Muotri Lab brain organoids laid the foundation for Pitt Hopkins syndrome gene therapy trial

31 January 2026

Mahzi Therapeutics-sponsored Phase 1/2 study to assess safety and efficacy of MZ-1866 gene therapy for children and adults with Pitt Hopkins syndrome is about to start.

The trial was announced by Mahzi in 2025, highlighting the sponsor's collaboration with the Pitt Hopkins Research Foundation and the Muotri Lab at UC San Diego in developing this long awaited treatment.

Pitt-Hopkins syndrome (PHS) is a rare genetic disorder caused by mutations in the transcription factor 4 (TCF4) gene which orchestrates neuronal differentiation, cortical development and synaptic maturation across embryonic and postnatal development. Individuals with PHS typically present with developmental delays, intellectual disability, behavioural differences, distinctive facial features, and breathing difficulties. Other features may include symptoms of autism spectrum disorder and seizures.

Until recently, the biomedical research into PHS had mainly focused on modelling PHS in mice as to study its mechanisms and work toward developing therapies. However, due to numerous human-specific features of genetics, gene expression regulation, brain anatomy and physiology, mouse models of PHS do not faithfully recapitulate the pathophysiology and clinical features of human PHS. The advent of complex human-based in vitro models has enabled unprecedented insights into the molecular mechanisms responsible for PHS pathogenesis, offering hope of effective treatment for this underserved  neurodevelopmental disorder.

In their 2022 study, the Muotri lab team describes how they have engineered patient-derived brain organoids that carry clinically relevant mutations in TCF4 and that closely match the neural phenotypes observed in vivo, laying the foundation for Mahzi's investigative gene therapy.

“We were surprised to see such major developmental issues at all these different scales, and it left us wondering what we could do to address them,” said first author Fabio Papes, PhD, associate professor at the University of Campinas and visiting scholar at UCSD School of Medicine, who jointly supervised the work with Muotri. Papes has a relative with Pitt-Hopkins Syndrome, which motivated him to study TCF4.

By employing lentivirus-mediated over-expression of an extra-copy of the TCF4 gene, the Muotri lab has demonstrated how reduced cortical neuron content and impaired electrical activity could be reversed in PHS patient-derived organoids.

Acting on the same biologic premise, Mahzi's MZ-1866 gene replacement therapy was produced by inserting TCF4 isoform B into an AAV9 expression cassette under the regulation of multimer E box sequences.

“At Mahzi, our mission is to work closely with patient communities as their drive and deep disease knowledge are essential for the development of safe and effective therapies,” said Yael Weiss, MD, PhD, CEO of Mahzi Therapeutics. “This partnership with CTI and the Pitt Hopkins Research Foundation exemplifies how collaboration can accelerate the path from research to meaningful therapies for families affected by rare genetic disorders.”

Initial recruitment took place in the 12–25 age cohort, and a second cohort, ages 2–11, is expected to follow later in 2026. Participants will receive a single dose of MZ-1866 by intracerebroventricular injection.