistics and Clinical Trials, Cancer Research Clinical Trials Unit , Univ. of Birmingham, UK
  • Daniel Slade, Biostatistics and Clinical Trials, Cancer Research Clinical Trials Unit, Univ. of Birmingham, UK
  • Christopher Quince; Earlham and Quadram Institutes, Norwich Research Park, Norwich, UK
  • Benjamin Mullish; St Mary’s Hosp. Campus, Imperial College London, UK
  • Ailsa Hart, St Mark’s Hosp. & Academic Institute; UK
  • Laith Al-Rubaiy, St Mark’s Hosp. &Academic Institute, UK
  • Douglas Thorburn; Royal Free Hosp. London, UK Martine Walmsley; PSC Support, UK

Start date: 01 February 2022

Duration: 48 months

Amount funded: £798,774

Partner funding: £50,000; PSC Support

Primary sclerosing cholangitis (PSC) is a rare liver disease where the body’s immune system attacks the bile ducts. The condition affects around 3,600 people in the UK – and can develop at any age, but most commonly in people under the age of 40.

In people with PSC, the bile ducts become blocked due to inflammation and scarring – causing bile (an important digestive juice made in the liver) to accumulate in the liver. Patients will experience repeated bile infections, liver failure and, in some cases, bile duct cancer. In four out of five people with PSC, the immune system also attacks the bowel, leading to inflammatory bowel disease (IBD). The combination of PSC and IBD also increases the risk of bowel cancer, with patients requiring a colonoscopy every year to screen for this disease.

Currently, there is no cure for PSC, but a range of treatments are available that can help control a person’s symptoms. Many people will ultimately need a life-saving liver transplant. Although a very rare disease, PSC accounts for around one in 10 of all liver transplants in the UK and is the leading reason for transplantation in several European countries. But liver transplantation is risky and unfortunately, the disease will return later in around a third of patients.

Scientists have identified differences in the population of microbes living in the gut of people with PSC compared to those who do not – and these gut microbial imbalances are thought to play a key role in driving the development of the disease.

The team, led by researchers at the University of Birmingham, is carrying out a clinical trial to find out whether a new treatment – called ‘faecal microbiota transplantation’ (FMT) – can help slow the progression of PSC and improve quality of life for patients.

In the FARGO study, the team will find out if taking stool containing microbes from the gut of healthy donors, refining it in a laboratory, and transferring it to the bowel of people with PSC, could help reverse the imbalance of gut microorganisms. This approach has shown promise for treating IBD in early research.

The trial participants will receive either FMT once a week for 8 weeks, or a placebo (an inactive FMT equivalent). Each group will continue to receive their usual routine standard of care for their IBD. The team will observe all patients for another 40 weeks. They will then compare information between the two groups – to find out if the treatment helps to improve liver blood tests, scarring in the liver, severity of IBD, and quality of life.

This study will lay the foundation for future work on a larger scale, with the goal of one day making FMT available more globally.

Refractory aplastic anaemia

Project title: Production of expanded autologous regulatory T cells to treat patients with refractory aplastic anaemia in a phase I dose study

Principal investigator: Prof Ghulam Mufti, Kings College London


  • Dr Shreyans Gandhi
  • Prof Giovanna Lombardi
  • Dr Abdel Douiri
  • Dr Shahram Kordasti
  • Dr Nazia Matto
  • Dr Giorgio Napolitani

Acknowledgements: The team is indebted to Prof Judith Marsh who initiated this innovative research prior to her retirement in early 2021

Start date: 18 September 2019

Amount funded: £1,000,000

Partner funding:  £152,655 from The Aplastic Anaemia Trust

The team’s earlier research had shown that patients with refractory aplastic anaemia (AA) have fewer T regulatory cells (Tregs) which dampen down the abnormal cells that destroy bone marrow stem cells.

The research team then used new technology to expand the Tregs from AA patients “in vitro”, confirming that they prevent the immune system from attacking the bone marrow stem cells.

Following these laboratory results, researchers plan to start a phase I/II clinical trial for AA patients who have not responded to standard treatments, examining the safety of administering Tregs that have been expanded in vitro back into the donor patients. This is a single site, open-label, phase I/II clinical trial at King’s College Hospital / King’s College London.

This form of cellular therapy for AA is a world first. The team will study the changes in the immune system in detail and determine if healthy bone marrow stem cells regenerate following administration of the expanded Tregs. The use of expanded ‘autologous’ Tregs is currently being evaluated in other autoimmune disorders such as type I diabetes mellitus, multiple sclerosis, Crohn’s disease and systemic lupus erythematosus – as  well as in organ transplantation.

Results so far indicate that this treatment is safe and may improve outcomes in these diseases.

The project outcome will be the availability of data to demonstrate how safe this potential treatment is and the optimal dose to be given.

