As part of our ongoing efforts to support the development of new therapeutics for rare genetic neurological diseases, we are proud to introduce a new preclinical research model for Angelman Syndrome within InnoSer’s portfolio. In collaboration with Professor Ype Elgersma, a world-renowned expert in Angelman Syndrome research and scientific director of the ENCORE Expertise Center at Erasmus MC, InnoSer now offers exclusive access to a validated and well-established, translationally relevant Ube3a mouse model of Angelman Syndrome.
Combined with InnoSer’s advanced preclinical drug development services, this integrated offering provides a powerful platform for leading biotech and pharmaceutical researchers to accelerate the development of disease-modifying therapies and drive wider adoption of standardized translationally relevant tools for preclinical Angelman Syndrome research.
Angelman Syndrome: understanding the genetic basis of this neurodevelopmental disorder
Angelman syndrome affects an estimated 500,000 people globally. The condition presents early in life and is characterized by intellectual disability, impaired motor coordination, epilepsy, and behavioural abnormalities including autism spectrum disorder features. The disorder has a profound and lifelong impact on patients and their families, as most individuals are unable to speak, require continuous care, and face significant challenges in daily functioning.
On the genetic level, this rare neurodevelopmental disorder is caused by maternal deletions within chromosome 15q11-q13, containing the UBE3A gene or by loss-of-function mutations in the maternally inherited UBE3A gene. A small percentage of Angelman syndrome cases is due to paternal uniparental disomy (UPD; whereby maternal chromosome is replaced by paternal chromosome) or imprinting centre defect (i.e., maternal chromosome behaves like paternal chromosome).
The UBE3A gene is an example of an imprinted gene, meaning it is expressed in a parent-of-origin–specific manner. Thus, although individuals inherit one UBE3A allele from each parent, only the maternally-inherited UBE3A allele is actively expressed in neurons, resulting in the observed maternal-specific inheritance pattern of Angelman syndrome. The paternally inherited UBE3A allele is silenced through neuron-specific genomic imprinting, which results in the allele-specific expression of a long antisense RNA transcript (UBE3A-ATS) in neurons. The UBE3A-ATS transcript interferes with transcription of the paternal UBE3A allele, leading to its silencing, making the loss or disruption of the maternal allele the primary cause of Angelman Syndrome (Madaan et al., 2023).
The UBE3A gene encodes a ubiquitin-protein ligase essential for regulating protein degradation in neurons, playing a key role in synaptic function and neurodevelopment. Loss of function of the maternal UBE3A allele disrupts this process, leading to abnormal protein accumulation and impaired neuronal function — underlying the symptoms of Angelman Syndrome.
This unique silencing mechanism of the paternal UBE3A allele holds great promise for the development of novel therapeutic strategies aimed at restoring gene expression in neurons. However, currently, the treatment for Angelman syndrome is limited to symptom management, with no available disease-modifying therapies, highlighting a critical unmet need in the field of neurodevelopmental disorders. Addressing this gap requires innovative research, including early-stage preclinical studies that help accelerate the discovery and development of effective targeted Angelman syndrome therapies.
Why early-stage research matters: the power of preclinical studies for Angelman Syndrome
Angelman Syndrome research is advancing rapidly, with both preclinical and clinical efforts increasingly focused on addressing the underlying genetic causes of the disorder. Leading pharmaceutical and biotech companies are actively developing innovative therapies targeting the genetic mutations responsible for Angelman Syndrome. Promising approaches include gene therapy, antisense oligonucleotide (ASO) technology, and small molecule therapeutics, all aimed at transforming the treatment landscape and offering hope to patients and families affected by this challenging condition.
Current therapeutic strategies under investigation include:
- Gene therapy: Delivering functional copies of the UBE3A gene using viral vectors.
- Paternal allele reactivation: Targeting the silencing mechanisms (such as the UBE3A-ATS transcript) to restore UBE3A expression from the paternal allele.
- Pathway modulation: Intervening in downstream pathways affected by UBE3A deficiency.
