Welcome to the 'Ten Deadly Sins of Rare Diseases' Column, where we delve into the intricate world of rare diseases, industry breakthroughs in gene therapy, and innovative pre-clinical research strategies to drive translational successes. In this edition, we shine a spotlight on Angelman Syndrome (AS), a rare disorder linked to the imprinted gene UBE3A.

Past Reviews:

1. Exploring RHO-Related Pathogenic Mechanisms and RHO Gene Therapy Research Progress [Ten Deadly Sins of Rare DiseasesⅠ]

2. Why are humanized mice more suitable for hemophilia research, which has a higher prevalence in men? [Ten Deadly Sins of Rare Diseases Ⅱ]

3. The TARDBP gene is closely associated with pathogenesis of amyotrophic lateral sclerosis (ALS), but is it an angel or a demon? [Ten Deadly Sins of Rare Diseases Ⅲ]

4. Reviewing Muscular Dystrophy: Types, Pathology, and Gene Therapy Research [Ten Deadly Sins of Rare Diseases Ⅳ]

5. Is Smn2 Gene Therapy the Key to Treating Spinal Muscular Atrophy? [Ten Deadly Sins of Rare Diseases Ⅴ]

6. Application of Humanized Mouse Models in DNA Repeat Expansion Diseases [Ten Deadly Sins of Rare Diseases Ⅵ]

Genomic Imprinting and Inheritance

Whether a person resembles their mother or father from a genetic perspective is a complex matter, with genomic imprinting playing a significant role. Genomic imprinting, also known as genetic imprinting, is a genetic process where parental origin information is marked on a gene or genomic domain through biochemical pathways. Genes of this kind are called imprinted genes, and some imprinted genes are expressed only from the maternal chromosome, while others are expressed only from the paternal chromosome. Imprinted genes are crucial for brain function, behavioral development, and more. When their expression is disrupted or defective, it can lead to the onset of diseases, including Angelman Syndrome. In this issue, we will focus on Angelman syndrome (AS), which is caused by abnormalities in the imprinted gene UBE3A.

Angelman Syndrome: Unraveling Clinical Manifestations and Pathogenesis

Angelman syndrome (AS) is a rare and severe neurodevelopmental disorder that is most commonly observed in children. Most AS patients exhibit characteristic behaviors such as raising their hands high, constant waving, unsteady gait, and a uniquely joyous demeanor. They also tend to protrude their tongues frequently, and have a flattened back of the head. Angelman syndrome is often referred to as "Happy Puppet Syndrome" because of the prolonged happiness and excitement exhibited by affected individuals due to abnormal brain function. In normal brain tissue, the maternally inherited UBE3A gene is actively expressed, while the paternally inherited UBE3A gene is relatively silent. When the gene is deleted from the mother's chromosome, it results in a child developing Angelman syndrome.

Gene therapy for UBE3A Abnormalities

With no specific treatment currently available for Angelman Syndrome, attention turns to gene therapy targeting the culprit gene UBE3A. ASO-related gene therapy takes the lead, aiming to reduce Ube3a-ATS levels through Antisense Oligonucleotides (ASOs), thereby reactivating the expression of the paternal UBE3A gene.

For example, Ionis's pipeline ION-582 aims to activate the expression of the paternal UBE3A gene by targeting the 3' end of the Ube3a-ATS gene downstream of the Snord115 gene using ASO drugs. Some researchers have also used the CRISPR-Pro system to effectively activate paternal Ube3a gene expression in neurons by targeting the Snord115 gene. In preclinical studies and literature related to drug pipelines, the Ube3a-KO mouse model is primarily used.

In order to further advance gene therapy for Angelman syndrome caused by UBE3A abnormalities, Cyagen has independently developed hUBE3A whole-genome humanized mice and UBE3A-KO disease model mice.These innovative models pave the way for deeper insights and potential breakthroughs in the quest for treating this rare and challenging neurodevelopmental disorder.

Next-Generation Humanized Mouse Models for Preclinical Gene Therapy Research: HUGO-GTTM

For in-depth pathogenesis research involving Angelman syndrome (AS) – but also for various disease types such as retinitis pigmentosa (RP), age-related macular degeneration (AMD), Parkinson's disease (PD), and others – long-segment or even whole-genome humanized mice are a better choice. However, the technology required for whole-genome replacement is challenging, and the large-scale introduction of exogenous sequences may affect the original gene's expression regulation.

