Babies born with a faulty maternal copy of the UBE3A gene will develop Angelman syndrome, a severe neurodevelopmental disorder with no cure and limited treatments. Now, for the first time, scientists show that gene editing and gene therapy techniques can be used to restore UBE3A in human neuron cultures and treat deficits in an animal model of Angelman syndrome.
This work, published in Nature lays important groundwork for a long-lasting treatment or cure for this debilitating disease, as well as a therapeutic path forward for other single-gene disorders.
Angelman syndrome is caused by a deletion or mutation of the maternal copy of the gene that encodes the ubiquitin protein ligase E3A (UBE3A). The paternal copy of UBE3A is typically silenced in neurons, so the loss of maternal UBE3A results in a complete absence of the UBE3A enzyme in most areas of the brain. That's crucial because the enzyme targets proteins for degradation, a process that maintains normal function of brain cells. When that process goes awry, the result is Angelman syndrome, a brain disorder with symptoms that include severe intellectual and developmental disabilities, seizures, and problems with speech, balance, movement, and sleep.
"Turning on the paternal copy of UBE3A is an attractive therapeutic strategy because it could reverse the underlying molecular deficiency of the disease," the senior author said. However, the paternal gene is silenced by a long strand of RNA, produced in the antisense orientation to UBE3A, which blocks production of the enzyme from the paternal copy of the gene.
The authors set out to devise a way to use CRISPR-Cas9 to restore the UBE3A enzyme to normal levels by disrupting the antisense RNA. In the Nature paper, co-first authors describe using an adeno-associated virus (AAV) gene therapy to deliver the Cas9 protein throughout the brain of embryonic mice that model Angelman syndrome. Because UBE3A is essential for normal brain development, early treatment is crucial.
The researchers found that embryonic and early postnatal treatment rescued physical and behavioral phenotypes that model core deficits found in Angelman syndrome patients. Remarkably, a single neonatal injection of AAV unsilenced paternal Ube3a for at least 17 months, and the data suggest this effect is likely to be permanent. The researchers also demonstrated that this approach was effective in human neurons in culture.
"We were blown away when we got these results," the senior author said. "No other treatments currently being pursued for Angelman syndrome last this long, nor do they treat as many symptoms. I am confident others will eventually recognize the advantages of detecting the mutation that causes Angelman syndrome prenatally and treating shortly thereafter."
While working to translate this research into the clinic, the lab will identify symptoms in babies that have the genetic mutation that causes Angelman syndrome. Anecdotal reports suggest these infants have difficulty feeding and reduced muscle tone, but these and other early symptoms have not been rigorously characterized to date.
"The idea is to use genetic tests to identify babies that are likely to develop Angelman syndrome, treat prenatally or around the time of birth, and then use these early symptoms as endpoints to evaluate efficacy in a clinical trial," the senior author said. "Our data and that of other groups clearly indicate that prenatal treatment has the potential to prevent Angelman syndrome from fully developing."
As part of the Nature study, the researchers also found that the gene therapy vector blocked the antisense RNA by integrating into the genome at sites cut by CRISPR-Cas9. This so-called "gene trap" could be exploited to disrupt other long non-coding RNAs and genes.
https://news.unchealthcare.org/2020/10/scientists-take-major-step-toward-angelman-syndrome-gene-therapy/
https://www.nature.com/articles/s41586-020-2835-2
CRISPR/CAS gene therapy for a neurodevelopmental disorder!
- 1,182 views
- Added
Edited
Latest News
A new brain circuit in mice…
By newseditor
Posted 08 May
Mechanism of choline entry…
By newseditor
Posted 07 May
Link between UTI and breast…
By newseditor
Posted 07 May
Sleep resets brain connections
By newseditor
Posted 07 May
Interplay of various enzyme…
By newseditor
Posted 07 May
Other Top Stories
A human organoid screen identifies a regulator of ER secretion as a…
Read more
Pitfall for correcting mutations in human embryos with CRISPR
Read more
Highly specific distribution of proteins on neurons
Read more
Developmental atlas of neuronal diversity
Read more
Brain place cells retrieve memory to guide spatial behavior
Read more
Protocols
Single-cell adhesive profil…
By newseditor
Posted 07 May
Parasympathetic neurons der…
By newseditor
Posted 07 May
Non-invasive measurements o…
By newseditor
Posted 05 May
A validation strategy to as…
By newseditor
Posted 04 May
Generation of rat forebrain…
By newseditor
Posted 03 May
Publications
Synaptotagmin-11 facilitate…
By newseditor
Posted 08 May
Astrocytic Slc4a4 regulates…
By newseditor
Posted 08 May
Diabetic retinopathy is a c…
By newseditor
Posted 08 May
A body-brain circuit that r…
By newseditor
Posted 07 May
Host response during unreso…
By newseditor
Posted 07 May
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar