Gene therapy, i.e. the delivery of DNA or RNA into cells to treat disease, is at the cutting edge of medical research, and often makes the headlines. More importantly, recent developments have demonstrated the potential clinical impact that gene therapy can have in treating rare inherited diseases, as well as potentially some of the world’s most prevalent conditions. In this article for IBI (International Biopharmaceutical Industry) Journal, Mathys & Squire partner Anna Gregson explains more.In April 2019, gene therapy made global news when the results of a Phase I/II safety and efficacy trial using gene therapy to treat infants diagnosed with X-linked severe combined immunodeficiency (SCID-X1) were published in The New England Journal of Medicine. The study provides the latest evidence of the potential for using gene therapy in modern medicine.SCID-X1 is an inherited disorder of the immune system which results in major abnormalities in white blood cell production and function, including devastatingly low levels of T cells and natural killer (NK) cells, together with non-functional B cells. The condition was brought to the attention of the world in the 1970s with photos of David Vetter, who, in the absence of a suitable bone marrow donor (the only effective treatment at the time), had to be kept in a sterile isolation chamber and later became known as the ‘Bubble Boy’.SCID-X1 is caused by mutations in the IL2RG gene, which encodes the common gamma chain, an essential component of a number of cytokine receptors which control the development and function of T cells, B cells and NK cells. In the present study, self-inactivating, HIV-1 derived viral vectors, containing IL2RG cDNA under the control of an EF1α promoter, were used to transduce blood stem cells (CD34+ cells derived from patient harvested bone marrow). The transduced cells were then infused into each of the patients following treatment to facilitate reconstitution.The resulting effects on the patients’ immune systems were striking. Seven of the eight patients on the trial displayed normal levels of the various T cell populations within two to four months following infusion. NK cell populations were also normalised in many of these patients. Furthermore, protective antibody responses against various infectious diseases were shown in a sub-cohort of patients who received vaccination following gene therapy, indicating the presence of functional B cells.This is a significant success, especially compared to the earlier attempts at treating SCID-X1 patients with gene therapy, which were reported to be associated with the development of leukaemia in some patients, or which failed to restore certain populations of immune cells in others (meaning a lifetime of immunoglobulin injections).Although the authors of this study are careful to remind us that long-term follow-up will be needed in order to assess the durability and long-term safety of this treatment regime, the study gives an indication of how far things have progressed in the gene therapy sector.Indeed, whilst gene therapy is generally considered to have been a very recent development, fundamental research in this sector goes back over half a century, with early proof of concept experiments demonstrating the replacement of defective DNA in cells using viruses. Some of the earliest gene therapy trials date back to the 1990s, and interestingly, these too were aimed at the treatment of a form of SCID (albeit ADA-deficient SCID which results from a mutation in the gene encoding adenosine deaminase). ADA-deficient SCID and SCID-X1 are, of course, exemplary targets for gene therapy, given they result from mutations in a single gene.The present study comes at a time of significant activity in the gene therapy world. Research into gene therapies continues apace. In early May 2019, a new gene editing company, Verve Therapeutics, co-founded by Harvard academic Sekar Kathiresan, was launched. The aim was to develop a treatment to significantly reduce the risk of heart attacks, the world’s leading cause of death, with a single injection. The therapy uses nanolipids to target the enzyme PCSK9 (proprotein convertase subtilisin kexin 9), which is involved in the production of so-called ‘bad cholesterol’, (also known as low-density lipoprotein).The therapy was designed to shut down one of the two copies of the PCSK9 gene in a patient, mimicking a mutation which occurs in a subset of the population who have naturally low cholesterol and a reduced risk of heart attacks. The initial trial will be conducted in patients with homozygous familial hypercholesterolaemia (HoFH), who have statin-resistant high cholesterol levels. If successful, the treatment could be used more widely to significantly reduce the occurrence of heart attacks and associated fatalities.Such advances are not restricted to the laboratory, with increasing numbers of potential gene therapies entering clinical trials and then into the clinic. In a recent statement, the FDA announced that it expects to approve between 10 and 20 new cell and gene therapy products per year from 2025 onwards, resulting from an anticipated 200 investigational new drug (IND) applications per year from 2020 onwards.This increase in activity is said to reflect ‘a turning point in the development of these technologies and their application to human health’, which has been driven, in part, through the adoption of adeno-associated viral (AAV) vectors for the delivery of gene therapy agents. The FDA has likened this increase in activity to that seen in the late 1990s with antibody therapies, following the development of platforms for producing fully human monoclonal antibodies.At the end of 2017, the Alliance for Regenerative Medicine reported that there were 946 clinical trials underway investigating gene and cell therapy products, with new trials constantly being announced. In February 2019, for example, Gyroscope Therapeutics successfully administered the first dose in a clinical trial which investigated the safety and efficacy of their gene therapy candidate for the