Soon after the last meeting in Oxford, experts in the field of gene therapy got together in the heart of Regent’s Park, in London. The meeting was focused on lentiviral gene therapy and the massive involvement of students and early career researchers gave the conference a special feel.
The first session, for the Fairbairn Awards, was introduced by Professor Luigi Naldini. The first nominee was Guilia Massaro, who explained the challenges of crossing the blood-brain barrier upon administration of adeno-associated virus (AAV) gene therapy to replace the glucocerebroidase enzyme gene, which is mutated in the neurodegenerative lysosomal disorder, Gaucher Disease. Helena Lund-Palau showed how a pseudotyped lentivirus, which has been approved for the first-in-human clinical trial for cystic fibrosis, can ameliorate pulmonary alveolar proteinosis in a murine model. Alex Baker, explained how advanced structural biology techniques, such as crystallography, can be used in order to further uncover the adenovirus-host interaction features for the design of replication-defective forms of human adenoviruses for gene transfer purposes. Natasha Myhill provided further evidence on the tumour-infiltrating lymphocyte (TIL) therapy for the treatment of metastatic melanoma. In particular, how T-cell receptors’ (TCRs) activation profiles may determine the efficacy of this immunotherapy in various cell populations.
After the coffee break, some of the most striking results in the field of gene therapy were presented by Claire Booth. Primary immune deficiencies are lethal disorders in children for which haematopoietic stem cell transplantation (HSCT) offers a potential cure; although there are a number of limitations to this therapy including the availability of suitable donors and the risks associated with cytoreductive chemotherapy. Gene therapy can be used to reduce morbidity and mortality caused by graft-versus-host disease (GvHD) by delivering the corrective cDNA of a specific gene to autologous haematopoietic stem and progenitor cells (HSPCs). This approach has been proven to be curative for the rare life-limiting adenosine deaminase-deficient SCID (ADA-SCID) disorder and can be used for other diseases such as Wiskott-Aldrich syndrome and chronic granulomatous disease in which finding a suitable donor is a major limitation. These remarkable scientific breakthroughs have led to the approval of Strimvelis® by NICE in February 2018 for the treatment of ADA-SCID when no suitable donor is available.
Later on, Kyriacos Mitrophanous went over the difference between ex vivo and in vivo gene therapy and the complex process of producing high-titre lentiviruses on a large scale for in vivo clinical trials. Despite these difficulties, there have been important improvements which have enabled the development of several clinical trials investigating viral gene therapy for the treatment of Parkinson’s disease, multiple cancers, corneal graft rejection, and many others. High-titre vector production is particularly relevant for the transduction of the lung due to its large surface area. Steve Hyde, as part of the UK Cystic Fibrosis Gene Therapy Consortium, discussed the challenges of scaling-up lentivirus production from small academic studies to cGMP manufacturing approaches necessary for clinical development. Important tips to achieve high quality and titre purified stocks of a vector include using suspension bioreactors and selecting reagents of good quality and consistency.
In common with Cystic Fibrosis, gene therapy for muscular dystrophies, caused by mutations in genes encoding cytoskeletal proteins, have faced the challenges of ensuring efficient delivery, the need to produce large vector titres, the requirement to transduce post-mitotic cells and the difficulties of packaging large genes. Giulio Cossu’s group have been working on Duchenne muscular dystrophy, where progressive weakness occurs due to the death of the skeletal muscle cells. In vivo targeting of skeletal muscle is difficult due to the extent of this tissue in the human body and so an in vitro approach transducing mesoangioblasts, progenitor cells originating from pericytes of skeletal muscle, may prove a successful alternative.
Janet Glassfor described advanced therapy medical products (ATMPs), which are gene therapy, somatic-cell therapy or tissue-engineered medicines. All of these are authorised centrally by the European Medicines Agency (EMA). Their approval does not grant marketing authorisation, although a clinical trial that closely reproduces the clinical scenario facilitates its later authorisation. In any case, the efficacy and safety of all ATMPs are carefully monitored after approval. Ian Rees spoke about regulatory challenges faced by the Medicines and Healthcare products Regulatory Agency (MHRA), which provide guidance for the development of medicines, medical devices or novel manufacturing processes. He provided details on how to engage with regulators and be compliant with Good Manufacturing Practise (GMP) standards to facilitate the success of a new product.
These were followed by a session on safety and novel vector design, with Keith Smith, emphasising the importance of the production plan of a new biological product to ensure optimal quality and safety for its translation to the clinic. If the production process is compatible with the GMP standards, cost and time for its translation to clinical manufacture may be reduced. Michael Themis, focussed on the importance of addressing the potential genotoxicity of gene therapy. For this purpose, his group developed the ‘Individualised Genotoxicity testing (InGeTox) test system’ and pre-screened patients’ tolerance to DNA damage repair before gene therapy in the clinic. Axel Schambach, reminded us of the relevance of developing safe integrating retroviral vectors to avoid risks, such as insertional mutagenesis, but maintaining their efficacy. From their experience, alpharetroviral SIN vectors may be good candidates for inherited diseases and anti-cancer immunotherapy. The scope of the session changed slightly with the last speaker, Jacob Giehm Mikkelsen, who presented a new delivery method based on the use of lentiviral particles incorporating and delivering foreign ‘hitch-hiker’ proteins – also known as ‘lentiviral protein transduction’ – possibly reducing the risk of mutagenesis.
Finally, a panel discussion about the risks and benefits of gene editing and gene therapy was held with panellists: Claire Booth, John Harris, Jacob Giehm Mikkelsen, Luigi Naldini. There was agreement on the potential of both techniques and the importance of making them as safe as possible. A huge amount of audience participation led to a very vibrant debate and an excellent close to the day.
This article was written by Helena Lund-Palau, Aarash Saleh and Robyn Bell who are all members of the BSGCT Communications and Promotions Committee.