Funding Research for Treatments and a Cure

Mapping UBE3A in Non‐Human Primates to Inform UBE3A Gene Therapy and Reinstatement Strategies to Treat Angelman Syndrome
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Ben Philpot, PhD Ben Philpot, Ph.D. UNC Chapel Hill
2020

Mapping UBE3A in Non‐Human Primates to Inform UBE3A Gene Therapy and Reinstatement Strategies to Treat Angelman Syndrome

Angelman syndrome is caused by deletions or mutations of the maternally‐inherited gene copy of UBE3A. The paternally‐inherited gene copy of UBE3A lies dormant, thus loss of the maternal UBE3A gene copy leads to a near complete loss of UBE3A protein in the brain. This biology suggests two major strategies to treat AS at its genetic core.

  • First, one could treat AS by delivering UBE3A using a traditional gene therapy approach – that is, adding the UBE3A gene back to brain neurons through a safe viral‐like delivery.
  • Second, one could treat AS by reactivating the dormant paternal gene copy of UBE3A.

Both of these approaches require knowing when, where, and in what cell types UBE3A protein is normally expressed in the developing brain, as this information is paramount to guide the desired biodistribution of delivered therapeutics, which likely changes over development. Currently we know a great deal about expression of UBE3A in the rodent brain, but almost nothing is known about the developmental expression pattern of UBE3A protein in the primate (human and non‐human primate; NHP) brain.

If the distribution of UBE3A in the primate brain is improperly inferred from rodent studies, this could lead to inappropriate delivery of AS treatments. To overcome this limitation, we propose to perform a complete study of UBE3A expression across development, from prenatal to adult ages, in the closest proxy we can get to the human brain – the brain of the rhesus macaque monkey. This non‐human primate (NHP) brain closely resembles that of the human brain, and has a high degree of evolutionary conservation. We will perform a complete study of the whole‐brain expression patterns of UBE3A in the primate brain, spanning early gestational periods to adulthood.

The temporal and regional expression patterns of UBE3A that we reveal in NHPs will critically guide emerging gene addition and reinstatement strategies to treat AS, including eventual prenatal treatments for AS.