Gene therapy delivered by AAV is expected to cure Angel syndrome

Written | Edited by Wang Cong | Typeset by Wang Duoyu | The picture shows a patient with Angel syndrome, from UNC Angel Syndrome (Angelman syndrome), a rare brain disease, about one in 20,000 newborns suffers Sick
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Affected children have severe intellectual disability, seizures, walking and sleep disturbances, and mutism (some even say nothing in their lives), and always have a smile on their faces, so it is also called happy puppet syndrome
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The disease was also included in the first batch of rare diseases list in China
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Angel syndrome is a single-gene genetic disease caused by the mutation or deletion of the UBE3A gene located on chromosome 15.
However, its genetic principles are more complicated than general single-gene genetic diseases
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There are usually two copies of each gene (one from the father and one from the mother).
This pair of genes is also called alleles
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However, the UBE3A gene is special.
The copy of the gene from the father is not expressed and is silent.
Mature neurons usually only express the copy from the mother.
If there is a problem from the mother, it will lead to angel syndrome
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To make things more complicated, under normal circumstances, there are two transcripts of the UBE3A gene expressed by neurons, one is the short version and the other is the long version.
The ratio of the two is about 3:1
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For this complex genetic disease, gene therapy is almost the only hope
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Recently, researchers from the University of North Carolina in the United States published a research paper titled Dual-isoform hUBE3A gene transfer improves behavioral and seizure outcomes in Angelman syndrome model mice in the JCI Insight journal
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The research team used adeno-associated virus (AAV) vector-delivered gene therapy to deliver the therapeutic UBE3A gene to the brain of a mouse model of Angel Syndrome, and successfully repaired its motor deficits, seizures and other neurological symptoms without obvious Side effects
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This further primate experiment and human clinical trials laid the foundation
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First, the research team constructed a mouse model of Angel Syndrome.
The mouse model lacks a mother-derived copy of the UBE3A gene.
Like humans with Angel Syndrome, these mice cannot express UBE3A in their neurons after birth.
Protein, and quickly develop motor deficits, seizures, and other neurological symptoms
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Then the research team constructed a double transcript UBE3A gene vector, which can be transcribed and expressed as two different length versions of UBE3A protein at the same time.
When it is expressed in neurons, it will produce short lengths at a ratio close to the normal 3:1.
Version and long version of UBE3A protein
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This therapeutic UBE3A gene was then loaded into the adeno-associated virus (using the PHP.
B serotype), and then injected into the ventricles in the brains of neonatal angel syndrome mice
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The research team found that within a few days after the injection, the UBE3A gene carried by AAV became active in neurons in the brain of the whole angel syndrome model mouse, and its expression level was similar to that of normal mice
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This treatment restored the mice's motor skills learning and the mice's basic digging, burrowing and nesting behaviors
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The untreated mice showed symptoms similar to Angel Syndrome
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The treated mice were not as sensitive to experimentally induced seizures as the untreated mice.
Importantly, this gene therapy did not observe any obvious side effects
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The research team said that this is a proof-of-concept study that confirms the feasibility of this gene therapy.
If these early results are translated into clinical trials, it will greatly improve the quality of life of patients with Angel Syndrome and reduce the burden on their families
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The research team is planning to further advance this research, and will conduct more tests in mice and monkeys to optimize dosage and delivery methods, and finally conduct human clinical trials
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The research team said that Angel syndrome is a brain development disorder caused by mutations or deletions in the UBE3A gene.
Therefore, the earlier the treatment, the better the effect.
From birth to 4 years old is an ideal time frame, during which the brain is restored UBE3A gene should bring obvious therapeutic effect
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Prior to this, Professor Mark Zylka, an authoritative expert in the field of angel syndrome research and director of the University of North Carolina Neuroscience Center, added a more radical treatment method: injecting the AAV virus-mediated CRISPR-Cas9 gene editing system into the brain of the fetus in the uterus , Use Cas9 to destroy the antisense transcript that silences the father's UBE3A gene, thereby reactivating the expression of the father's UBE3A gene
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This is a radical treatment that has never been tried before.
Related experiments have shown that this gene therapy can achieve the best therapeutic effect when the fetal brain is in the second trimester of development
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Link to the paper: https://insight.
jci.
org/articles/view/144712 ​​is open for reprinting, welcome to forward to Moments and WeChat groups