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Translational Research Office

Cell and Gene therapy

Treatment of disease using gene and stem cell therapy is now a reality. The UK, and UCL in particular, is at the forefront of developing cell and gene therapy for clinical application to a wide range of human genetic disorders. 

Case study: Professor Nathwani - an end to injection for Haemophilia

Professor Amit Nathwani, UCL Cancer Institute, has seen gene therapy for haemophilia go from dream to reality. He and his colleagues have successfully treated adults with haemophilia B, caused by mutations affecting the blood clotting protein factor IX. For some trial participants, the therapy has been life-changing. Even low-level expression – 2 per cent of normal – can do away with the need for regular injections of protein IX, the regular treatment.

Professor Amit Nathwani

Professor Nathwani’s work has significant economic importance. It currently costs £140,000 a year to provide a haemophilia B patient with the protein they are missing through regular injections. If this can be replaced with a single dose of gene therapy, in addition to the huge commercial opportunity (a global market worth £8bn), the new technology would also be economically beneficial to the health service. To date, Professor Nathwani estimates that the haemophilia B trial alone has saved around £2m in health service costs.

A similar treatment has been developed for the more common haemophilia A, caused by abnormal factor VIII. This is technically more challenging – factor VIII protein has a shorter half-life while the factor VIII gene is larger and not a good fit for the viral vector his group uses. Nevertheless, with more engineering, Professor Nathwani has generated vectors showing excellent performance in animal models. This technology has been licensed to the US biotech company Biomarin, which is scaling up production for clinical trials and possible clinical use.

Professor Nathwani is also looking at other potential applications of his technology. Alongside other single-gene blood and metabolic conditions, he has also developed a vector targeting liver cancer, which is switched on in cancer cells, producing a cytotoxic protein, but inactive in normal cells.

Case study: The London Project to Cure Blindness

London Project to Cure Blindness

The London Project to Cure Blindness aims to use Stem Cells to restore sight, prevent progression and ultimately improve the quality of life for patients with Age – Related Macular Degeneration (AMD).

The London Project is a collaboration between Professor Pete Coffey from UCL and Dr Lyndon da Cruz a retinal surgeon at Moorfields Eye Hospital. The aim is to combine cutting edge knowledge and technology from the laboratory, clinic and operating theatre in order to accelerate the development of new treatments for AMD.

Case study: SCID - in search of a lifelong cure

Professor Bobby Gaspar (left) and Professor Adrian Thrasher

‘Cure’ is a dangerous word to use, but in paediatric gene therapy, the signs are that the pioneering work of Professor Bobby Gaspar (left), Professor Adrian Thrasher and colleagues is leading to genuine lifelong cures.

Gene therapy has had its fair shares of ups and downs. But, argues Professor Bobby Gaspar, that is only to be expected of a new medical technology. With researchers and clinicians at the UCL Institute of Child Health and Great Ormond Street Hospital, Professor Gaspar, Professor Thrasher and colleagues have pioneered the use of gene therapy in children with inherited immunodeficiencies – running two of the world’s first four successful clinical trials. Now, a major challenge is to find ways to establish gene therapy as a routine treatment.

Conceptually, gene therapy is very simple: a new gene is inserted into a patient’s cells to restore missing or abnormal function. For one class of patients, the approach seemed very attractive. Children with inherited forms of severe combined immunodeficiency (SCID) can be treated by bone marrow transplantation, but if the match between donor and recipient is poor, the likelihood of success is greatly

The first two gene therapy trials, in 2001 and 2003, were for two forms of SCID, caused by mutations in different genes. They were remarkably successful, with the children treated now at school and living essentially normal lives.

One issue did emerge, however. The viral vector used to deliver the gene to a patient’s cells had a tendency to activate growth control genes close to points of insertion, leading to proliferation of some forms of blood cell. The effect was seen in all early trials; one UK patient was affected (but successfully treated).

As a result, the vector has been newly engineered so that it cannot activate genes close to insertion sites. New trials are now underway for SCID and also for other conditions affecting bone marrow cells, including Wiskott–Aldrich syndrome and chronic granulomatous disease. In addition, some patients are being treated on compassionate grounds, outside the context of a clinical trial.

The technology is entirely ‘homegrown’, having been conceived, developed and first used locally. Professor Gaspar and Professor Thrasher pay tribute to the many individuals that have contributed to its success – laboratory scientists, translational researchers, clinicians, clinical research facility staff and many others.

Now, having solved numerous technical issues, the team faces a new challenge – ensuring others can benefit from the technology. Discussions are underway with potential commercial partners with a view to making the technology more widely available. The diseases are rare, and there are no precedents for the commercialisation of gene therapy, so Professor Gaspar and Professor Thrasher are again breaking new ground. Although very different from the scientific challenges, solving them will help to ensure many more patients gain access to life-changing treatment.

Case study: Dr Martin Pule – Cell Engineering in Cancer

By combining technologies held in academia and industry, Dr Martin Pule is developing a new generation of ‘smart’ cell therapies for cancer.

The idea of using the body’s own defences to tackle cancer is far from new. But despite enormous effort, conventional cancer vaccines have mostly been a disappointment. Use of specific types of T cell has been more encouraging, but has been limited to special cases. Now, says Dr Martin Pule, innovative forms of genetic manipulation are greatly expanding the therapeutic potential of T cells.