treatment of dry age-related macular degeneration (AMD), one of the leading causes of blindness in the world. Although traditionally gene therapy has been seen solely as a potential modality for the treatment of monogenic disorders, should this investigation be successful, it could widen our view of the applicability of gene therapies (given that dry-AMD is a multifactorial disease).As shown by the data generated from the SCID-X1 patient trials discussed above, these advanced therapeutic modalities are showing success in the clinic. Novartis’ Luxturna, an AAV vector delivering a functional copy of the RPE65 gene to cells of the retina, has now been approved for the treatment of inherited retinal dystrophy in both the US and Europe, and follows in the footsteps of Strimvelis (an approved gene therapy for the treatment of ADA deficient-SCID).With this flurry of successes has come (renewed) interest in gene therapy, highlighted by recent multi-billion dollar acquisitions by big pharma companies. For example, AveXis Inc. (who developed Zolgensma, a spinal muscular atrophy treatment candidate) was acquired by Novartis in 2018 for $8.7 billion. More recently, Roche paid $4.8 billion for Spark Therapeutics and its haemophilia treatment candidates.This is good news for SMEs too, of which there are many who are building on the foundational research of the last few years to develop new and exciting gene and cell therapy products. The United Kingdom in particular is evolving into one of the leading places for the development of gene- and cell-based therapies. A world-leading combination of academics, large pharma, manufacturing facilities, contract research organisations, innovation agencies and pool of active investors, together with dedicated and co-ordinated advanced therapeutics research centres has provided the perfect ecosystem for these emerging companies to flourish.Whilst the hive of activity should encourage researchers and innovators working in the gene therapy sector, the challenges facing this sector should be kept in mind. Even positive clinical trial results and regulatory approval will not ensure success, as exemplified by the withdrawal of Glybera, which became the first gene therapy product to be approved in Europe in 2012. Eye-watering price tags (Glybera reportedly cost €1 million per treatment), small patient populations, and complex regulatory exercises are just a few of the challenges facing the industry.There appears to be consensus in the industry that innovation in commercial-scale manufacturing methods will be key in order to bring costs down and facilitate availability of these often life-changing therapeutics to patients. The production of AAVs has, to date, been one of the key hurdles to overcome. Unlike other viruses, AAV requires an additional ‘helper’ virus in order to allow them to replicate in cells. Whilst methods have been developed to eliminate the need for these helper viruses, through the generation of producer cell lines expressing key helper virus genes, empty vectors (i.e. AAV particles not containing the gene therapy construct) is still a major issue requiring expensive and time-consuming purification methods in order to produce the required titres. Importantly, SMEs developing and trialling gene therapy products should always look to the future to ensure that their methods/processes are scalable when necessary.As well as the complex manufacturing methods and state-of-the-art facilities required to produce gene therapies (in particular, the viral vectors used to deliver nucleic acid), the costs of these agents also reflect the lengthy and expensive journey of a gene therapy from the bench to bedside. Companies in this sector should carefully consider and protect their innovations to ensure their efforts are not only safeguarded, but also recompensed.Whilst patent protection of the gene therapy products themselves (i.e. vectors, nucleic acids, formulations, etc.) is apparent, companies should also bear in mind innovations in their manufacturing processes and the like. As indicated above, manufacturing innovations are likely to be key to the success of gene therapy; protection of these aspects can be a useful strategy to maintain exclusivity (even beyond the patent life of the product) and generate additional income through licensing. Of course, in order to obtain a patent, one must adequately disclose the innovation in the patent application, and as such, timing is likely to be crucial.The gene therapy sector faces numerous challenges, not least from a regulatory, safety and, indeed, ethical perspective. Despite this, as the SCID-X1 study has shown, gene therapy represents one of the most powerful treatment modalities available to date, which, in many cases, can provide life-changing results. A concerted effort from those in academia, industry and policy will be required to continue this success, making safe and effective gene therapies available to wider patient populations. The current excitement around this technology is likely to attract a flurry of new players to the market and, as such, intellectual property will be a vital foothold for those wishing to establish their position in this field.Indeed, the recent UK ATMP Investor Day (co-sponsored by Mathys & Squire) gave 11 such companies the opportunity to pitch to life sciences investors. Mathys & Squire Partner, Anna Gregson, who spoke at the event and has extensive expertise in this technical field, noted: “The UK has an incredible ecosystem for cell and gene therapy research – with supporting organisations such as the Cell and Gene Therapy Catapult, an active investment community and a thriving research community. All these factors together enable the UK to produce world-class cell and gene therapies; as evidenced by the calibre of the SMEs who pitched at the UK ATMP Investor Day. It is a really exciting time to be involved in cell and gene therapy research, and I am thrilled to play a part in supporting SMEs in this space!”This article was originally published in the Summer 2019 edition of IBI Journal.