Gene and cell therapy for neuromuscular disease

Our team of writers are reporting live from Athens and have picked key notes from Day 3 - use the links to skip to the sections below, or scroll to view the full summary.


Gene and cell therapy – a brief introduction 

The day started bright and early with a plenary session on gene therapy. For those of us not intimately familiar with the subject, Professor Basil Darras provided a general introduction. Together with a later talk by Professor Robert Steinfeld, this laid an excellent foundation for understanding the finer points of the presentations. Most of the attention in gene therapy is currently on the use of adeno-associated viral vectors (AAV) for gene replacement strategies, that is to deliver genes to replace the function of mutated or lost ones. Unlike lentiviral or gamma-retroviral vectors, AAV does not integrate into the genome and instead remains as an episome within the nucleus. This avoids the dangers of insertional mutagenesis where the transgene integrates near to oncogenes and causes uncontrolled growth of the transduced cells. The disadvantage of AAV is that episomal DNA is not replicated and thus repeated cell division will lead to daughter cells not containing the episome, though this is not an issue with non-dividing cells such as motor neurones. A bigger problem with AAV is the limited cargo capacity (<5 kilobases of DNA), which is halved when using ‘self-complementary’ AAV (scAAV). These self-complementary AAVs have been engineered to fold back upon themselves, forming double-stranded DNA, as this results in increased and prolonged transgene expression. Another issue with AAV is pre-existing immunity, but this can be circumvented by pseudotyping, that is replacing the vector shell with capsids from other AAV subtypes or engineered versions.

New therapeutic modalities


Onasemnogene abeparvovec (Zolgensma®

In case you are having trouble deciding how to say onasemnogene abeparvovec, don’t worry – most of the speakers did too!

Professor Darras then quickly focused on onasemnogene abeparvovec for the treatment of spinal muscular atrophy (SMA – check yesterday’s blog for more details) as the leading example of a whole host of gene therapies in clinical trials. This is currently being considered for approval by the European Medicines Agency (EMA) and is already approved by the FDA. As we heard yesterday, long-term follow-up from the START onasemnogene abeparvovec Phase 1/2a clinical trial (NCT02122952) showed that all 12 patients from the START higher dose cohort (2x1014 vector genomes per kg; vg/kg) are still alive and free of permanent ventilation, though four of the ten patients enrolled in the long-term follow up study require respiratory support. Three patients in the study are now on concomitant nusinersen treatment. None of the motor milestones achieved during the original START study have been lost, and two children who have never received nusinersen can now stand with assistance.

The presented data clearly support that earlier treatment leads to better outcomes as was discussed in yesterday’s blog (see here). There is still a significant delay between symptom onset and diagnosis. This is unlikely to change much – as Professor Muntoni put it in a later symposium “I don’t believe that we can get every GP to recognise the symptoms of upwards of 2000 rare diseases.” Newborn screening programmes for diseases that are gaining disease-modifying therapies are absolutely essential.

Two more talks on onasemnogene abeparvovec are scheduled for tomorrow morning, so make sure to check back for more information.

Other neuromuscular gene therapies in clinical trials

Professor Darras then handed over to Dr Florian Eichler who presented on the development of the AAVrh74.MHCK7.microdystrophin gene therapy for Duchenne muscular dystrophy (DMD). As mentioned, AAV has a limited cargo capacity and the large size of dystrophin (the cDNA is still 14 kilobases) has been a hindrance so far. However, a shortened ‘microdystrophin’ with parts of the protein lacking, analogous to what is seen in the milder Becker muscular dystrophy is now being trialled in 4 patients (NCT03375164). After IV injection of 2x1014 vg/kg, an impressive 81.2% of muscle fibers from the gastrocnemius showed microdystrophin expression. Some improvement in motor function was evident nine months after treatment. It will be interesting to see how much of the dystrophin function the microdystrophin can replace over a longer-term follow-up.

Another gene therapy in clinical trials for neuromuscular disease is AT132, a treatment for X-linked myotubular myopathy (XLMTM). Like SMA, this disease is characterised by progressive loss of motor function ranging from mild to severe. In the open label phase 1 ASPIRO study (NCT03199469) seven patients received 1x1014 vg/kg and three patients 3x1014 vg/kg. Patients showed a mean increase of 19 points on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale, which have been maintained. There were significant and rapid reductions in ventilator use in all patients and four achieved ventilator independence.

New therapeutic modalities 

To finish off the session, Professor Stephanie Schorge introduced us to new therapeutic modalities that we can expect to enter clinical trials in the near future. One example is CRISPR activation, where a modified CAS9 without DNA cutting ability and conjugated to ten VP16 repeats is used to direct transcription factors to the targeted promoter and increase transcription from the promoter. This streategy would be applicable to diseases caused by haploinsufficiency such as upregulation of Kcna1 to stop seizures. Moving beyond rare diseases to diseases that are not due to single genes, chemogenetics seem promising. This approach uses designer receptors exclusively activated by designer drugs (DREADDs) – the name reallysays it all. Both these strategies and a number of others are still in the research phase or preclinical testing, but results are very promising.

Check back tomorrow for more on onasemnogene abeparvovec and what next generation sequencing might mean for your medical practice.

Back to homepage


Publications (4)
  • Even more on gene therapy…

    Even more on gene therapy today – see the new data from the SPR1NT and STR1VE-EU studies in spinal muscular atrophy and a thought-provoking discussion of the ethical dilemmas associated with gene therapy trials. What are the adverse events seen with gene therapy and how will next generation sequencing change your medical practice?

  • The last leg

    Discover the neuromuscular treatments that will be the talk of the EPNS Congress 2021.

Login/ Register Maximise Minimise