ASOs in Angelman Syndrome

Quick Overview

Angelman Syndrome is a genetic disorder caused by the loss of function of the UBE3A gene, which is important for brain function. The paternal copy of the gene is silenced by a non-coding RNA called UBE3A-ATS. Researchers are investigating the use of antisense oligonucleotides (ASOs) to unsilence the paternal copy of the gene. ASOs are designed to bind to the UBE3A-ATS RNA and prevent its action. The ASOs are administered through a lumbar puncture and travel to the central nervous system. They enter neurons and bind to the UBE3A-ATS RNA, leading to its degradation. This allows the paternal UBE3A gene to be transcribed and produce functional UBE3A protein. Animal models have shown positive outcomes, and human clinical trials are underway.

Introduction

Angelman Syndrome is a neurodevelopmental disorder caused by the loss of function of the UBE3A gene on chromosome 15. This gene is crucial for the brain’s control of speech, movement, and learning. In individuals with Angelman Syndrome, the UBE3A gene inherited from the father is silenced by a mechanism called the antisense transcript. This mechanism involves the production of a long, non-coding RNA called the UBE3A-ATS, which covers the functional paternal UBE3A gene, resulting in its silencing.

Unsilencing the Paternal UBE3A Gene

Research funded by FAST (Foundation for Angelman Syndrome Therapeutics) is exploring a promising strategy to unsilence the paternal copy of the UBE3A gene. This strategy involves the use of antisense oligonucleotides (ASOs), which are a mixture of DNA and RNA designed to bind to the RNA of the UBE3A antisense transcript at a specific location. The ASO’s sequence of RNA and DNA bases is arranged in a complementary order to the RNA, inhibiting the silencing effect. The ASO is administered through a lumbar puncture into the spinal fluid.

Targeting the Central Nervous System

Once administered, the ASO travels through the cerebrospinal fluid and reaches the neurons of the central nervous system. It enters the cell nucleus through a process called endocytosis, where it engages with the chromatin, which is composed of tightly wound DNA. The ASO’s complementary sequence allows it to bind to the UBE3A antisense transcript, forming two complementary strands. This binding leads to cleavage through RNAase degradation, facilitated by cellular enzymes. The RNA molecule that was blocking gene transcription is degraded, allowing the paternal copy of the UBE3A gene to be activated.

Protein Production and Neuronal Function

With the paternal UBE3A gene now unblocked, it can be transcribed into mRNA, which then enters the protein manufacturing ribosomes. Ribosomes build functional copies of the UBE3A protein, replacing the non-functional or missing maternal supply. This recovery of proper neuronal function is a crucial step towards treating Angelman Syndrome.

Promising Results and Clinical Trials

These research strategies, including the use of ASOs, have shown positive outcomes in animal models of Angelman Syndrome. As of 2020, two of these strategies are now in human clinical trials, bringing us closer to finding a cure for Angelman Syndrome.

In conclusion, the use of ASOs to unsilence the paternal UBE3A gene shows promise in the treatment of Angelman Syndrome. Ongoing research and clinical trials are providing hope for individuals and families affected by this neurodevelopmental disorder.