Neuron-specific Aav-mediated WWOX Gene Therapy Rescues Mortality and Seizure Phenotypes in a WOREE Syndrome Mouse Model
Abstract number :
1.14
Submission category :
2. Translational Research / 2D. Models
Year :
2022
Submission ID :
2204603
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:25 AM
Authors :
Rami Aqeilan, PhD – Hebrew University of Jerusalem; Srinivasarao Repudi, PhD – Hebrew University of Jerusalem; Daniel Steinberg, BSc – Hebrew University of Jerusalem; Yael Weiss, MD. PhD – Mahzi Therapeutics Inc.
This abstract has been invited to present during the Basic Science Poster Highlights poster session
Rationale: WWOX-related epileptic encephalopathy (WOREE) syndrome, also known as developmental epileptic encephalopathy-28 (DEE28, OMIM 616211), and spinocerebellar ataxia 12 (SCAR12) are caused by human germline biallelic mutations in WW domain-containing oxidoreductase (WWOX). WOREE/SCAR12 are neurodevelopmental disorders characterized by intractable epilepsy, severe developmental delay, ataxia and premature death at the age of 2-4 years. The underlying mechanism of WWOX actions in WOREE and SCAR12 syndromes development is poorly understood. _x000D_
Methods: Using genetic mouse modeling and patient-derived induced-pluripotent stem cells (iPSCs) and brain organoids, we studied WWOX in brain homeostasis and in its loss of function in WOREE/SCAR12 syndromes. WWOX restoration was achieved using an adeno-associated viral vector (AAV9) harboring human WWOXcDNA and driven by the human neuronal Synapsin I promoter (AAV9-SynI-WWOX).
Results: We demonstrated that specific neuronal deletion of murine Wwox produces phenotypes typical of the Wwox-null mutation leading to brain hyperexcitability, intractable epilepsy, ataxia and postnatal lethality. The phenotypes of this mouse model closely resembled that of WOREE patients. In-depth characterization of these mice revealed a major myelination defect that results in reduced maturation of oligodendrocytes, reduced myelinated axons and impaired axonal conductivity. Brain hyperexcitability as well as dramatic cellular and molecular CNS abnormalities, including neural population changes, cortical differentiation malfunctions, and Wnt-pathway and DNA-damage response impairment were also revealed in human unpatterned brain organoids derived from CRISPR-engineered human ES cells and from patient-derived iPSCs. Remarkably, intracerebroventricular injection of AAV9-SynI-WWOX resulted in widespread expression of WWOX and rescued Wwox null phenotypes, including seizures, myelination defects and mortality. _x000D_
Conclusions: Our results support the clinical development of AAV9-SynI-WWOX as an effective and targeted disease-modifying approach to WOREE and SCAR12 syndromes.
Funding: The Aqeilan’s lab is funded by the European Research Council (ERC) [No. 682118], Proof-of-concept ERC grant [No. 957543], and Research Sponsored Agreement through Mahzi Therapeutics.
Translational Research