The death of pioneer patient Terry Horgan is a warning about the risks of viral vectors but the focus is now on the first gene therapy being approved in the US

On the chellenging frontier of advanced therapies, every death is a pain from which everything possible must be learned. The inauspicious outcome of the individual treatment for Duchenne muscular dystrophy developed by the non-profit Cure Rare Disease for Terry Horgan, and tested solely on this American boy, can teach little about the specifics of CRISPR. Indeed, the death occurred before the molecular editing machine could get into action. But the information on the case, circulated in May on a preprint archive awaiting peer-reviewed, is nonetheless a valuable contribution to the advancement of knowledge in an area where science has no intention of giving up.

Cure Rare Disease summarises the results of the post-mortem studies as follows (see the FAQs): “the patient’s lungs had sustained injury likely due to a strong immune reaction to the high dose AAV [adeno-associated viral vector], and that unfortunately the gene therapy itself did not have a chance to do what it was designed to do”. In short, CRISPR did not have time to do its job, which was to get a silent copy of the dystrophin gene (brain isoform) expressed in the muscles.

The risk of high-dose AAV triggering the immune system was no surprise, in fact the same problem seems to have played a role in the deaths of eleven other patients in other gene therapy trials. Many groups are actually working on better suppressing the immune reaction with the aim of making high-dose vectors more tolerable or allowing lower, repeated doses (a single administration may not be enough as patients grow and muscle fibres renew).

Specifically, Terry was too weak to withstand the toxicity of the vectors currently in use. In the future, new-generation vectors will be needed, not necessarily viral (many hopes are pinned on lipid nanoparticles, assuming they can be directed towards the muscles). In addition, the selection of participants in clinical trials will have to take this into account: they need to be sufficiently healthy to combat the initial acute immune reaction that occurs within the first week of the treatment. 

Rich Horgan reiterated that he intends to honour his brother Terry by pursuing the 19 research lines of Cure Rare Disease and claimed the importance of what has been done so far: the miracle did not happen, but the model of collaborative science and the innovative approach to funding for rare and ultra-rare diseases remain.

As for the state of the art of advanced therapies for Duchenne dystrophy, an up-to-date picture has been drawn by both Science and Nature on the occasion of the Food and Drug Administration’s possible green light for a classic type of gene therapy. Called SRP-9001, it has been developed by the company Sarepta Therapeutics and is aimed at Duchenne patients aged 4-5 years.

In this treatment – as in others being developed by Pfizer, Solid Biosciences and Généthon – patients are given a mini-dystrophin gene, because the whole gene would be too bulky to fit into viral vectors. The data collected so far, however, have not convinced all researchers (the advisory panel split with 6 votes against and 8 in favour).

The decision expected by 22 June, therefore, could have only a limited effect in time, pending the completion of a more extensive trial that should make it possible to better assess efficacy. In any case, the problem of immune defences will have to be solved in order to be able to repeat the treatment, because no one thinks that a one-shot intervention in a child can be sufficient during growth and last forever.

Another approach, this time based on the use of CRISPR to correct the defective gene and under development by Vertex Pharmaceuticals, has shown encouraging results in animal models and could reach clinical trials within a year.