Event Review: Transforming Medicine - The Promise of Human Genome Editing for Rare and Genetic Disease

'We may be nearing the beginning of the end of genetic diseases'- Jennifer Doudna, Professor at UC Berkley and co-founder of Intellia Therapeutics.

At the 2019 FORUM Annual Lecture at the Academy of Medical Sciences in London, Dr John Leonard, president and chief executive officer at Intellia Therapeutics gave an enlightening overview of the work they are doing towards clinical application of genome editing and his thoughts on the general genome editing field. The lecture was followed by a lively and insightful panel discussion.

Genome editing is a technology that has taken the scientific, clinical and ethical worlds by storm. Despite being around - in one form or another - since the 1980s, the real potential of this technology came to light in 2012 with the development of the CRISPR/Cas9 system. The prospect of germline genome editing is controversial and has garnered the most column inches. However, the vast majority of genome editing in preclinical research uses somatic cells, which is non-heritable and aims to treat patients with a genetic condition, cancer or certain viral diseases. There have been promising steps forward in trials with mice, and other animal models of human disease, including non-human primates, with this research paving the way to testing in patients. Indeed, some clinical trials have begun, some with older technology, but now also with increasingly sophisticated versions based on CRISPR.

Genetic conditions are often very rare, and sufferers and their families are concerned that little is done to research or find treatments for them, because they are not as ubiquitous as other diseases. However, while rare individually, collectively they are very prevalent, with nearly three million people in the UK having some form of genetic condition.

Intellia Therapeutics was started by CRISPR pioneer Jennifer Doudna, with a mission to: 'develop curative genome editing treatments that can positively transform the lives of people living with severe and life-threatening diseases.' For example in transthyretin (TTR) amyloidosis – a severe disorder caused by excess build-up of abnormal or normal TTR protein in organs and tissues – the goal is to use genome editing to disable the TTR gene, eliminating the production of excess proteins. The work has progressed to preclinical research in non-human primates, but advancing to patients can be difficult. Dr Leonard argued that genome editing requires a new clinical trial paradigm for rare disorders.

While it is proving possible for genome editing to also 'fix broken genes', Dr Leonard emphasised the potential for this technology to 'alter normal genes', to give therapeutic benefit in some cases. In theory, this could include complex disorders of the immune system or cancer. Something Dr Leonard was keen to get across was that genome editing is unlikely to supplant certain existing therapies, eg for hypertension. He suggested that it would be a misallocation of resources. Given that the few marketed somatic gene therapies are currently very costly patient-specific treatments, this is certainly true.

Dr Leonard concluded that genome editing is a very powerful and exciting technology, thus deep consideration of benefit and risk is warranted 'as we proceed beyond somatic medicine', by which he meant germline applications. In my view, it is also important to think ethics when it comes to somatic genome editing: what if rogue somatic genome editing clinics began to pop up, offering unproven treatments or enhancements?

Questions from the floor included whether genome editing could be used for chromosomal conditions, for example, Down's syndrome? Dr Leonard answered by simply stating he didn't know how to do it for these types of conditions. This issue has been discussed previously in much more depth (see BioNews 963).

Another audience member asked if CRISPR is 100percent accurate? Dr Leonard responded that 'nothing in life, but gravity, death and taxes are 100 percent'. He added that while there are off-target effects with CRISPR, you characterise them, eliminate guide RNAs that might be problematic and choose ones that have the desired performance characteristics. But in the end, it comes back to risk versus benefit.

Following on, Dr Matthew Garnett discussed the role of genome editing in understanding drivers of diseases, Dr Nicola McCarthy talked about next-generation genome editing research tools and Dr Alison Kay, in her capacity as a patient representative, spoke about the impact on patients and families that treatment of rare diseases will bring. An interesting and important point raised was that often mutations that occur 'de novo' are not talked about and not enough research is being done on this. The final speaker, Dr Sarah Chan, contemplated the ethical considerations around potential genome editing applications.

The panel discussion was vibrant and thought-provoking, although I was most intrigued by topics which touched on the ethical considerations. Prior to the audience conversation, each panel member gave a brief talk around their expertise. Audience questions focused on accessibility, regulation, research funding, and the parallels between germline genome editing and mitochondrial donation. One of the summarising comments, something all agreed on, was that bringing the public and patients along on the journey is of crucial importance.

The event was interesting and further consolidated the excitement around the technology and its potential. There were some missing opinions, such as those of research funders, journal publishers and regulators. However, it was very useful to have an event that emphasised the promise of somatic genome editing. This is important because, as highlighted, a lay audience may sometimes conflate somatic with germline genome editing. While they may be used to target the same disorders, this is problematic because the former is a treatment, the latter would be used to avoid having affected children. Moreover, they often use quite different methods, have different constraints, risks and potential benefits.