Gene Therapy Webinar

On Wednesday 16th September 2020, our gene therapy webinar discussed the new gene therapies being developed for NKH and ASA, and future developments which may also be suitable for those living with other conditions including MSUD, PFIC2, MMA, PA and OTC. Please see the webinar, details of the talks given and the questions and answers from the webinar below.

Gene Therapy Webinar Topics

Elin Haf Davies, Chair, Metabolic Support UK
Introduction to Metabolic Support UK, and the purpose of the webinar

Section 1 | Concepts of Gene Therapy
Simon Waddington, Professor of Gene Therapy, University College London

  • What is gene therapy
  • Overview of core concepts

Simon has been working in the field of gene therapy for more than twenty years, mainly on the development of treatments for Inherited Genetic Diseases. In the mid-2000s he was developing treatments for haemophilia. As the field advanced, he started to witness how gene therapy could be applied to severe childhood genetic diseases.

Section 2 | Gene Therapy Technologies
John Counsell, Senior Research Fellow, University College London

  • Different therapies under development
  • Pros and cons of each approach in context of Inherited Metabolic Disorders (specifically liver applied)
  • Possible use of lentivirus

John is a Senior Research Fellow based at UCL Great Ormond Street Institute of Child Health. He specialises in engineering viral vector technologies for treating Inherited Metabolic Diseases by gene therapy.

Section 3 | Urea Cycle Disorders
Julien Baruteau, MRC Clinician Scientist, University College London

  • Gene therapies under development for ASA (model for other UCDs)
  • Status of lentivirus work

Julien is a MRC Clinician Scientist Fellow based at UCL Great Ormond Street Institute of Child Health and a consultant at Great Ormond Street Hospital. His work focusses on designing novel therapies for Inherited Metabolic Diseases.

Section 4 | Non-Ketotic Hyperglycinemia
Nick Greene, 
Professor of Developmental Neurobiology, University College London

  • NKH gene therapy programme
  • How liver rescue could help

Nick is Professor of Developmental Neurobiology at UCL Great Ormond Street Institute of Child Health, where he has led a research group since 2001. Nick’s group focus on development and disease of the nervous system using a range of experimental approaches. Over recent years he has particularly worked on disorders of the glycine cleavage system which he will talk about today.

Section 5 | Clinical Translation
Paul Gissen, Clinical Professor and Honorary Consultant in Paediatric Metabolic Diseases, University College London

  • How do gene therapies get to clinic
  • Which gene therapies are close
  • What should we expect from the projects that we heard about, and the timeframes

Paul is a Clinical Professor of Paediatric Metabolic Medicine at UCL Great Ormond Street Institute of Child Health and Consultant at GOSH.  He has 25 years clinical experience and leads both laboratory projects and clinical trials .


Q1. Why can the virus based gene therapy only be injected once?
A1. The most efficient vectors look like viruses on the outside, so when they are injected, they essentially “vaccinate” the patient against any more vector injections. Now, in theory, one injection should be sufficient to treat for life, but that might not be the case for all diseases and people are now looking into whether it might be possible to inject a second time, either by suppressing the immune system at the time of the first injection, or by injecting a different vector the second time around.

Q2. How do you measure the effectiveness and the longevity of a virus entering the liver cells?
A2. The first experiments have to be done in mouse models of the genetic disease – strains of mice which replicate the gene mutation. However, mice only live for two years. Therefore, the only way to find out is to do Phase I/II clinical trials where the experimental medicine is given to patients. The tough bit is doing the “preclinical” experiments well enough that we can be confident – and the regulators can be confident – that the gene therapy will show some efficacy in patients.

Q3. Why does neonatal injection result in a higher rate of death than an adult injection? Is it related to the injection procedure, the virus side effects or something else?
A3. I think what Julien was showing here is that if the mice are not treated at all with vector, then they will get sick or die. I think he was showing that the neonatal injections weren’t as effective as the adult injections using this particular vector. This is because the neonatal liver is small and growing rapidly, so when the vector is injected, it gets diluted out as the liver grows. However, when injected into adults, the dilution effect no longer happens.

Q4. With 10 day injections of exosome, is it just 10 days or does the process need to be repeated several times afterwards?
A4. The exosomes have to be given repeatedly.

Q5. Is there a biomarker that tells you that glycine has decreased in the brain?
A5. We assess brain glycine directly by taking tissue samples from the mice.

Q6. Is gene therapy only for loss of function mutations?
A6: Most of the early successes were in loss-of-function because they were amenable to the technology at that time. However, as the technology improves in efficiency and versatility, gain-of-function mutations are becoming targets for gene therapy, but I think these are still in development in mouse models. Not sure if there are any examples in human trials yet.

Q7. Is there a parent organisation that offers information on clinical trials for metabolic disorders?
A7. Yes, the team at Metabolic Support UK can help with your enquiry. Please contact us on You can also contact disorder-specific patient organisations, such as Joseph’s Goal, but get in touch with the Metabolic Support UK team and we’ll signpost you to the best place.

Q8. Can integrated GT (lentiviral) be inherited by patients’ children?
A8. No. The lentiviral vector only integrates into certain tissues – such as the liver. It doesn’t reach the germline (sperm or ovaries), so it can’t be inherited. In fact, “germline gene therapy” is prohibited across the world.

Q9. Are there any concerns about the lentivirus having a permanent/untoward effect on the cell genome?
A9. Yes, like all gene therapy products that access the nucleus, lentivirus could interfere with the human cell genome, depending on where it integrates. Several studies have looked into this and found that if the lentivirus is designed carefully to minimise the risk of these effects, then its safety profile in the liver is good. This is why preclinical development of gene therapies takes a long time, as we need to do extensive studies to check that our design is as safe as possible.

Q10. What system is in place in the UK to surpass the obstacle of cost for patients for gene therapy? It is a very expensive therapy and I would like to know how this aspect is being addressed in the UK or Europe.
A10. All licensed therapies for rare disorders are “expensive”. If you look at it from a UK-wide perspective, to treat a rare disorder patient is no more expensive than treating common disorders. The high cost is necessary to encourage therapies to be developed and for the companies that develop and market therapies to be reimbursed appropriately. There are maybe only 50 patients with a particular rare disorder in the UK whereas there are thousands or even millions of patients with common disorders, such as hypertension.
The cost of a gene therapy drug is no more expensive than current therapies, such as enzyme replacement where the NHS pays £250,000-£500,000 per year for life. Gene therapy may only need to be given once hence the advantage of such an approach. The first drug approved in the UK was Strimvelis with the cost of around £700,000 (the exact price that the NHS pay is not available). It is said to be under-priced and the newer drugs are priced at >£1M.
There are special departments within the NHS that deal with the highly specialised drugs including gene therapy.

Q11. What was the name of the company with the exosome technology?
A11. Evox Therapeutics

Q12. Gene therapy for macular degeneration in patients with MMA CblC – how close is it to reality?
A12. In terms of the lentiviral gene therapies that are being developed, these are mainly focused on treating the liver, rather than the eye. So for macular degeneration, I would expect this would be an AAV-based therapy, as these are more widely used for treating the eye.
Most MMA gene therapies are focusing on mutase deficient MMA. So, a gene therapy for MMA CblC is likely to be at a very early stage. It is possible that somebody could initiate this work, as an MMA CblC mouse model has been developed. However, any gene therapy product being developed from scratch could take as long as 10 years to arrive in clinic, although this approach is getting faster in some cases, e.g. if a similar gene therapy has proven safe and effective before.

This webinar was in collaboration with Joseph’s Goal.