Gene therapy has long since established itself as the cornerstone of modern medicine, and the first step into the field of personalised medicine. The British Society for Gene and Cell Therapy (BSGCT) has worked tirelessly since its inception in 2003 to promote the global reputation of UK gene therapy research.
Gene therapy research in the UK cuts across a broad arena of both inherited and non-inherited diseases, utilises a range of viral and non-viral gene transfer approaches, and, importantly, has been at the leading edge of translating experimental gene therapy to the clinic. This is exemplified by clinical trials, for example, in patients with severe combined immunodeficiency and haemophilia B. These experiments have led the field internationally, provided direct measurable benefit for patients and provided mechanistic insight into the function of gene therapies in patients.
22,000
Pages in the report submitted by Geron to the FDA
£125m
Funding for the CTC
Latterly, the synergy between research efforts in the gene and cell therapy communities triggered the change of name to include ‘cell’ therapy and the adoption of the new society aim. Initial engagement with stem cell researchers is expanding via active engagement of BSGCT members from the stem cell community, including the election of several high-profile stem cell researchers to the BSGCT board.
Gene therapy is a relatively mature field of research. Following the initial early positive pre-clinical data in the 1990s, gene therapy suffered from a series of events that had a dramatic effect on the field, both at the industry and commercial level, and at the level of academic funding. These included the death of Jesse Gelsinger on a gene therapy clinical trial in 1999, and serious adverse events on trials using integrating viruses on children. The reactions were profound but the field reacted positively and has, in the last decade, made substantial progress at the scientific and clinical levels. This has shaped the landscape for new engagement by large pharma, and small and medium enterprises alike.
Today, the BSGCT engages the UK’s academic and industrial sectors in both gene and cell therapy. The formation of the field of gene therapy predates that of human pluripotent stem cell biology by about 10 years, but many of the lessons are the same. In both cases, early media expectation created an unrealistic fantasy that a ‘cure for all within five years’ was forthcoming. However, this was soon followed by the realisation that slow and cautious progress towards the clinical treatment of specific diseases was required. Long timelines allow high-quality, safe products to be developed, funding to be secured, and the public and regulators to be fully engaged.
Overcoming hurdles
The cost of research and development, and progress to clinic is high. Geron Corporation pioneered the first-ever human embryonic stem cell trial in 2011 into spinal cord injury. Monumental effort was required to make this happen, including a 22,000 page submission to the Food and Drug Administration (FDA). Even then, the trial only came about after the election of Barack Obama, who is significantly more open to stem cell research than his predecessor George W Bush. Phase 1 clinical trials were completed successfully but later the same year Geron was forced to shut down its stem cell operation due to insufficient funds. It has since sold rights to a San Francisco-based company, BioTime. Advanced Cell Technology has also experienced a series of financial missteps that may jeopardise the future of its clinical trials.
It is within this context that the UK has made several regulatory and strategic decisions over the last 20 years. Recognising the special status of the human embryo, the Human Fertilisation and Embryology Authority (HFEA) was established in 1982, leading to the Human Fertilisation and Embryology Act being passed by Parliament in 1990. The act has since been twice revised: first in 2001 to permit isolation and research on human embryonic stem cells for strictly regulated purposes; and then in 2009 to permit the strict but facilitating regulatory regime for embryonic stem cell-based regenerative medicine.
Though the UK remains a much more favourable environment for stem cell research than the US, there are still severe regulatory and structural limitations to advancement of the field. Recently, the government announced the HFEA was to be disbanded and its activities consolidated into the Care Quality Commission – however, strenuous opposition from organisations including the British Medical Association and the Wellcome Trust forced a reversal. The HFEA will remain but is expected to make numerous cuts because of governmental spending plans.
In parallel to these changes, the UK government commissioned the Pattison report – also known as the UK Stem Cell Initiative – in 2005 to set out a long-term vision for UK stem cell research. The report made 11 key recommendations aimed at consolidating the UK’s current position of strength in stem cell research and turning it into a global leader in this technology over the next decade.
A BSGCT public engagement day, where students, patients and members of the public are educated on the science behind gene and cell therapy
However, the impact of the report has been slow to materialise and has since been superseded by a more proactive report from the Department for Business, Innovation & Skills (BIS), which urged the government to continue to facilitate the adoption of cell therapy in the National Health Service. The process has been long and convoluted as opposing parties seek to have their views represented every step of the way.
Securing progress
The BIS report led to the inception of technology ‘catapults’, ranging from satellite applications and future cities to renewable energy and regenerative medicine. This was termed the ‘Cell Therapy Catapult’ (CTC) and has attracted £125m funding from the Technology Strategy Board and UK government. The remit of the CTC is to promote and build the UK cell therapy industry by bridging the gap between basic research and clinical translation. This transition often stalls due to lack of funding, resources, experience, regulatory skills and/or manufacturing skills, as well as the unwillingness of large pharmaceutical companies to engage with early stage products.
