My name is Marianna Fontana, I am a professor of cardiology at University College London and I work at the National Amyloidosis Centre as a cardiologist.

What is the importance behind the study?

For me, as a cardiologist working with patients with ATTR amyloidosis, working generally in cardiovascular medicine, there are several points that we need to think about when we think about the importance of the study.

So first was the first time that CRISPR-Cas9 based technology was ever used in any cardiomyopathy. So this is I think an important milestone for the field of cardiology. So this is a proof of concept that can be used and a single infusion that can be used in this specific field to treat patients with ATTR cardiomyopathy. So it's extremely important for the future of ATTR cardiomyopathy because this one was the phase one study showing the effectiveness that is extremely effective and safe. And a single infusion leads to deep, sustained and durable reduction in the serum TTR level and these associated with favourable clinical outcome. But at the same time I think it's got implication for the wider field because the proof of concept that cardiomyopathies can be treated with CRISPR-based Cas9 technologies.

Could you tell us about the unique features of the CRISPR gene editing system?

I mean the very unique element of this product is that with a single infusion we can permanently edit the DNA of the liver cells. And so this treatment is just one-off infusion for the rest of a patient's life. So this one for me is really the unique element of these. And this was an important step not just in the field of ATTR cardiomyopathy but was the first time that CRISPR-Cas9 was used to edit the genome in any cardiomyopathy. So it was really a milestone step for cardiology.

What was the study design and patient population?

So this study included 36 patients with ATTR cardiomyopathy, heredity of wild type. So this was a phase one ongoing, open-label, single-arm study where every patient received treatment.

There was a part one study which was dose escalation and a part two where there was dose expansion that all the patients received a fixed dose. And the primary objective of the study were to assess safety and tolerability NPD, so the TTR levels. And the second objectives of the studies were to assess blood biomarkers so NT-proBNP and troponin, functional capacity. We [indistinct] pulmonary access and six minute walking test, KCCQ, and then various parameters assessed on cardiac imaging, i.e., cardiac MRI and echocardiography.

What were the key findings?

I mean what we found is that after a single infusion nex-z, we saw a very deep and sustained and durable reduction in the TTR levels of reaching a percentage reduction at 28 days of 89%, so a very rapid reduction. And, but importantly, also the levels were sustained over time. So from all the 24 months of observation, we saw that the levels were unchanged. So there was a rapid reduction at 28 to 89%, this was very deep and they were the same in every single patient. So there was not lots of variability, and then they were sustained over time.

And so what we saw is that these deep, durable and sustained reduction translated in stability or improvement in some of the patients across a wide range of markers of disease progression that we used for the study. So we used established threshold for the NTproBNP, the troponin, the six minute walking test. And what we saw is actually the patients were stable or improvement.

And this was in spite the patient population being a very severe patient population. I mean, there was 50% of the patients were NYHA functional Class III. There was a high proportion of our patients, two of which were homozygous, so a very aggressive form of disease. The peak oxygen uptake was extremely low, so functional capacity severely reduced: 12.7 ml/kg/min. And also the NTproBNP was a median of 2000, but went up to 20,000. So in spite of the patient population being extremely severe, the patient remained stable and some of them improved. So it was an extremely remarkable study.

What further research is needed in this area, and what are the next steps?

The field is very exciting. I mean, a CRISPR-Cas9 gene editing approach is a module that can be used for any gene in the genome because you can basically produce a guide for the various gene and then you can target the various genes. So the potential for the future for CRISPR-Cas9 is really incredible.

And in ATTR cardiomyopathy, the future is that there is already an ongoing phase three study, the [indistinct] study, which assess the efficacy and safety on nex-z in a large population of patients with ATTR cardiomyopathy. And so the study is a classical double-blind, randomized, multicentre placebo controlled trial and uses hard outcome as the endpoint.