Last year, Angelman grandfather Michael Paech, travelled to Vienna to attend the Angelman Syndrome Alliance Conference and learn more about current research, trials, clinics and what the future might hold for his granddaughter Anna.

In the capacity of an interested grandparent of a 4-year-old grandchild with AS (UBE3A mutation), I attended the 7^th International Angelman Syndrome (AS) Scientific Congress from 15-17 Sept 2022 in Vienna, Austria.

The meeting was essentially a meeting of neuroscientists, mainly from Europe and the USA, who are investigating the basic science of and early therapeutic possibilities for AS. The third day had some elements of interest to parents and families, mainly related to communication or industry involvement in clinical trials of anti-sense oligonucleotides (‘ASOs’) which are designed to activate the paternal (father’s) gene and cure AS. I will attempt to summarise various aspects, hopefully in vaguely understandable language!

Basic science

There are several amazing research laboratories exploring the mechanisms and impact of the low levels of the UBE3A protein in the brain and spinal cord of those with AS. A group in Portugal are using stem cells derived from the skin or blood of AS patients (and matched controls) to grow neurones (’mini-brains”) and investigate the regulation of the gene and the impact of ASOs on the different genetic variants that cause AS (as you know, the majority being a gene deletion, but mutations and other causes probably representing another 10-20%). This stem cell research will hopefully allow, within 3 years, potential drug screening of several potential therapies at one time. The same group is interested in the cerebellum, at the back of our brain and containing 80% of all our neurones, traditionally thought to control movement mainly, but now also known to be involved in memory, emotions, and abstract thinking. They have demonstrated anatomical cellular abnormalities, higher excitability and functional disturbance in those with AS.

An Israeli group has used bioinformatics to identify a gene profile that clearly distinguishes AS from normal. This will clarify diagnosis for some cases and assist with further development of cell and mouse models of AS, both of which are essential to the future of therapies for humans. They have shown the importance of altered calcium dynamics leading to impaired synaptic transmission between neurones in AS and the role of glutathione in reducing the increased ‘programmed neural precursor cell death’ in those with AS. In the future, this bioinformatics and ‘machine learning’ (artificial intelligence) approaches have the potential to allow individual, personalised decisions about optimum therapy, for example the best anti-convulsant drug(s) for that person.

The Netherlands group has long had advanced mouse models of AS that allow study of how the UBE3A protein regulates other protein activity in the nucleus of the cell, which areas of the brain are most affected, and provide a good means of testing correction of AS behaviours (as shown by mice!). This model is vital for preclinical testing of drugs that might improve the symptoms of AS.

The USA centres include those studying the regulation (control) of UBE3A-ATS which is the section of DNA made by the UBE3A gene that silences the paternal gene – finding how it works exactly will allow the development of new therapies to stop ‘imprinting’ and ‘turn on’ the father’s gene. An exciting report from the North Carolina, USA group was that they studied almost 3000 potential compounds and have identified a molecule that activates the paternal gene very effectively in the mouse model of AS. The previous drugs that were found to do this never progressed due to toxicity and the need to be directly injected into the cerebrospinal fluid (CSF) via a lumbar puncture, but this new molecule has the potential to be given systemically (this refers to a conventional route such as an injection or by mouth). Initial research shows it very effectively restores low levels of the UBE3A protein in all areas of the brain after a single injection without obvious adverse effects – but of course there are years of work to be done to find exactly how it works, if it improves symptoms and behaviours firstly in mice and then humans, how safe it is, how long it lasts, what doses are required, even before possible studies in us humans!

Along similar lines of future therapy that could be so straightforward, an Italian laboratory is developing a delivery system for ASOs that uses approved (known safe) nanoparticles as carriers to deliver the ASO into the brain after an intranasal spray. This early investigation has worked well in the mouse model of AS. They have also shown that the brain cortical response to visual signals, measured non-invasively based on near-infrared spectroscopy, can distinguish AS from ‘wild-type’ (normal) mice and a study in humans is commencing. This might prove another non-invasive way of assessing UBE3A function in future therapy trials.

