Accelerating novel therapies - our impact

Lysine is an amino acid that is found in many foods. Some inherited metabolic disorders prevent our bodies from being able to breakdown and metabolise lysine. These arise when one of the genes in our genetic code that’s responsible for making the enzyme that’s needed for the process of breaking down lysine doesn’t work properly. This variation causes a blocker in the process, leading to a build-up of chemicals created in the early stage of the process (metabolites) that are thought to be toxic to the brain and nervous system, and if left untreated children with these conditions can die.

The most common disorders on this pathway include ALDH7A1-deficiency and glutaric aciduria Type I (GA1), with incidences of 1 in 64,000 and 1 in 30,000 - 1 in 100,000, respectively.

Highly restrictive dietary interventions that can reduce the amount of lysine that a child eats, and therefore the levels of toxic metabolites that build up, have been trialled for ALDH7A1-deficiency and for GA1. However, the effects of these diets can be limited.

Using a treatment called ‘oligonucleotide therapy’ we have shown that by reducing the activity of an enzyme responsible for the first stage of lysine breakdown (α-aminoadipic semialdehyde synthase, or ‘AASS’) can prevent the accumulation of the harmful metabolites.

This is done by targeting the gene which creates the AASS enzyme using antisense oligonucleotides (ASOs) or small interfering RNAs (siRNAs). Treatment of other genetic disorders using these approaches has been approved recently by the FDA and EMA thereby paving the way for this as a therapy for ALDH7A1-deficiency and GA1.

Using this approach in skin cells from patients with ALDH7A1-deficiency, we can reduce the activity of the gene that makes AASS by up to 98% and therefore prevent the accumulation of the neurotoxic metabolites by more than 99%. We also saw success when using a similar approach with cells from patients with GA1. This suggests that a single treatment may be suitable for all disorders on this pathway.

If this oligonucleotide therapy approach works as well in children with ALDH7A1-defiency and GA1 as it does in their skin cells, this treatment will be life-changing, allowing patients and their families to live a near normal life. GA1 is one of nine disorders currently screened for at five days after birth in every child born in the UK.

ALDH7A1-deficiency is currently being screened for in the Genomics England pilot Newborn Genomes Programme, ‘The Generation Study’. The availability of an oligonucleotide treatment in conjunction with new-born screening would ensure early treatment of these disorders thereby preventing damage to the brain and the life-limiting problems associated with them. Patients and their families would not have to endure the extremely restrictive diets currently prescribed. Specialist advice and close monitoring by a metabolic dietitian to ensure that patients do not become deficient in other dietary requirements as a consequence of these diets would also no longer be required.

An initial funding award from the NIHR GOSH Biomedical Research Centre led to our initial proof of concept findings, which then helped us to secure additional funding. The NIHR GOSH BRC has also provided support for the Biological Mass Spectrometry Centre which helped facilitate this study.

A ketogenic diet, which is low in carbohydrates and high in fat, shows promise as an alternative treatment option for infants with drug-resistant epilepsy.

The study, led by researchers at GOSH and UCL GOS ICH, was the first in the world to compare the impact of a ketogenic diet to further anti-seizure medication for infants aged one to 24 months with drug-resistant epilepsy.

The study found both treatment options to be effective for reducing seizures in infants.

Epilepsy is most common in children under two years of age (around 56–88 cases in 100,000 infants each year.) and infants with epilepsy remain most at risk for continuing seizures and neurodevelopmental delay in the long term. Early seizure control is associated with improved developmental outcome, but many infancy-onset epilepsies have a poor prognosis for seizure control.

This study has impacted changes in service delivery and developing and delivering operational excellence. It will also likely have an impact on future epilepsy guidelines. More infants with epilepsy are now on a ketogenic diet in the UK and Ireland, compared to five years ago.

Our study results were published in Lancet Neurology and as an NIHR report and presented at international conferences such as the American Epilepsy Society annual meeting, International Epilepsy Congress and British Paediatric Neurology Association annual conference. This enabled promotion of ketogenic diets as a treatment for epilepsy to healthcare professionals globally who may not otherwise be aware of its benefits.

We conducted a webinar to share the results with healthcare professionals and families, with 422 international registered attendees. The study has also been reported in UK media, making members of the public aware of this treatment option, particularly for those who may not have been made aware of it by their healthcare team.

The study would not have been possible to conduct without NIHR funding and the support of research nurses at all study sites, aiding screening, recruitment, collection of study data and follow-up study visits. This national network also continued to support the study throughout its no-cost extension. The NIHR GOSH BRC also contributed funding towards a patient and public involvement and engagement project related to an international database we are setting up at the UCL GOS ICH to collect information on people with epilepsy referred to start a ketogenic diet.

In the last 5 years, our research has contributed to life-changing new treatments for rare diseases getting regulatory approval in Europe and the USA, with the potential to affect millions of people, worldwide.

From leading lab-based drug development to running clinical trials, and collaborating with global teams to providing evidence that supports drug approval, we have played pivotal roles.

Supported by our NIHR Clinical Research Facility we have also taken part in 53 phase 1 and 83 phase 2 clinical trials of novel interventions for children and young people with rare or complex diseases.

SMA, a rare genetic condition, causes progressive muscle weakness and poor movement due to loss of muscle function. It is usually diagnosed when the child is over four months old and is not moving normally.  Three studies, two from GOSH, have recently shown that a treatment called Zolgensma can improve the symptoms for children with SMA.

Zolgensma is a new gene therapy that, when injected, reaches brain cells responsible for muscle function. Children with SMA who were given Zolgensma showed increased movement and breathing improvements. However, children given the treatment who were already at an advanced stage of the condition continued to experience significant disability.

BRC researchers were instrumental in delivering a clinical trial (Sprint) in which Zolgensma was given to children with SMA in the first month of life, well before they showed symptoms. These children were identified either via newborn screening or as a newborn tested and diagnosed because of a sibling with SMA.

The results of this ongoing study demonstrate that the majority of those who took part in the trial met normal walking and movement milestones. In fact, their development appears to be the same as children without SMA.

Zolgensma is now approved for use in the NHS and our results show that we need to find a way to identify children with SMA as early as possible, so that they can have this treatment before they have symptoms and permanent damage.

Our BRC, in collaboration with the GOSH Newborn screening laboratory, with a small amount of funding from Biogen, and in consultation with the UK Newborn Screening Committee, has piloted a study to understand whether a test for SMA could be included in the Guthrie blood spot – the so-called ‘heel-prick’ test, which all newborn babies get around 10 days of age. We have now examined 5,000 Guthrie cards, including some known to have SMA, and we correctly identified the positive results from infants with SMA.

We presented our findings to a meeting of the NHS Newborn Screening committee, NICE (the body responsible for healthcare guidelines in England and Wales), and patient advocacy groups – the meeting agreed we should submit an application in 2022 to include SMA testing in 10-day heel prick test. If approved and implemented this will improve the lives of the around 100 children born each year with SMA and their families.