Antisense oligonucleotide therapy of X-linked protocadherin 19-related autism and epilepsy

  • Awarded: 2021
  • Award Type: Targeted: Genomics of ASD: Pathways to Genetic Therapies
  • Award #: 889861

PCDH19-clustering epilepsy (PCE) is a severe developmental and epileptic encephalopathy caused by loss-of-function variants in the PCDH19 gene on the X chromosome. PCE is characterized by early onset seizures, autism and cognitive impairment. The disorder affects females and mosaic males while male carriers are spared. Mosaic expression of PCDH19 due to random X-inactivation is thought to cause impaired cell-cell interactions between mutant and wildtype PCDH19-expressing cell populations to produce this unique PCE inheritance pattern. Although some progress has been made in understanding PCE mechanisms, potential therapeutic strategies for PCE remain unexplored.

Wei Niu, Jack Parent and colleagues at the University of Michigan have recently developed human brain organoid and rodent models that robustly recapitulate PCE phenotypes1. They hypothesize that attenuating wildtype PCDH19 expression to recapitulate the asymptomatic hemizygous male state will relieve the imbalance between wildtype and mutant PCDH19-expressing cells, and thereby prevent PCE-related brain abnormalities. Antisense oligonucleotides (ASOs) can effectively modulate the level of protein production through targeting of mRNA. The goal of this project is to test whether candidate ASOs mitigate PCE-related phenotypes in human organoid and mouse PCE models.

Teaming with Ionis Pharmaceuticals, Niu and Parent will test whether ASO treatment to suppress wildtype PCDH19 expression can attenuate or reverse PCE-related brain abnormalities in the models. First, they will identify ASOs that target human and mouse PCDH19 to suppress wildtype PCDH19 expression. Second, they will determine whether ASO knockdown of wildtype PCDH19 prevents or reverses neurodevelopmental disease phenotypes in a human brain organoid PCE model. Third, they will establish whether attenuating Pcdh19 expression in PCE mice via ASO treatment prevents or reverses structural brain abnormalities and hyperthermia-induced seizures.

Progress in this work should improve our understanding of the pathological mechanisms of PCE and may identify ASOs as a therapeutic strategy with the potential for preventing or halting the progression of seizures and cognitive impairment in patients with PCE. This strategy also should have more widespread application to mitigate other X-linked female-specific neurodevelopmental disorders that are amenable to knockdown strategies.


1.Tidball A.M. et al. bioRxiv (2022) Preprint
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