T cells are excellent ‘killing machines’. The challenge has been how to direct their firepower so that a patient’s own T cells recognise and attack cancer cells. Dr Pule’s take on this approach is the ‘chimeric antigen receptor’ (CAR), which combines the recognition region of an antibody with the intracellular signalling domain of a T cell receptor. These are the ultimate smart weapons, moving under their own steam, dividing and signalling to other cells. Within UCL, a clinical trial is already underway to treat acute lymphoblastic leukaemia, a second is opening soon for neuroblastoma, and a suite of others are in development.

Dr Pule has teamed up with French company Cellectis to develop an innovative genome-editing technology known as ‘TALENs’. This technology can, specifically and with high efficiency, modify or disrupt any gene in the human genome. Such ‘universal’ CAR T cells could be used as an off-the-shelf product, eliminating the need to modifying a patient’s own cells.

The first universal cells will be targeted at a B-cell marker, for treatment of leukaemias such as chronic lymphocytic leukaemia (CLL). Dr Pule is excited at the potential of combining UCL’s cell engineering and early clinical trial expertise with Cellectis’s technology in a genuine industry–academia collaboration.

Case study: Professor Robin Ali – gene therapy for eye disease

Professor Robin Ali and a team of scientists and clinicians are making ground-breaking progress in both gene and cell therapies for eye diseases. A geneticist by background, Professor Robin Ali has spent 20 years pioneering gene therapy for inherited retinopathies, achieving some of the world’s first positive results in any kind of gene therapy. With a complementary highly promising cell therapy research programme, he and his colleagues have generated a translational research portfolio of remarkable breadth, spanning rare and more common diseases of the eye.

Professor Robin Ali

Over the past decade, gene therapy has begun to realise some of its immense potential, with a string of successful applications. One of the most notable was work carried out by Professor Ali, Professor James Bainbridge and colleagues on Leber’s congenital amaurosis (LCA), published to some acclaim in 2008.

Further LCA patients have now been treated, with similarly positive results. However, LCA is just one of a range of conditions that Professor Ali’s team has been targeting. In proof-of-concept studies,

Professor Ali has shown that gene therapy is a feasible approach for around a dozen inherited retinal conditions. Moreover, the approach may also be a way to deliver therapeutic molecules to treat other, more common conditions.

Although less advanced, exciting progress is also being made in cell transplantation. In a series of landmark papers, Professor Ali and colleagues have shown that early retinal progenitor cells – from a narrow developmental window – can integrate into the mouse retina, wire up with existing cells and improve vision. His group has also shown that such cells can be grown from embryonic stem cells in culture. However, more work will be needed before clinical trials can be considered.

Nevertheless, Professor Ali’s team has begun to gain experience of clinical application, in a trial being carried out in partnership with the US company Advanced Cell Technology, Inc (ACT) and led by Professor Bainbridge. ACT has developed a way to generate one type of retinal cell, retinal pigment epithelial cells, from embryonic stem cells, which are being tested as a possible therapy for the inherited retinopathy Stargardt disease.

Back in the laboratory, Professor Ali is also making exciting progress in cone transplantation. Responsible for colour vision, cones are an even greater challenge, but would offer additional visual benefits.

Both gene therapy and cell therapy are attracting commercial interest, particularly the former. Professor Ali is in discussion with UCLB and potential investors to identify routes of commercialisation, potentially through a new spinout company. Part of the challenge is to identify the business models that will make gene therapy economically sustainable – requiring extensive discussion with regulators on possible pricing arrangements. Resolving these issues, and finding commercial investors willing to fund late-stage clinical development, will be essential if gene therapy for the eye is ultimately going to move from experimental to mainstream treatment.

Case study: Dr Anna David – gene therapy to promote fetal growth

An innovative application of gene therapy led by Dr Anna David may offer a much-needed new approach to fetal growth restriction.

An ultrasound scan mid-pregnancy usually provides assurance that all is going well. But for a small number of mothers, it can bring bad news, revealing abnormally slow fetal development – fetal growth restriction. With no treatment available, mothers unfortunately give birth to a severely underdeveloped baby.

To address this serious problem, Dr Anna David is preparing to treat pregnant mothers by gene therapy to boost blood supply to the uterus and placenta to promote fetal growth –the first programme of its kind anywhere in the world.

The programme uses gene therapy to enhance levels of vascular endothelial growth factor

(VEGF) in the uterine artery. Known to be critical to normal placental development, VEGF has several potentially useful properties, including the ability to promote new blood vessel growth.

Positive results helped Dr David secure €6m funding from the EU Framework Programme 7 for a six-year programme to apply the technology clinically. Funded through the Health 2012 initiative, the programme was one of just four funded in the ‘gene medicines’ stream.

Other consortium members include FinVector, which will be manufacturing the gene therapy vector used in the trial, and a new company, which will handle the innovation and exploitation aspects of the programme. This will include managing IP issues and dealing with regulatory affairs in preparation for phase I and, if all goes well, later phase II trials.

Dr David’s main aim is to buy time – to enable the fetus to develop for an additional four weeks in the uterus. Currently, babies are delivered very early, to avoid stillbirths, at the very limits of their survival potential and at high risk of many developmental abnormalities. Moreover, given the high cost of neonatal intensive care, effective treatment could have a substantial economic impact, potentially saving the EU around €50m a year.