UM School of Medicine team wins NIH TARGETED Challenge with brain genome editing technology

A team of researchers from the University of Maryland School of Medicine (UMSOM) recently won a $250,000 prize from the National Institutes of Health (NIH) to improve technologies for delivering genome editing tools to targeted cells in the body. They were one of four winners in a competition after successfully demonstrating a new technique to deliver genome editing biotechnology across the blood-brain barrier to brain cells in preclinical models. 

The team included Pavlos Anastasiadis, PhD, Alexandros Poulopoulos, PhD, Jung Soo Suk, PhD, and Graeme Woodworth, MD, who called themselves the Crisaptics Trans-BBB Genome Editing Team. They used a combination of engineered nanoparticles, microbubbles, and focused ultrasound to open the blood-brain barrier and deliver advanced CRISPR agents to edit genes in narrowly targeted clusters of brain cells in an in vivo animal model. 

The work earned them a top winning spot and the monetary prize from the NIH Targeted Genome Editor Delivery (TARGETED) Challenge, which the team plans to use to further their ongoing research into their technologies.

“All of us on the team were thrilled and honored to be among the challenge winners taking this critical step on the path to develop genome therapeutics for the brain,” said Dr. Poulopoulos, an Associate Professor of Pharmacology and Physiology. “We’re excited to continue developing this technology, which could one day help treat diseases that have proven extremely difficult to manage, including Huntington’s disease, genetic epilepsies, and glioblastoma.”

The NIH launched the TARGETED Challenge in 2023 to foster innovation in delivering genome editing tools and the delivery of those tools across the blood-brain barrier to target central nervous system tissues. Developing the right genome editing tools with the precision to target tissues could allow researchers to cure rare genetic disorders by editing the malformed genes that cause them. For example, researchers like Dr. Poulolpoulos are trying to edit an error in the IT15 gene in neurons in the brain’s basal ganglia, which could alleviate the progressive cognitive and motor dysfunctions of Huntington’s disease.

Taking place in three phases, the TARGETED Challenge offers a total of $6 million in prizes awarded to a narrowing field of competitors. The Crisaptics Trans-BBB team was one of four teams that each won a $250,000 prize in Phase 2 of the challenge. In Phase 3, the NIH will select six teams and test their cross-blood-brain barrier delivery and editing technologies in large animal preclinical studies before awarding a final winning team a $650,000 prize. 

The Challenging Delivery of Cures

Genome editing tools such as CRISPR have the potential to treat or cure genetic conditions that existing therapies, including gene therapy, do not, such as Huntington’s disease. “It turns out that 95 percent of human genetic disease is not about the part of a gene that codes for a protein,” said Dr. Poulopoulos, “but the regulatory portions of the gene sequence that tell a cell when, where, and how much to express that protein. Traditional gene therapy, which inserts a healthy copy of the protein-coding portion of a gene, cannot address those issues.”

The potential of genome editing tools such as CRISPR to treat or cure challenging diseases hinges both on the power of those tools and the ability to get to where they need to go in the body. That’s why the part of the TARGETED Challenge focused on proposals to deliver those tools across the blood-brain barrier, a system of specialized cells lining capillaries in the central nervous system that prevent large molecules or pathogens from traversing from the blood into the brain, according to Dr. Poulopoulos. “These CRISPR agents are quite large, and so do not easily cross the blood-brain barrier,” he said. 

The Crisaptics Trans-BBB team’s approach to that challenge arose organically from the already ongoing research and collaboration between the four labs. While Dr. Poulopoulos’s lab was developing advanced CRISPR/ Cas9-RC agents for the treatment of conditions like Huntington’s, Dr. Suk, an Associate Professor of Neurosurgery and UM-MIND, Dr. Anastasiadis, an Assistant Professor of Neurosurgery, and Dr. Woodworth, Professor and Chair of Neurosurgery, were developing methods for getting those agents through the brain’s security fence called the blood-brain barrier – which prevents 98 percent of pharmaceuticals from getting into the brain. 

Dr. Suk studies polymer and lipid-based nanoparticles engineered to encapsulate therapeutic agents for delivery to target tissues in the body by injection into the bloodstream. “Our particles are designed to circulate for a long time in the blood by minimizing their interactions with blood components and the liver,” he said. “We found particles as large as 130 nanometers in diameter can pass through the blood-brain barrier with an aid of focused ultrasound-mediated blood-brain opening,” providing a delivery vehicle large enough to carry Dr. Poulopoulos’s CRISPR agents.

The work of Drs. Woodworth and Anastasiadis provided the key to successfully opening the blood-brain barrier to the CRISPR agent-containing nanoparticles. The two researchers have been studying the use of focused ultrasound to treat brain tumors, with Dr. Woodworth and his team currently leading the first-in-human clinical trial of this technology to treat brain cancer in the U.S. The technique involves the creation of tiny microbubbles of compressible gas injected into the blood alongside the nanoparticles.

Focusing multiple beams of ultrasound waves to converge at a targeted point in the brain then causes the microbubbles there to resonate within the sonic field, and this activity causes a localized and temporary opening of the blood-brain barrier at the junction of the ultrasound beams. The nanoparticles can then diffuse across to deliver their CRISPR agent payloads to the target tissues.   

“We showed our technology allowed for those CRISPR agents to enter neurons or astrocytes in a specific part of the animal brain and carry out local genome editing,” Dr. Poulopoulos said. “That’s what won us the challenge.”

Innovation Made Possible Through Collaboration

The intensive collaboration that made the Crisaptics Trans-BBB team’s victory possible serves as an ideal example of the multidisciplinary synergies that UM-MIND can facilitate, according to Dr. Anastasiadis. Established by UMSOM Dean Mark T. Gladwin in 2023, UM-MIND brings clinicians and preclinical researchers, neurosurgeons, pharmacologists, psychiatrists, and other specialists together under one umbrella. 

“The four of us principal investigators come from different training backgrounds, but UM-MIND offered the platform that allowed us to address a major challenge in neuroscience,” Dr. Anastasiadis said. “Our close collaboration is a clear example of UM-MIND’s core mission in action.”

The collaboration will continue as the team waits to learn if they will be one of the six selected for the large-scale NIH testing. The NIH will announce the grand prize-winning team sometime in the fall of 2026. Regardless of the outcome, the research team will keep developing their technology in pursuit of innovative treatments for patients struggling with difficult diseases. 

“Winning this phase of the challenge is a big external validation for the work we’ve been doing for, in some cases, 15 years or more,” Dr. Woodworth said. “It confirms that we’re headed in the right direction with this work and has reinvigorated us all to keep going.”