A whole community invests, collaborates, and works hard for a cure to Angelman syndrome, a condition similar to autism caused by mutations in a single gene. The research community hopes the research model may lead to a blueprint to treat similar diseases such as autism.
What is Angelman syndrome?
As reported in Spectrum News, it is a developmental disorder involving development delays, motor problems, seizures, sleep problems, and in many cases, autism. The majority afflicted are minimally verbal, walk with a wide-spaced, unsteady gait (ataxia) and exhibit repetitive behaviors including hand-flapping. Those afflicted are often still overall happy in life.
The disorder is caused a mutated gene, UBE3A, which holds the key to potential therapies. Apparently, a copy of the UBE3A gene inherited from the mother is frequently active in neurons. This maternal copy is nonfunctional in those with Angelman syndrome. However, the paternal copy is perfectly normal—but silent.
Treatments have centered on restoring expression of UBE3A either by replacing the maternal copy (gene therapy) or activating the silent paternal copy. Researchers are making considerable progress.
In regard to gene therapies, multiple pharmaceutical companies and academic medical centers are working to calibrate the gene dose as they work on investigational gene therapies for Angelman syndrome. Active pursuits include those with University of Texas Southwestern Medical Center, the University of Pennsylvania and PTC Therapeutics.
Other challenges involve gene therapies with UBE3A, reports author Stormy Chamberlain, such as the fact that the UBE3A gene can produce three slightly different proteins situated in various parts of a neuron. Unfortunately, gene therapy can only likely replace one form.
Activating the silent paternal copy of the gene could be feasible, as by 2011 researchers developed proof of this approach by screening approximately 2,400 small molecules to see if any of them could turn on the silent copy—and, apparently one did—known as a topoisomerase inhibitor, a blocker of enzymes that untangle DNA. So inhibiting these enzymes could halt RNA production—the kind that silences UBE3A. But this process produces topoisomerase inhibitors, containing side effects. Apparently, Dr. Chamberlain reports “small DNA-based drugs can do the same thing with more precision.” These drugs are similar to nusinersen (Spinraza), a treatment for spinal muscular atrophy.
Finally, a few years ago, investigators tested an antisense oligonucleotide for Angelman Syndrome. This molecule unsilenced the paternal UBE3A and improved cognition in a mouse model. Three companies, including Ionis, Roche and GenTx, are pursing similar therapies for the syndrome. They will probably require repeated spinal injections.