A Therapy for Angelman Syndrome Shows Promise, but Adverse Effects Leave Questions

Angelman syndrome begins at birth and although symptoms vary, most children exhibit common developmental delays such as:

• Infants showing an inability to support their head
• Unable to pull themselves up to stand
• An inability to crawl
• Various feeding issues

Young children may develop an unstable gait or may have balance issues causing an inability to walk. Seizures are another problem beginning at 18 months through the age of three. Sleep problems may surface early. For example, sleep-wake cycles abnormalities and not as much need for sleep. Infants tend to lack the usual cooing and babbling while young children will use nonverbal communication as their speech is limited or non-existent.

According to a recent press release issued by Ultragenyx, approximately 60,000 people worldwide have Angelman syndrome. The condition is often misdiagnosed as cerebral palsy or autism.

Our Genetic Makeup

Humans carry 46 chromosomes within each cell in their body. We inherit 23 chromosomes from our mother and 23 from our father. The Angelman syndrome gene UBE3A is on number 15 chromosome.

You may notice a reference to a gene that is “expressed,” meaning it is turned on. If it is turned off, it is said to be “silent.” Brains of individuals with Angelman’s syndrome are unable to decipher information needed to control movement, speech, and learning. These errors occur during fetal development and become part of the genetic makeup. On an upbeat note, Angelman children tend to be happy, frequently laugh, smile and are easily excitable.

Last Monday Ultragenyx announced that its nucleic acid therapy, GTX-102, which is currently under development for Angelman syndrome, was helpful. It improved function, behavior and thinking for the study participants who were diagnosed with the neurological disorder. Ultragenyx is now in a position to discuss conducting a larger clinical trial with regulators.

Good News Along with a Word 0f Caution

The treatment is known as an antisense oligonucleotide and has been developed to reactivate the expression of UBE3A, a gene that is silenced in Angelman patients. Seventy-four Angelman pediatric patients have been treated to date.

However, Ultragenyx found that three study participants displayed mild to moderate weakness in their lower extremities. Study observers and investors were quick to associate the incident with the new gene therapy. Although this was a “second occurrence” in connection with GTX-102, regulators did not halt the trial due to Ultragenyx’ exposure.

About the Disclosure

The recent trial disclosure included data that was obtained from 24 participants who were enrolled in the Angelman study and were followed for six months. There were significant changes on the majority of tests with some being “clinically significant” such as behavior, cognition, sleep, hyperactivity, and motor function.

Lead study investigator and Angelman clinic director Erick Sell commented that the children who participated in the study will eventually have more independence. The weakness in three patients that was reported during the study resolved with no lasting effects. One patient was retreated with no recurring adverse events. Ultragenyx anticipates a meeting by mid-year to prepare for a Phase 3 clinical trial.

Rose Duesterwald

Rose Duesterwald

Rose became acquainted with Patient Worthy after her husband was diagnosed with Acute Myeloid Leukemia (AML) six years ago. During this period of partial remission, Rose researched investigational drugs to be prepared in the event of a relapse. Her husband died February 12, 2021 with a rare and unexplained occurrence of liver cancer possibly unrelated to AML.

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