CRISPR – Cas 9: Expanding the Pharmacopeia

Dr Leonard then talked in more detail about the progress in developing gene therapy for TTR amyloidosis and haemophilia B, specifically talking about the work that has been done in non-human primates (NHPs). In haemophilia B, gene therapy could be applied to young children to potentially give a permanent effect by increasing the levels of factor 9. In TTR amyloidosis the NHP work indicates it might be possible to reduce the levels of TTR to a therapeutically relevant level.

In acute myeloid leukaemia the approach would be to treat with ex vivo engineered cells introducing a new T cell receptor that can recognise the tumour cells. This would have the potential to treat acute myeloid leukaemia which is the most common type of acute leukaemia in adults and has a 5 year overall survival rate of < 30%.

CRISPR/Cas9 can also be used to engineer cell approaches for cancer treatment of solid tumours.

Currently Dr Leonard said there were multiple programmes across genome editing companies in the clinic and we can expect the first human data in the next few months. There is an expansion in addressable diseases and continued news from academic settings around the world. He said that although we can imagine CRISPR/Cas9 edited products breaking through in the next few years they are unlikely to supplant many existing effective therapies. There will be a range of medical uses and adaptability to very rare conditions. These treatments will be used for traditionally undruggable severe genetic diseases, poorly treated severe autoimmune disorders and advanced cancers.

The trial design will be based on pre-clinical work and there will need to be a different approach to the clinical trial process and highly evolved economic models. There may be few patients available to include in traditional clinical trials and of course if you cure a disease then the market disappears. This comment started me thinking that although I currently describe myself as a clinical trialist I may need to start to call myself an ‘evidence generator’ if traditional clinical trials are conducted less frequently in the future!

Dr Leonard then discussed briefly the difference between somatic and germline gene editing – in the former you treat the individual patient and the latter the next generation. Germline editing is not the work currently taking place in industry or in most academic institutions. In fact, germline editing would rarely be necessary for the treatment of monogenic diseases, and we already have pre-implantation genetic diagnosis to select un-diseased embryos without requiring any editing (except in the rare case where both parents are homozygotes for a disease). He commented that he thought the research in this area should move forward but very thoughtfully.

He mentioned the discussion about non-medical uses of germline editing and that in this case the benefit/risk would be very difficult to determine as single genes do not act in a vacuum. There is also the issue that consent could not be obtained in the affected individual. There are potential non-human uses e.g. in plants, animals and the environment.

To conclude his lecture Dr Leonard summarised by stating that genome editing is a powerful technology and an important tool to expand the pharmacopeia but which we have only just begun to explore. He said that although gene editing tests the limits of some of the standard assumptions, and that we need to carefully consider the benefit/risk balance, it is here to stay!