The National Institutes of Health has awarded the first phase of a roughly $40m grant to Yale University to advance a novel CRISPR-based gene-editing delivery platform for the targeted treatment of neurogenetic diseases.
The two diseases being targeted in the project are Angelman syndrome and H1-4 (HIST1H1E) syndrome.
The project team named under the grant includes representatives from Dr Yong-Hui Jiang’s team and Dr Jiangbing Zhou’s team at Yale, Dr Elizabeth Berry-Kravis’ team at RUSH University Medical Center, and Dr Allyson Berent and Jennifer Panagoulias from the Foundation for Angelman Syndrome Therapeutics (FAST).
The grant is intended to support the entire trajectory of drug development – from the proof-of-concept studies through to the IND-enabling studies required for a clinical trial and the Phase I/II clinical trial for both diseases.
The new delivery technology – called Stimuli-responsive Traceless Engineering Platform (STEP) – enables brain-wide delivery of ribonucleoproteins (RNPs) via intrathecal administration and has the potential to cure diseases in the brain through a one-time treatment.
“As a versatile platform technology, STEP-engineered RNPs could be potentially adopted for treatment of many neurogenetic disorders,” said Dr Zhou.
‘Astonishing’ results in Angelman syndrome
For Angelman syndrome, the researchers say the results to date are showing substantial promise in the mouse model at both birth and adult ages, with wide brain biodistribution and a long-lasting effect. Importantly, the gene editing platform avoids the need for viral delivery, which is the common way that CRISPR technologies have been delivered to the brain.
“In our mouse model of Angelman syndrome, we’re seeing very efficient gene-editing in neurons throughout the brain accompanied by reactivation of the Ube3a gene and improvements in neurobehavioral phenotypes,” said Dr Jiang. “It’s astonishing.”
“This grant supports a complete bench-to-bedside arc,” said Dr Berent, Chief Science Officer at FAST. “It not only pushes forward the scientific promise already proven in the rodent model, but provides the resources for our team to advance the programme through the regulatory requirements needed to get this into a first-in-human clinical trial. It’s an innovative way of fulfilling our mission at FAST: managing and protecting the therapeutic pipeline so that treatments can get to people living with Angelman syndrome as quickly and safely as possible.”