Tim Tai, Senior Photographer

The National Institutes of Health has awarded researchers at the Yale School of Medicine, alongside the Foundation for Angelman Syndrome Therapeutics and Rush University Medical Center, $40 million for the development of a novel gene editing platform that could offer treatments for genetic brain disease.

The genome editing platform, which uses CRISPR-Cas9 technology, was developed in a collaboration between neurosurgery professor Jiangbing Zhou and genetics professor Yong-Hui Jiang. It is designed to deliver cures for two rare genetic brain diseases: Angelman syndrome and HIST1H1E syndrome.

The grant to develop the platform has two phases. The first, worth $26.5 million, will fund the technology for testing in non-human primates, during which the team will apply for approval from the Food and Drug Administration for the gene therapy delivery platform. In the second phase, which is worth $13.4 million, both the Foundation for Angelman Syndrome Therapeutics and Rush University Medical Center — which specialize in bringing technologies from the lab to patients — will begin clinical trials.

“This grant supports the translation of promising technologies from the laboratory into the clinic, where it can directly benefit patients — known as ‘bench to bedside’ — which is the hallmark of FAST’s unique patient advocacy strategy,” Alana Newhouse, president of FAST, wrote to the News. “The group, the largest funder of Angelman syndrome research in the world, is dedicated to bringing effective treatment into current medical practice.” 

According to the NIH, Angelman syndrome affects the nervous system, causing delayed development and seizures. HIST1H1E syndrome, which is more rare than Angleman syndrome, can cause intellectual disability and heart anomalies. Both diseases are diagnosed in children.

The grant will fund a new gene therapy technology called stimuli-responsive traceless engineering platform, which supports the delivery of molecules called ribonucleoproteins throughout the brain. This platform, according to experts the News interviewed, could cure diseases in the brain through a one-time treatment. 

Zhoe developed the technology, and Jiang tested it in mouse models. Their labs will continue to work together on the grant. 

“This is really a fruitful collaboration between myself, a biomedical engineer, and Yong-Hui, a physician scientist who has a lot of knowledge in disease modeling and clinical translation and first line experience dealing with patients with neurogenetic diseases,” Zhou wrote to the News. 

In the past, researchers have attempted to deliver gene therapy to the brain using two methods: viral vectors and nanoparticles. 

However, viral vectors remain in cells long after reaching them. Viral vectors can continue to cut and unintentionally edit the genome, making them a dangerous cancer risk, according to Zhou and Jiang. 

Nanoparticles are less dangerous, but they are too large to reach the brain. At 100 to 200 nanometers across, they can not pass the blood-brain barrier and reach the brain cells, Jiang said. 

In contrast, the STEP delivery platform uses molecules that are only 12 to 14 nanometers in diameter, allowing them to disperse through the brain with ease. 

Zhou told the News that the platform for drug delivery he designed is versatile and can be applied to over three thousand different neurogenetic diseases.

“We hope to characterize the delivery system as a platform and if successful we can apply the same or similar systems for other neurogenetic diseases,” Zhou wrote to the News. “We are actually developing similar therapies for a few other diseases, including Alzheimer’s disease, at this moment.”

Jiang, who designed the mouse model for Angelman syndrome that is now widley used in research in his lab 20 years ago, also spoke about the potential impact of the gene delivery technology. 

There are some diseases, he said, that can be treated with the insertion or deletion of genetic information in a single location. Through a combination of the new delivery platform and existing CRISPR-Cas-9 gene editing technology, those diseases could be cured.

After the platform is FDA approved, only the targeting molecules that CRISPR uses to find specific genes would need to be switched out to cure a new disease, Zhou said. 

“There are at least a few hundred diseases for sure which may be cured,” Jiang told the News.

He said he hopes this will make treatments for neurogenetic diseases more accessible for patients. 

Zhou described the possibility of getting approval for the swapping mechanism as being similar to the COVID-19 vaccine approval process. While the first vaccine was difficult to get approved, the boosters were not, since they use the same underlying technology. 

For the researchers involved, treating these genetic diseases can be personal. Jiang, in addition to working in the lab, is a doctor who helps treat patients with Angelman and HIST1H1E syndromes. He spoke to the News after a full day at work. 

“I am a physician, and I see all these patients in my clinic,” Jiang said. “I really connect to these families.”

Clinical psychologist James McPartland, the director of the Yale Developmental Disabilities Clinic, will be working on the grant in its second phase once the gene editing platform is being tested in humans.

According to McPartland, the research the NIH grant funds could play a major role to help those affected by the genetic diseases.

“I got an email from a mom of a child with Angelman syndrome this morning, and it said ‘let’s cure Angelmans’, and I think that’s the goal of this kind of work,” he said.  “For a clinical psychologist doing research on the outside of human skulls using EEG, this is science fiction — it’s very exciting to be even a small part of it.”

Angelman syndrome affects 500,000 individuals worldwide.