CRISPR – Cas 9: Expanding the Pharmacopeia

Posted on: Friday 27 September 2019
Author: Dr Susan Tansey FFPM

A report of the 2019 FORUM Annual Lecture and panel discussion

On Thursday 5 September 2019 I was fortunate enough to attend a very interesting afternoon that was arranged by FORUM/the Academy of Medical Sciences at the Hallam Conference Centre in London.

The afternoon commenced with the FORUM Annual Lecture which was given by Dr John Leonard, CEO of Intellia Therapeutics. His talk, ‘The Promise of Human Genome Editing for Rare and Genetic Disease’, explained the science of genome editing and the promise it brings for the 90% of rare diseases that currently have no treatment options.

I was particularly excited to attend this lecture as I have been involved for several years in designing and conducting clinical trials in rare diseases particularly in paediatrics. I also know from my prior clinical experience (as a paediatrician) of the devastating effects on children and families of many rare diseases and therefore was delighted to hear that we may have new treatments and even cures for some of these in the future if the promise of genome editing is realised.

Dr Leonard started by showing us that while diseases such as cystic fibrosis, retinitis pigmentosa and amyloidosis are among the 100 most common monogenic rare diseases, there are many others such as sickle cell disease and haemophilia B that are much less common. He mentioned that as well as monogenic disorders, genetic approaches can be applied to complex immunological disease as well as to the immune responses to malignancies.

Sue Tansey
Sue Tansey [Photograph by Abi Moore]

He then discussed the prerequisites for success when applying genetic editing which are as follows:

  • A tractable disorder
  • A causative gene
  • A target tissue
  • An editing tool

CRISPR – Cas9 is an editing tool and refers to ‘Clustered Regularly Interspersed Short Palindromic Repeats’ and Cas9 is the enzyme. This forms part of the bacterial adaptive immune system. The Cas9 enzyme plus the guide/protein RNA complex ensures that the viral DNA is cut at the right place. The cell survives by disabling the virus. By using this tool there is the potential to modify any gene within the genome using guide RNA directed at human sequences of DNA.

The type of edits are as follows, with example diseases that will potentially benefit from the therapies shown in brackets:

  • Knockouts – inactivation /deletion of the gene-causing sequence
    (TTR (transthyretin-type systemic) amyloidosis, hypercholesterolaemia)
  • Repairs – correction of the ‘misspelled’ disease-driving DNA sequence
    (haemachromatosis, alpha 1 antitrypsin deficiency)
  • Inserts – insert new DNA sequence to produce a therapeutic protein
    (haemophilia A and B)

CRISPR is the therapy to fix the broken gene in genetic diseases.

The promise of a potential cure for haemophilia B reminded me of my days as a paediatric registrar seeing a young boy repeatedly attending the ward for infusions of factor 9. I recall his distress at the repeated venepunctures not to mention the impact on his schooling and family life. How fantastic if we could cure this serious disease and others like it.

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!

Following his talk there were some short presentations from four panellists (Dr Matthew Garnett, Dr Sarah Chan, Dr Alison Kay and Dr Nicola McCarthy) followed by a roundtable session. During this session the need to engage the public was mentioned despite this being difficult as the science is challenging to communicate. Nicola talked about the advantage of being able to screen cancer drugs by using primary cells rather than established lines. Alison (lay representative) mentioned that important issues to consider for CRISPR were understanding, accessibility, timescale and accountability. Finally, Sarah talked about the ethical aspects asking us to consider what is an acceptable risk and emphasising that we need to carefully consider the off-target effects. There was also some further discussion about the ethics of germline gene editing and the need to consider the socio-cultural context.

I found the lecture and subsequent discussion extremely informative and thought provoking. The promise of a potential cure for haemophilia B reminded me of my days as a paediatric registrar seeing a young boy repeatedly attending the ward for infusions of factor 9. I recall his distress at the repeated venepunctures not to mention the impact on his schooling and family life. How fantastic if we could cure this serious disease and others like it.

The 2019 FORUM Annual Lecture can be viewed in its entirety at

Header image credit: Ernesto del Aguila III, National Human Genome Research Institute, NIH

Portrait image credit: Abi Moore