- Symptom management: Addressing seizures, motor impairments, and behavioural challenges to improve quality of life.
The development of effective therapies begins with robust, translationally relevant preclinical Angelman Syndrome models. Preclinical studies using Angelman syndrome mouse models are not only crucial in the identification of drug targets but also provide important information about the therapeutic dose, optimal age of treatment, and the best outcome measures to be used in a clinical trial. In particular, the motor deficits, seizure susceptibility, sleep deficits EEG anomalies, and some of the behavioural deficits are of high translational value. With several Angelman Syndrome clinical studies underway, these advancements further underscore the importance of robust preclinical models to evaluate therapeutic efficacy and safety before transitioning to human trials.
The Ube3a mouse model: A key tool in Angelman Syndrome research
To identify targeted treatments and ensure the successful translation of these therapies to clinical trials, mouse models are needed that have:
- High construct validity (similarity at genetic level), meaning a high degree of genetic similarity to the human condition.
- Face validity (similarity at phenotypic level), referring to the phenotypic similarity between the mouse model and the clinical features observed in patients, including robust behavioral phenotypes that reflect the human disease.
Similar to the human course of Angelman Syndrome, mouse models with Ube3a deficiency exhibit a range of neurological and behavioral abnormalities. As a result of the disrupted maternal Ube3a allele and the silencing of the paternal Ube3a allele through imprinting, these mice fail to produce functional UBE3A protein in the brain, leading to phenotypes that closely mirror those observed in individuals with Angelman Syndrome. A comprehensive review of multiple developed mouse models of Angelman Syndrome from the Elgersma lab can be found in Rotaru et al., 2020.
At InnoSer, we offer the Ube3amE113X/p+ (MGI:5911277) variant of this model originally identified and well-characterized by the laboratory of Dr. Ype Elgersma. This model together with a selected behavioural test battery was replicated in eight independent cohorts, by five different researchers (Sonzogni et al., 2018), and has been used in multiple preclinical drug testing studies since. By promoting the broader recognition and more consistent use of the mouse model, along with access to robust protocols, experienced scientific staff and complimentary preclinical drug development studies, we aim to help leading industry innovators accelerate the progress towards life-changing Angelman Syndrome treatments.
Accelerating Angelman Syndrome Research with InnoSer
The establishment of centralized resources and standardized protocols is crucial for advancing preclinical research and facilitating the development of effective therapies for Angelman Syndrome. The model aligns with efforts toward standardization in preclinical pipelines, which the community increasingly demands for translational relevance. This collaboration offers researchers a robust platform for early-stage drug development, one that is both scientifically rigorous and translationally relevant.
As a preclinical rare neurological disease CRO, InnoSer brings the resources, scalability, and regulatory experience necessary to translate promising ideas into viable therapies. InnoSer enables industry innovators to take a therapeutic from concept through preclinical studies, all under one roof, which saves time and increases data consistency. With InnoSer, researchers using the Ube3a mouse model of Angelman Syndrome gain access to a fully integrated preclinical platform, including:
- InnoSer’s track record in neuroscience research spanning from rare genetic neurological disease models to state-of-the-art readouts focused on behavioral phenotyping (automated home cages PhenoTyper) as well as EEG
- In-house expertise in pharmacokinetics (PK), pharmacodynamics (PD) profiling studies
- Early-stage toxicology and bioanalysis studies
- InnoSer’s expertise in performing therapeutic efficacy studies complemented with histopathology analyses, biomarker analyses etc.,
- InnoSer’s complementary expertise in other rare genetic disorders
This streamlined approach allows for faster decision-making, reduced variability, and the flexibility to adapt study designs in response to early data, ultimately accelerating the path from concept to clinic. Expert guidance ensures careful refinement of study design, welfare assessments, dosing schedules, and bioanalytical analyses. Research teams can streamline their workflows and accelerate the path from discovery to clinic.
Partner with InnoSer to leverage the validated Ube3a mouse model of Angelman Syndrome, expert scientific support, and integrated preclinical services — all designed to help you move faster and with confidence, from discovery to clinic.