Angelman Syndrome Foundation Awards $200,000 to Research CRISPR as Potential Gene Therapy

The Angelman Syndrome Foundation has awarded a $200,000 research grant to investigate the use of CRISPR-Cas9 gene editing technology as a therapy to rescue the faulty gene underlying the disease.

A rare but serious disease, Angelman syndrome is caused by the absence or malfunction of the UBE3A gene.

We inherit two copies of the UBE3A gene, one from each parent. Unlike other body parts, in the brain only the copy inherited from the mother is active. This means that, upon loss or malfunction of the maternal UBE3A gene copy (and because the paternal gene is turned “off”), brain cells are no longer able to produce the protein coded by that gene, called ubiquitin protein ligase E3A.

This protein is important to help cells dispose of damaged or unnecessary proteins, helping to maintain normal cellular function.

As a result, affected children develop malfunctions in the central nervous system, including delayed development, intellectual disability, severe speech impairment, and ataxia (impaired balance).

There are several mechanisms underlying the loss of function of the maternal UBE3A gene. The most common, which occurs in 80 percent of cases, is a deletion in the maternal inherited chromosome that carries the UBE3A gene.

Now, researchers at the University of North Carolina School of Medicine, led by Mark Zylka, PhD, have developed a strategy to rescue the UBE3A gene and compensate for the missing maternal copy by turning “on” the paternal copy of the gene.

This paternal copy is intact but kept silenced by a small RNA molecule called UBE3A antisense transcript, or UBE3A-ATS.

This type of RNA belongs to a group of molecules called long noncoding RNAs whose function is to regulate gene activity.

Following previous work, where the team was able to correct UBE3A gene deficiency in an Angelman mouse model, researchers will now use the genome-editing tool CRISPR-Cas9.

CRISPR technology is the latest of a series of robust genome-editing technologies. It allows scientists to edit genomes with unprecedented precision, efficiency, and flexibility.

CRISPR is originally a bacterial defense system against invaders, such as viruses. Bacteria capture snippets of viral DNA and use it to create DNA segments that are highly similar to the foreign, viral DNA. With this strategy, bacteria not only store a record of invading viruses but also create a type of memory, to help destroy the virus in future encounters.

These DNA snippets are used by the bacterium to detect and destroy DNA from similar viruses during subsequent attacks.

A set of genes was found to be associated with CRISPR repeats and was named “cas” (for CRISPR-associated genes). The cas genes encode special enzymes that can cut or unwind DNA and are always located near the CRISPR sequences.

Researchers will use the CRIPR-Cas9 gene editing technology to target the paternal UBE3A gene copy, this way activating it and restoring the function of UBE3A protein in the brain.

This strategy would be a one-time treatment and, if it works as expected, would provide a possible cure for Angelman syndrome.