For the BSGCT, guidance through the quagmire will be required to ensure good manufacturing grade products, to engage with the regulators and to recruit patients into early phase clinical trials. The CTC should also lead and lobby on other regulatory areas, such as developing a pan-European consent form for taking biopsies to produce human pluripotent stem cell lines. A review in this area has already been undertaken by the Californian Institute for Regenerative Medicine in the US, but needs to be addressed in the UK and EU.
In time, the CTC will also find the right strategy to consolidate a wide range of knowhow into manufacturing cell products within its facilities at Guy’s Hospital in London. To this end, in 2013, the UK Research Councils provided £20m to five regenerative medicine hubs, aiming to create a complete process line from bench to bedside. This has been a significant step in the development of UK-based R&D, however limited the funding.
The fact is that, despite being largely explored in the media as a promising technology with the potential to save countless lives, the high cost of research has meant gene therapy remains costly on an industrial scale. Between 2000 and 2010, there was significant dropout from research by big pharma, as companies became reluctant to invest in R&D with so little promise of returns. The global financial crisis resulted in the collapse of many small biotech companies and associated funding streams. This has led to gene therapy being mainly driven by publicly funded academic groups for the past decade. Relative restrictions in grant funding from research councils, charities and industry groups resulted in a comparatively difficult and very competitive decade – although it was clear governments and funders were still interested in promising areas of gene therapy.
However, there is light at the end of the tunnel as positive results consistently emerge from clinical gene therapy studies. The knock-on effect has been that the field of gene therapy is now on a steep upward trajectory. In a number of disease areas, gene therapy has led to improved clinical outcomes, which has restored confidence in the basic concept of gene-based therapeutics. In turn, this has led to renewed investments in small biotech companies and the interest of big pharma. The interaction between industry and academia appears to be improving, and research is increasingly structured in a more collaborative fashion.
Safeguarding the future
The development of clinical gene therapy is expensive and traditional short-term funding models are not best suited to ensure the successful transition from lab bench to bedside, which often takes a decade or more. A major obstacle is the production of clinical grade gene transfer vectors.
Access to suitable manufacturing facilities and high costs of production are key bottlenecks that should be addressed with a national and international agenda.
However, funding bodies frequently require a prediction of real costs for new gene therapy-based treatments, even during pre-clinical phases of development. These are difficult to calculate and can be prohibitively high at the onset of a project. However, as shown numerous times, technological advances will reduce manufacturing costs over time and theoretical calculations, in very early phases of a research programme, should perhaps not be an important factor when deciding on funding.
It is important, however, to balance such arguments against costs of competing technologies, as these will ultimately determine if a product will go to market. The provision of the first fully approved gene therapy in the Western world, Glybera, for a very rare condition known as lipoprotein lipase deficiency, has furthered interest and improved the outlook for both academic and industrial sectors in gene-based medicine.
As the technology develops and becomes more widely used, the BSGCT aims to educate and engage with the public on all issues relating to the development, testing and implementation of gene and cell therapies. This spans research progress on emerging technologies and pre-clinical studies together with current legislation that governs clinical testing and implementation of gene therapies. The importance of public education is to both highlight current research and discuss the associated ethics – such as the use of animals as models of human disease, and the implementation of clinical trials on healthy volunteers and patients.
Public engagement
For the BSGCT, educating the public about the critical issues relating to new medicines is very important when responding to key findings – whether positive or negative. The society holds annual public engagement events where students, patients and members of the public are educated on the science behind cell and gene therapy through informative talks, hands-on activities, interaction with actual researchers and panel discussions.
“Our audience increases year-on-year and we look to expand our events through collaborations with other societies and organisations,” says a spokesperson for the group. “In addition, we encourage the development of young scientists in the field by providing financial support for laboratory placements and registration to our conference. We are keen to expand the number of bursaries by collaborating with relevant organisations as well as the industry.”
As more and more gene and cell-based therapies emerge in the clinical industry, the BSGCT wants to be at the forefront of educating the public and increasing awareness on regulatory issues. This is particularly relevant when the recent House of Lords Report of Regenerative Medicine is considered. It targets the regulatory landscape in the UK for streamlining: a decision that could be hugely advantageous for research. This is in agreement with a report from the Academy of Medical Sciences that suggests the importance of a “one-stop shop” for regulation.
“We have formed partnerships with organisations such as the Nuffield Foundation, Progress Educational Trust and Society of Biology in our effort to expand our reach,” says the BSGCT. “We hope to work closely with the Cell Therapy Catapult to foster awareness of the key issues in development of cell-based therapies in the UK. We want to be directly involved in gene and cell therapy regulation development in the UK.”