Using antisense oligonucleotides (ASOs), a series of genetic material, to rescue abnormal brain rhythms and sleep patterns in a mouse model targeting a molecule known as UBE3A-ATS. Angelman syndrome.
Treatment effects were seen in both juvenile and adult mice, but were more pronounced in young mice.
“If ASO therapy can reduce sleep disturbances, it will improve the quality of life for both Angelman syndrome patients and their caregivers,” the researchers wrote. study, “Antisense oligonucleotide therapy rescues brain rhythm disruption and sleep in juvenile and adult mouse models of Angelman syndromewas published in e-life.
roughly everyone inherits one copy of UBE3A genes from each biological parent. Both copies are active in most cells, but in some brain regions only the copy from the biological mother is active.
In Angelman syndrome, the mother’s UBE3A copy missing, inactive, or dysfunctionalAbnormal brain rhythms (usually measured by electroencephalography (EEG)) and sleep disturbances are two prominent clinical features of this disease.
ASOs are short strings of DNA or RNA that can control the amount of protein produced within a cell.UBE3A-ATS, known as an antisense transcript, is silenced because it binds to messenger RNA molecules and blocks their translation into proteins Parental UBE3A gene activity in neurons.
“A promising therapeutic approach to treat Angelman syndrome is to reactivate the intact father. UBE3A by suppressing UBE3A-ATS’” wrote the researcher.
Genetic approaches targeting UBE3A-ATS are being investigated in mice and ASO clinical trials are underway. However, evidence from animal studies indicates that gene-targeted therapy may have to be administered before the age at which Angelman syndrome is usually diagnosed in children, so the timing of therapeutic intervention is Doubts remain.
Also, whether brain rhythm and sleep alterations due to this disorder are reversible in young and adult mice with Angelman syndrome-like syndrome remains to be elucidated, as this is a clinically relevant developmental stage.
targeting UBE3A-ATS with ASO therapy
US researchers, along with researchers at Ionis Pharmaceuticals, are working on a new mouse model of disease,here maternal UBE3A no copyJuvenile and adult mice were given a single injection of an ASO targeting UBE3A-ATS.
The team used two mouse-specific ASOs, Ube3a-as and Snord115, to reduce UBE3A-ATS levels. A third group received a non-targeted ASO as a control.
In wild-type (healthy) mice, both UBE3A-AS and Snord115, given via intracerebroventricular (into the fluid-filled cavities of the brain) injections, were found to boost paternal activity. Ube3a Lower messenger RNA molecules from gene copies and Ube3a-ATS in the brain. It should be noted that Ube3a is a mouse format of UBE3A.
In young Angelman mice, ASO Ube3a Protein levels at 3 weeks of injection – up to about 28-71% of normal mice – in various brain regions.
Ube3a-ATS levels decreased by 29–73%, but Ube3a Genes were up to 22-57% of normal levels.
Notably, the Ube3a-as ASO results remained stable for at least 10 weeks, whereas the effects of Snord115 on gene activity and protein levels declined significantly at 6 weeks of injection.
In adult mice, both ASOs significantly decreased and increased Ube3a-ATS levels. Ube3a gene activity and Ube3a protein levels in 3 weeks. However, increasing Ube3a protein at this age was slightly less effective in some brain regions than in younger animals, the scientists noted.
The effects of the Ube3a-as ASO decreased slightly over 10 weeks in adult animals, again more pronounced with the Snord115 ASO.
Also, Ube3a-as ASO broadly normalized EEG findings related to brain rhythms in juvenile mice, whereas adult mice showed similar effects only in a brain region called the frontal cortex 3 weeks after injection. . The researchers noted that this difference between ASOs correlated with differences in Ube3a protein upregulation. In adult animals, both her ASOs reversed abnormal EEG rhythm activity.
ASOs injection also normalized sleep patterns in juvenile mice.Time spent in the rapid eye movement phase (REM; characterized by increased brain activity and intense dreams) was similar to healthy mice. In adult animals, it was less effective in restoring sleep.
Results demonstrate a single injection of ASO targeting Ube3a-ATS The Angelman mouse model rescued the salient clinical features of the disease, but showed that the treatment was more effective in juveniles than in adults.
“EEG power spectrum perturbations and sleep reversibility may decrease with age, similar to other neurological disorders,” the researchers wrote, adding that the results suggest a “therapeutic window for gene therapy in Angelman syndrome.” is wider than previously thought,” he adds. EEG power spectra and sleep architecture can be used to assess treatments.