Information about clinical symptoms, outcomes and services

Results of the Roche and Genentech Endpoint Enabling Study in AS (FREESIAS) biomarker study were presented. This study evaluated information about outcomes important to parents (include expressive communication, independence and self-care, behaviours, sleep, fine and gross motor skills, seizures, cognition) that will be useful to determine the impact of future therapy studies. Sleep was a major outcome of interest. Sleep disturbances are age-dependent and correlate with the clinical severity of AS but generally those with AS were more awake, sleep less and in a more disturbed fashion. The study found that a sleep scale and diary were reasonable assessment tools, as was an EEG (which has typical features in AS) if practical – and a sleep mat perhaps less valuable. Another small study randomised AS children to a 6-week behavioural sleep therapy program or usual interventions (cool dark room, routines, pacifiers, etc.). There was a minor improvement in reducing night visits and parental impacts – the message remains to educate new parents about strategies and to use video-somnography (observation of sleep) monitoring to guide changes and interventions.

There are also completed studies, such as the natural history of AS (see NCT00296764) and a new but very small study on quality of life was presented. This found that the severity of AS may not reflect the quality of life, that parental stress was high but could be positive. For those with AS, emotional and behavioural problems, having a deletion or being of older age were factors associated with a lower quality; and for parents emotional and behavioural problems and sleep disturbance in their child the major increasers of stress.

The ‘industry’ (Ionis and Biogen) has developed an accurate assay of UBE3A protein levels in the CSF which will be helpful in evaluating therapy effects in some future studies.

I attended a physicians’ meeting about the establishment of specialised AS clinics, this being led by doctors and health-care professionals from a large centre in the Netherlands. FAST Australia and the ASF in Australia are currently working toward establishing such clinics in major eastern state cities.

Management and therapies 

There were presentations on communication (systems, tools, signing, technologies and devices) and ‘augmentative alternative communication’ devices. These obviously need to be tailored to the individual but are improving rapidly.

The LADDER database and learning network (https://www.angelman.org/as-research/ladder/) has multiple contributors from around the world and aims to connect patients to care centres, care providers to one another, support clinical trials and collect information (currently doing so on seizures). It is a central repository collaboration of the ASF and dup 15 Alliance to collate and give better access to data from many organisations, research groups, the AS global registry and Natural history studies, and clinical services- these data were previously fragmented in many locations and difficult to find.

A couple of ‘industry’ companies presented updates on their studies. These studies are to assess safety, tolerability and kinetics (rather than efficacy) in humans, after success in the mouse model. Roche is developing an ASO given by lumbar puncture that is in a “phase 1” ascending dose trial (named TANGELO: see NCT04428281) in AS children, with a long-term extension. A completed volunteer study under analysis injected radiolabelled drug and followed its distribution using positive-emission tomogcraphy (PET) scans.

Ionis has completed the first part of a phase1/2 trial of its ASO (named HALOS: see NCT05127226) in AS patients of all ages and has approval for a long-term extension. Ultragenyx is a USA company only investigation therapies for rare diseases and also has a phase 1/2 trial (see NCT04259281) in progress.  PTC Therapeutics is doing preclinical research (mouse model) on adenovirus associated vectors for gene replacement.

Cannabidiol which is a major component of the Cannibis plant and a prescription drug in some countries, was discussed by a German paediatrician/AS mum. There is some suggestion it reduces seizures and cnecdotally has helped her child in other respects, but this is NOT proven science and there are major issues with reducing effect over time, and legal access. For interest only!

Not mentioned was the current Neuren small open-label phase 2 study in children with AS of the safety, tolerability, and pharmacokinetics of oral NNZ-2591. This drug was very effective in managing dysfunctional behaviours in the mouse model and findings are expected to be available in the second half of 2023.

This was an interesting meeting if you understand the science (I only did partially!) but maybe not the ideal congress if you do not have a science background or are more interested in developments in the care and therapeutics for Angelman Syndrome. There were some parents (and two ‘Angels’ and one other set of grandparents!) attending but only the last half-day had much of direct relevance to them. Nevertheless, it was a pleasure and privilege to be there.

Mike Paech

Devoted Pa of Anna

Emeritus Professor of Obstetric Anaesthesia, University of Western Australia