To overcome these obstacles, Cyagen has launched the groundbreaking Humanized Genomic Ortholog for Gene Therapy (HUGO-GTTM) Program initiative - a remarkable leap in Next-Generation Humanized Mouse Model Development. Powered by our innovative TurboKnockout-Pro technology, this program enables the seamless in situ replacement of mouse genes. This breakthrough paves the way for the creation of fully humanized mice carrying entirely human genomic DNA segments, opening a realm of possibilities for diverse intervention targets and preclinical gene therapy research. 

Below are tables with the currently available HUGO-GTTM mouse models and other humanized mouse models of disease:

Validated Next-Generation HUGO-GTTM Humanized Mouse Models

Product Number Product Name Strain Background Application
C001396 B6J-hRHO C57BL/6J Retinitis Pigmentosa (RP), Congenital Stationary Night Blindness (CSNB), and other retinal diseases.
C001410 B6-htau C57BL/6J Frontotemporal Dementia (FTD), Alzheimer's Disease (AD), and other neurodegenerative diseases.
C001418 B6-hTARDBP C57BL/6J Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and other neurodegenerative diseases.
C001427 B6-hSNCA C57BL/6N Parkinson's Disease.
C001428 B6-hCOL7A1 C57BL/6N Epidermolysis Bullosa.
C001437 B6-hIGHMBP2 C57BL/6N Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1) and Charcot-Marie-Tooth Disease Type 2S (CMT2S).
C001495 B6-hRHO-P23H C57BL/6J Research on retinitis pigmentosa (RP), congenital stationary night blindness (CSNB), and other retinal diseases.
C001504 B6-hSMN2(SMA) C57BL/6N Spinal Muscular Atrophy (SMA)

Next-Generation Humanized HUGO-GTTM Mouse Models Under Development

Disease Type Disease Name Target Gene Target Type
Ophthalmology Leber Congenital Amaurosis Type 10 (LCA) CEP290 Humanization(WT, Mut)
Age-Related Macular Degeneration (AMD) VEGFA Humanization
ABCA4 Humanization(WT, Mut)
Neurology Amyotrophic Lateral Sclerosis (ALS) SOD1 Humanization
FUS Humanization(WT, Mut)
Rett Syndrome (RTT) MECP2 Humanization(WT, Mut)
Spinocerebellar Ataxias (SCAs) ATXN3 Humanization(WT, Mut),TG
Familial Dysautonomia (FD) ELP1 Humanization(WT, Mut)
Muscle Duchenne Muscular Dystrophy (DMD) DMD Humanization(WT, Mut, KO)
Spinal Muscular Atrophy (SMA) SMN1 Humanization
Metabolism Atherosclerosis (AS) APOE2 Humanization
APOE3 Humanization
APOE4 Humanization
Blood Hemophilia A (HA) F8 Humanization(WT, Mut)
Others Transthyretin Amyloidosis (ATTR) TTR Humanization(WT, Mut),TG

As we stand at the forefront of immense scientific innovations in gene therapy, HUGO-GT
TM emerges as a catalyst for transformative breakthroughs in preclinical research. Whole gene humanization aims to improve the potential for more efficient clinical translation of groundbreaking gene therapies for genetic disorders such as AS,  in addition to more common conditions, such as Alzheimer's Disease (AD), age-related macular degeneration (AMD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), retinitis pigmentosa (RP), etc. Compared to the commercially-available partial gene humanization mouse models, HUGO-GTTM mouse models aim to provide a higher degree of fidelity in recapitulating the human disease pathology for your preclinical research. Discover the HUGO-GTTM difference today - learn more about the HUGO-GTTM Program >>



[1]Meng L , Ward A J , Chun S ,et al.Towards a therapy for Angelman syndrome by targeting a long non-coding RNA[J].Nature, 2015, 518(7539):409-412.DOI:10.1038/nature13975.

[2]Wolter J M , Mao H , Fragola G ,et al.Cas9 gene therapy for Angelman syndrome traps Ube3a-ATS long non-coding RNA[J].Nature, 2020, 587(7833):1-4.DOI:10.1038/s41586-020-2835-2.