Angelman syndrome
What is AS?
A report describing AS was published in 1965 by a British pediatrician
Harry Angelman. AS is a genetic disorder causing
neurodevelopmental disease with a conserved and recognizable set of symptoms. Most often, AS is characterized with serious
intellectual disability (complete lack of speech and decreased cognitive performance), happy demeanor with easily provoked
laughter, movement and balance disorders (ataxia). Among common symptoms are seizures, that start in early childhood; notably,
AS shows a characteristic electroencephalographic pattern. Finally, children with AS have sleeping disorders and disrupted
circadian rhythm. Less often symptoms include microcephaly and body dysmorphia, gastrointestinal tract disorders, and
hypopigmentation. Features, resembling autistic-spectrum disorders, could be observed in people with AS.
Although AS
is
considered rare, it’s prevalence is about 1/10,000-1/20,000. AS could be recognized at 6-12 months’ age, when babies start to
exhibit lack of usual motor activities, like crawling. Hence, it is important to undergo genetic testing as soon as parents
suspect AS: although the definitive cure is (so far) absent, different therapeutic approaches are available to increase the
quality of life and mitigate symptoms.
What are molecular causes of AS?
Mutations interfering with the expression of UBE3A gene, coding for ubiquitin protein ligase E3A, lead to the AS. In humans, the UBE3A gene is subject to genomic imprinting, a process that results in the gene being expressed in a parent-of-origin specific manner. For the region of chromosome 15 that includes UBE3A (15q11-q13), only the maternal copy of the gene is usually active in certain areas of the brain, while the paternal copy is typically silenced by a process involving DNA methylation and the imprinting center.
The silencing of the paternal UBE3A allele is controlled by an imprinting control region located upstream of the SNURF-SNRPN gene, within the same 15q11-q13 region. This region includes the Prader-Willi syndrome/Angelman syndrome (PWS/AS) imprinting center. The paternal allele of the imprinting center is methylated, a chemical modification of DNA that does not change the DNA sequence but affects gene expression. Methylation of the ICR on the paternal chromosome prevents the binding of transcription factors necessary for the expression of UBE3A, leading to its silencing. The silencing mechanism also involves the transcription of an antisense RNA from the SNURF-SNRPN locus on the paternal allele, which spans the UBE3A gene. This antisense RNA, UBE3A antisense transcript (UBE3A-ATS or SNHG14), is thought to interfere with the transcription of the paternal UBE3A allele. The exact mechanism by which UBE3A-ATS silences UBE3A is still under investigation, but it is believed that the transcript might block the progression of RNA polymerase during the transcription of UBE3A, prevent the proper splicing of UBE3A pre-mRNA, or recruit chromatin-modifying enzymes that repress transcription. The methylation of DNA and the action of antisense RNA are associated with changes in chromatin structure that further reinforce the silencing of UBE3A on the paternal allele. Histone modifications, such as deacetylation and methylation, lead to a more condensed chromatin state, making the DNA less accessible for transcription.
AS can result from several genetic mutations, all of which lead to a lack or loss of function of the maternal UBE3A allele:
Deletion of the maternal copy of chromosome 15q11-q13. This is the most common cause, accounting for about 70% of cases. The deletion removes the active UBE3A gene along with neighboring genes, leading to the syndrome.
Mutation of the maternal UBE3A gene. In about 11% of cases, a mutation within the UBE3A gene itself prevents the production of functional UBE3A protein from the maternal allele.
Paternal uniparental disomy (UPD). A rare cause where the child inherits two copies of chromosome 15 from the father and none from the mother. Since the paternal UBE3A gene is normally silenced in the brain, this results in no active UBE3A gene expression in the child’s brain.
Imprinting defect. Also rare, this involves a failure in the process that normally
silences the paternal copy of UBE3A in the brain, without a deletion or mutation in the gene itself. This can be due to
deletions or mutations in the imprinting center.
The UBE3A gene encodes an E3 ubiquitin ligase that tags defective
proteins for degradation. The absence or insufficiency of this enzyme in the brain disrupts the normal turnover of
proteins, affecting neuronal function and development, and leading to the symptoms of Angelman Syndrome.
Gene therapy solutions for AS treatment and management
Currently, GeCure Solutions is advancing a next-generation precision gene therapy platform for Angelman syndrome. Our strategy is based on complementary CRISPR-mediated epigenetic approaches designed to restore endogenous UBE3A expression, followed by comprehensive molecular, functional, and preclinical validation to support future clinical translation.
Precision Gene Reactivation Platform
GeCure Solutions is developing a precision genome and epigenome editing platform designed to restore the physiological expression of the silenced paternal UBE3A allele in Angelman syndrome. Rather than introducing an additional copy of the gene, our approach focuses on reactivating the endogenous paternal UBE3A allele through targeted epigenetic modulation while preserving its natural regulatory mechanisms.
The platform is being established as a versatile scientific and technological foundation for developing next-generation genome editing approaches aimed at restoring endogenous gene function without gene replacement. The project is currently in its early research phase, with activities focused on platform design, refinement of the therapeutic concept, and preparation for experimental validation.
Precision Gene Reactivation Platform
GeCure Solutions is developing a precision genome and epigenome editing platform designed to restore the physiological expression of the silenced paternal UBE3A allele in Angelman syndrome. Rather than introducing an additional copy of the gene, our approach focuses on reactivating the endogenous paternal UBE3A allele through targeted epigenetic modulation while preserving its natural regulatory mechanisms.
The platform is being established as a versatile scientific and technological foundation for developing next-generation genome editing approaches aimed at restoring endogenous gene function without gene replacement. The project is currently in its early research phase, with activities focused on platform design, refinement of the therapeutic concept, and preparation for experimental validation.
Orthogonal Dual-CRISPR Strategy
A key innovation of our platform is an orthogonal dual-CRISPR strategy that combines two independent yet complementary mechanisms targeting distinct regulatory pathways responsible for paternal UBE3A silencing.
The first module is designed to epigenetically activate the paternal UBE3A promoter, while the second independently suppresses pathogenic antisense transcription within the UBE3A-ATS locus. By simultaneously targeting two complementary regulatory mechanisms, this strategy is intended to promote more effective restoration of endogenous UBE3A expression than approaches based on a single mechanism alone.
Its modular architecture enables each component to be optimized independently as the platform evolves, providing flexibility for future development and creating opportunities to adapt similar genome and epigenome editing strategies to other genetic disorders driven by dysregulated gene expression.
Integrated Preclinical Development Platform
Our research program integrates advanced molecular engineering with comprehensive preclinical validation to establish a robust therapeutic platform for Angelman syndrome.
Development includes generation of patient-derived cellular models, optimization of guide RNA design, functional assessment of UBE3A restoration, transcriptomic analysis, neuronal phenotyping, and safety evaluation prior to animal studies. Candidate therapeutic systems will undergo iterative optimization based on efficacy, specificity, and long-term biological performance.
The overall objective is to generate a clinically translatable precision gene therapy platform supported by rigorous preclinical evidence.
