Innovative Viral Vector-Based Gene Therapy for DEAF1-Associated Neurodevelopmental Disorders (DAND)

• Grant number: 25/07783-8
• Support Opportunities: Research Grants - Innovative Research in Small Business - PIPE
• Start date: January 01, 2026
• End date: December 31, 2027
• Field of knowledge: Biological Sciences - Biology
• Principal Investigator: Diego Grando Módolo
• Grantee: Diego Grando Módolo
• Principal investigators: Carolini Kaid Dávila ; José Antonio Sánchez Alcázar ; Pedro Henrique Machado Rodrigues
• Associated researchers: Carolina Nunes Santo ; Raphael Severino Bonadio

Abstract

The limited effectiveness of current treatments for neurodevelopmental disorders, often hindered by the blood-brain barrier (BBB) and CNS complexity, makes gene therapy a challenge. Autism Spectrum Disorders (ASD) has been associated with various mutations in the DEAF1 gene, including missense, frameshift and indels variants. These mutations give rise to two distinct intellectual disability (ID) syndromes: the autossomal dominant Vulto-van Silfhout-de Vries syndrome (VSVS) and the recessive neurodevelopmental condition (NEDHELS). Both conditions are clinically classified as DEAF1-associated neurodevelopmental disorders (DAND), caused by loss-of-function or dominant-negative effects of the DEAF1 transcription factor. Currently, there are no effective treatments available for DAND, highlighting an opportunity for gene therapy development to provide an effective and affordable therapeutic solution for patients. Existing viral vectors, approved for gene therapy, often have limited CNS targeting and cargo capacity, restricting their use for complex genetic diseases. Here, we propose developing EviOZ, a safe, non-replicative flavivirus-based vector with potential for CNS tropism, and large RNA payload delivery, to explore dual gene therapies for DAND. First, we aim to evaluate the expression of DEAF1 protein (monomer/dimer) and CRISPR-Cas12 machinery delivered by EviOZ-encapsulated ZiOZ mRNA. Second, we will validate EviOZ tropism and gene therapy effectiveness in patient-derived neuronal models for both VSVS and NEDHELS. Finally, we will assess EviOZ safety in an animal model for regulatory purposes. Together, these efforts seek to establish a first-in-class viral vector platform capable of delivering CRISPR-Cas12 machine and therapeutic genes in vivo. An unprecedented strategy for treating DEAF1-associated and other complex neurodevelopmental disorders currently lacking effective therapies. (AU)