Even more on gene therapy…

Our team of writers are reporting live from Athens and have picked key notes from Day 4 - use the links to skip to the sections below, or scroll to view the full summary.


Ethical considerations for gene therapy

Today’s Neuromuscular session started off with a thought-provoking presentation on the unique ethical issues with gene therapy trials by Professor Francesco Muntoni. He highlighted that in ‘traditional’ small molecule drug trials, children initially receiving a lower, perhaps ineffective, dose may later receive a higher dose. This is not possible with AAV gene therapy as repeat exposure to the same viral vector would cause a significant immune response. These children are also unlikely to be eligible for future clinical trials.

He also discussed the question that has come up a number of times during the meeting - is AAV really a once in a lifetime treatment? As we mentioned yesterday, AAV does not integrate into the genome but is retained in cells as a circular episome. When cells divide, only one of the daughter cells will contain the episome. It is also not guaranteed that each daughter cell will inherit one episome if two or more vector genomes are present. This is a concern in the treatment of primary myopathies, as muscles continue to grow and ongoing regeneration requires cell division. This uncertainty raises more questions: 

  • How do you explain this complex matter to children who may have developmental delays to gain informed consent? Clearly, this is difficult
  • What is the optimal treatment window? At birth or soon after will result in more vector dilution, but later on damage may already be present and difficult to undo
  • Why not use high doses straight away? Gene therapy treatment is not without side effects (more on this coming up) so every vector has to be tested carefully

Another point Professor Muntoni made is that placebo controlled or delayed treatment trials may be required for regulatory approval, but that it is very difficult to keep these studies blinded. Not just due to obvious benefits such as a drastic drop in creatine kinase (CK) levels, but also because of typical side effects such as elevated transaminases that may require management. Obvious treatment benefits also bring their own problems: “Youtube treatment misconception” as Professor Muntoni called it. Videos of the best responders trend easily on social media and prospective trial participants and their families expect this level of benefit from their treatment. Delayed treatment instead of placebo-controlled trials risk AAV seroconversion in these control patients which would exclude them from receiving AAV gene therapy. 

Even more on gene therapy

Professor Kevin Strauss then updated us on the ongoing SPR1NT phase 3 study (NCT03505099) of onasemnogene abeparvovec (Zolgensma®) in pre-symptomatic spinal muscular atrophy (SMA) patients less than six weeks old. This one-time gene therapy contains the following components within the recombinant AAV9 capsid shell:

One-time gene therapy contains the following components within the recombinant AAV9 capsid shell

Completely new data from the SPR1NT study that has just been released (read the press release). All 24 patients in the study (10 with two SMN2 copies and 12 with three) are alive, free of ventilation and able to swallow normally. All ten patients with two SMN2 copies achieved a minimum score of 50 on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale at three months of age. Seven of the ten achieved a minimum of 60 and five the maximum score of 64. A score of 60–64 is considered normal at that age. Keeping in mind that the mean age at last study visit was 6.6 months, six patients were able to sit without support for at least 30 seconds and three were able to stand with assistance within the time periods expected of healthy children. Since the official cut-off for the interim data (31 May 2019), three patients have achieved walking. 

Professor Eugenio Mercuri then compared and contrasted new STR1VE-EU (NCT03461289) data with the STR1VE-US data (NCT03306277). Both trials are evaluating onasemnogene abeparvovec in SMA patients less than six months of age with two SMN2 copies, but there were some differences in outcome measures and patient demographics. At age 10.5 months, 90% of 33 patients in the EU trial were alive and free of ventilation. Numbers for the US trial were similar, with 89.5% of 22 patients event free at 13.6 months. In the US, 95% achieved a CHOP INTEND score above 40, 64% above 50 and 14% above 60, while in the EU 55% achieved more than 40 points, 9% more than 50 and none more than 60. However, mean follow-up in the EU trial was significantly shorter than in the US (4.2 versus 12.1 months). None of the attained milestones have been lost, indicating that treatment benefit is ongoing.

Gene therapy adverse events

So far, we have not specifically mentioned the adverse events profiles of any of the gene therapies we have covered. This is mainly because the side effect profile seems to be largely similar across all of them. ‘Flu-like’ symptoms are common as well as transient increases in liver transaminases. Typically, patients will receive 30 days of 1 mg/kg prednisone starting the day before administration to suppress the immune response and trials will exclude patients with anti-AAV antibody titers of ~1:50. Serious side effects such as platelet depletion, troponin elevation with cardiac involvement or complement mediated nephropathy have been seen in some trials, but generally are rare.


In a very engaging and easily understood talk Professor Han Brunner explained about next generation sequencing (NGS) in paediatric neurology and why “Doctors are great – exomes are better”. In an ideal world, a doctor would see a patient, recognise the syndrome, order a genetic test that confirms the diagnosis and then commence treatment. Reality is that 1 in 17 individuals will be affected by a rare disease in their lifetime. Rare diseases often have a genetic origin, are rarely diagnosed and often misdiagnosed. No doctor can be familiar with the identifying symptoms of all of the rare diseases (case in point, only one doctor in the audience could identify CHARGE syndrome from a picture and symptom description). Next generation sequencing can provide a diagnosis straight away. In a way it is like a puzzle – lots of small pieces (sequence DNA fragments) need to be put in the right place (mapping onto chromosomes). Funny looking pieces then become obvious (annotation). However, finding the variant that causes disease is still a challenge. Every patient has up to 20,000 variants, 100 of which are unique. You then have to figure out which of these causes the disease. 

On the other hand, the diagnostic hit rate is better than paediatric neurologists achieve (see Vissers et al., 2017). It is at least comparable in cost if not cheaper than the standard diagnostic pathway as on average 5.4 single gene tests are needed to diagnose a patient. However, some caveats exist: whole exome sequencing cannot pick up triplet repeat expansion disorders such as fragile X syndrome and may not detect large duplications or mosaic copy number variations.

 Some doctors in the audience disagreed with the idea that NGS should be the first test ordered, emphasising that a ‘good’ doctor would (or should?) be better at diagnosis. We think that progress is rapid and a good doctor would consider the available data and choose the best option for their patient, not their own ego.

Don’t miss tomorrow’s report from the EPNS Academy session on (Auto)Immune disorders in child neurology.


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