1. Academic Validation
  2. Emerging Gene and Small Molecule Therapies for the Neurodevelopmental Disorder Angelman Syndrome

Emerging Gene and Small Molecule Therapies for the Neurodevelopmental Disorder Angelman Syndrome

  • Neurotherapeutics. 2021 Jul;18(3):1535-1547. doi: 10.1007/s13311-021-01082-x.
Nycole A Copping 1 2 Stephanie M McTighe 3 Kyle D Fink 2 Jill L Silverman 4
Affiliations

Affiliations

  • 1 School of Medicine, Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California, Research II Building 96, 4625 2nd Avenue, Suite 1001B, Davis, Sacramento, CA, 95817, USA.
  • 2 Stem Cell Program and Gene Therapy Center, Department of Neurology, MIND Institute, University of California, Davis, Sacramento, CA, USA.
  • 3 Arkuda Therapeutics, 200 Arsenal Yards Blvd, Suite 220 , Watertown, MA, USA.
  • 4 School of Medicine, Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California, Research II Building 96, 4625 2nd Avenue, Suite 1001B, Davis, Sacramento, CA, 95817, USA. jsilverman@ucdavis.edu.
Abstract

Angelman syndrome (AS) is a rare (~1:15,000) neurodevelopmental disorder characterized by severe developmental delay and intellectual disability, impaired communication skills, and a high prevalence of seizures, sleep disturbances, ataxia, motor deficits, and microcephaly. AS is caused by loss-of-function of the maternally inherited UBE3A gene. UBE3A is located on chromosome 15q11-13 and is biallelically expressed throughout the body but only maternally expressed in the brain due to an RNA antisense transcript that silences the paternal copy. There is currently no cure for AS, but advancements in small molecule drugs and gene therapies offer a promising approach for the treatment of the disorder. Here, we review AS and how loss-of-function of the maternal UBE3A contributes to the disorder. We also discuss the strengths and limitations of current animal models of AS. Furthermore, we examine potential small molecule drug and gene therapies for the treatment of AS and associated challenges faced by the therapeutic design. Finally, gene therapy offers the opportunity for precision medicine in AS and advancements in the treatment of this disorder can serve as a foundation for other single-gene neurodevelopmental disorders.

Keywords

Angelman syndrome; Animal models; Antisense oligonucleotides; Delivery; Gene therapy; Pharmacology; Precision medicine; Preclinical; Seizures; Small molecules; Stem cells; Treatment.

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