Severe ichthyosis

Project title: Using JAK inhibitors to repair the skin barrier in severe ichthyosis

Principal investigator: Professor Edel O’Toole, QMUL


  • Dr Emanuel Rognoni
  • Dr Matthew Caley, QMUL

Start date: 18 March 2021

Autosomal recessive congenital ichthyoses (ARCIs) are rare genetic skin disorders where babies are born covered with a membrane which sheds to leave red, scaly skin all over their bodies. ARCIs are life-long disorders and reduce quality of life significantly.

The most severe form of ARCI, harlequin ichthyosis (HI), is caused by a mistake in a gene called ABCA12 that transports lipid (fats) in the upper part of the skin. This defect makes the skin leaky, resulting in loss of water and protein and increased risk of infection.

JAKS are proteins in a cell involved in processes such as immunity, cell division, cell death and tumour formation, which communicate via a signalling pathway. In a tissue culture model of HI, the research team found that blocking a cellular pathway known as the JAK pathway with a licenced drug called tofacitinib (a JAK pathway inhibitor), reversed the leakiness of the skin. This improved the skin barrier.

As HI is a very severe skin barrier disorder, it is likely that JAK inhibitors will also work in less severe forms of ARCI if this success is confirmed.

JAK inhibitors are in clinical trials for many common skin diseases, particularly atopic eczema. In this study, the team will generate models of HI and one of the other ARCI types in a tissue culture dish and treat them with five available JAK inhibitors.

The team will record changes in the skin model in detail. They will profile the lipids and genes in the treated model and then pick two JAK inhibitors to use in a mouse model of HI. These data should allow the team to choose the right JAK inhibitor for treatment of patients with HI and other severe ichthyoses and improve understanding of how these drugs work in repairing the skin barrier.

Spastic paraplegia 47

Title: Gene Replacement Therapy for Spastic Paraplegia 47

Principal investigator: Professor Mimoun Azzouz

Institution: University of Sheffield


  • Professor Dame Pamela Shaw, University of Sheffield
  • Dr. Laura Ferraiuolo, University of Sheffield

Start date: 1 April 2020

Duration: 36 months

Amount funded: £470,066

Spastic paraplegia type 47 (SPG47), an inherited condition affecting children, is due to loss of neurons in the brain leading to muscle weakness.

Patients develop cognitive defects including poor speech and intellectual disability, in addition to loss of movement. A deficiency of the AP4B1 protein causes the loss of neurons.

The project aims to restore the AP4B1 gene into cells using virus carriers modified to remove all their harmful properties, making them safe for human use. The team successfully used this approach to restore the level of AP4B1 protein in skin cells donated by an SPG47 child and demonstrated the safety of the approach in healthy mice. These results generated great hope and optimism among patients and their families but further studies are needed before entering clinical application.

The project aims to:

  • test the approach in neurons derived from skin cells donated by SPG47 children
  • determine the minimal dose of the carrier that generates impact in the animal model
  • assess potential adverse effects in a research pilot safety study
  • request advice from the regulatory body in the UK and the USA
Spinocerebellar ataxia

Project title: Preclinical development of TRPC3 inhibitors for Spinocerebellar Ataxia

Principal investigator: Prof Esther B. E. Becker, University of Oxford

Co-investigator: Prof Paul Brennan, University of Oxford

Start date: 4 March 2020

Duration: 36 months

Amount funded: £424,262

Ataxia comes from a Greek word meaning ‘lack of order’ and is a term for a group of disorders that affect movement, balance and speech.

These clinical symptoms reduce patients’ quality of life. Sometimes, people suffering from ataxia develop cognitive disabilities and many ataxias lead to premature death.

The subgroup of the Spinocerebellar Ataxias (SCA) are inherited neurodegenerative disorders. They are characterised by the loss of specific nerve cells called Purkinje cells in the cerebellum, the part of the brain that controls movement and coordination.

There is currently no cure for SCA and patients urgently need new treatment strategies.

Although more than 40 gene mutations lead to SCA, it is believed that many genetic forms are caused by common underlying disease mechanisms. Notably, TRPC3 – a transient receptor ion channel that regulates the calcium balance in Purkinje cells – acts abnormally in people with SCA. The team is investigating whether inhibiting TRPC3 could improve outcomes for people with SCA.

While there are currently no selective and potent inhibitors of TRPC3, the team identified two hit compounds that act against TRPC3 in a previous collaboration.

The funding enables the team to study these compounds to generate drug leads that offer the best prospects for inhibiting TRPC3. They will then test those compounds in disease-relevant models with the aim of translating them into a treatment for patients with SCA.

Thrombotic thrombocytopenic purpura (TTP)

Project title: Thrombotic Thrombocytopenic Purpura: A novel assay to monitor disease and prevent relapse

Principal investigator: Prof Marie Scully, Institute of Cardiovascular Science, UCL


  • Dr Rens de Groot, Institute of Cardiovascular Science, UCL
  • Dr Claudio Capelli, Institute of Cardiovascular Science, UCL

Start date: 1 June 2021

Duration: 24 months

Amount funded: £223,066

This project aims to improve the treatment of patients who have the rare life-threatening disease Thrombotic Thrombocytopenic Purpura (TTP) – a disease often only diagnosed when patients show symptoms of multiple organ dysfunction caused by multiple small blood clots in the vessels that supply the organs with oxygen.

TTP occurs in people with a deficiency of a specific enzyme, ADAMTS13. The enzyme is important in preventing excess bleeding or clotting and its primary role is to keep the level of an important protein in blood clotting under control.

Following initial treatment, patients require lifelong monitoring to prevent subsequent episodes. Laboratory tests measure ADAMTS13 activity to both confirm the diagnosis and minimise the risk of subsequent episodes.

But anticipating which patients are relapsing when their levels of ADAMTS13 fall from a normal range is difficult to assess as some patients’ levels stay below 10% throughout remission. This makes decisions about the timing of treatment (with the drug rituximab) challenging.

In addition, these tests only tell clinicians the level of the enzyme and do not help them understand the underlying impact of the small clots that cause symptoms.

The team has developed a new test for TTP patients which mimics high blood flow through a small vessel and provides a comprehensive assessment of the increased small blood clot risk, the cause of organ damage in TTP patients. The aim is to optimise and evaluate this new test in a large number of TTP patient samples so that it provides additional information on the underlying disease and enables personalised patient therapy.

Preliminary data shows that it is possible to distinguish the blood of a TTP patient from normal healthy control blood. The test detects increased formation of microthrombi (a microscopic clump of fibrin, platelets, and red blood cells) in TTP patients with normal platelet counts, which explains non-acute symptoms that have previously been overlooked.

Ultimately, the team plans to develop the test so it is available on routine coagulation analysers that analyse fresh or stored blood samples and could produce results within half an hour.

The team plans to optimise and evaluate the test in a large number of TTP patient samples at different stages of their condition. They will compare the results to current standard ADAMTS13 tests, clinical data and routine laboratory tests. This should improve the new test by making it less labour-intensive and more attractive for regular use in patients. It will provide additional information on the underlying disease pathology to enable personalised patient therapy.

X-linked lymphoproliferative disease (XLP)

Project title: Pre-clinical studies to support a Phase I/II clinical trial of autologous T cell gene therapy for X-linked lymphoproliferative disease (XLP)

Principal investigator: Dr Claire Booth, UCL Great Ormond Street Institute of Child Health, London

Co-investigator: Prof Adrian Thrasher, UCL Great Ormond Street Institute of Child Health, London

Start date: 1 August 2019

Duration: 24 months

Amount funded: £396,926

X-linked lymphoproliferative disease (XLP) is a rare genetic condition that affects boys. Symptoms vary but most patients have abnormal immune responses to some viral infections (called haemophagocytic lymphohistiocytosis or HLH). These can result in rapid death. They also often experience recurrent infections and about a third develop lymphoma.

Affected boys become sick in childhood or early adolescence. Patients are often treated with lifelong immunoglobulin therapy. Bone marrow transplants can be effective as a treatment but the results depend on whether the transplant takes place before any symptoms develop, as well as having a well-matched donor.

Up to half of patients who receive a transplant from a mismatched donor with active disease will not survive. There is a clear unmet need for patients who do not have a suitable transplant donor. Alternative approaches are required to reduce the burden of disease complications, avoid regular immunoglobulin therapy and reduce the risks of malignancy and HLH.

Dr Booth’s approach would offer a cost benefit over bone marrow transplant, which typically costs more than £250,000 and even more if patients develop transplant-related complications.

Most of the immune system abnormalities seen in this condition arise due to abnormal function of T-cells. The team had already shown, using an XLP mouse model and through studies on XLP patient T-cells, that some of the abnormalities could be corrected by using gene-corrected T-cells. The benefits include improved immunoglobulin production and antibody responses to immune challenge and tumour formation.

The team therefore believes that gene therapy correcting patients’ T-cells will help many of their symptoms and may be a safer treatment option than a bone marrow transplant from an unrelated donor. Using the patient’s own cells avoids any risk of graft versus host disease – which can cause significant morbidity and mortality after transplant. With less chemotherapy required, this approach would reduce toxicity associated with the procedure.

As in other gene therapy clinical trials underway at UCL Great Ormond Street Institute of Child Health, this project uses a type of virus (a lentivirus) to transfer a normal copy of the defective gene into patient T-cells. There have been no safety concerns associated with this type of virus or infusing patients with gene modified T-cells (for example to treat specific forms of cancer).

The research aims to reach the clinical trial stage, offering patients lacking a suitable donor for bone marrow transplant an alternative treatment.

The funding supports generating and testing the virus for clinical use, undertaking the required safety and efficacy studies and ensuring the appropriate regulatory framework is in place to initiate a Phase I/II clinical trial at Great Ormond Street Hospital. This is the first trial of its kind for XLP and the T-cell gene therapy approach could be used to treat other immune disorders affecting T-cells. UCL Great Ormond Street Institute of Child Health has extensive experience of translating and delivering successful gene therapy trials for immune disorders and the treatment, if effective, will be taken forwards to a pivotal (phase III) registration trial so the therapy can be licensed and made more widely available.