Gene and cell therapy (GCT) has the potential to cure genetic disorders, cancers, and other medical conditions by repairing, replacing or enhancing cellular functions. This burgeoning field holds great promise, but progress hinges on the development of new and more precise techniques to deliver therapy to where it is needed most. Researchers at the Brigham are engineering tools and technology to modify genetic sequences and translate the information found in nucleotides, and they are also developing futuristic biomaterials to deliver therapies with precision.

In 2022, the Mass General Brigham Gene and Cell Therapy Institute was launched under the leadership of Roger Hajjar, MD to create a collaborative environment in which physicians and researchers can share their knowledge and expertise to improve patient outcomes. The Institute’s multidisciplinary approach sets it apart from others in the space, helping researchers to rapidly advance new therapies and push the technological and clinical boundaries of this new frontier.

Among those at the Mass General Brigham Gene and Cell Therapy Institute are researchers Omar Abudayyeh, PhD, Jonathan Gootenberg, PhD, and Natalie Artzi, PhD, who are working on building a bridge between their research and patient care.

New Tools for the Cellular Engineering Toolbox

Omar Abudayyeh, PhD and Jonathan Gootenberg, PhD

Abudayyeh and Gootenberg joined the Brigham and Beth Israel Deaconess Medical Center (BIDMC), respectively, from the Massachusetts Institute of Technology (MIT), to further their work in translational GCT research. Their combined group, known as the AbuGoot lab, brings together expertise in biological discovery and molecular engineering to develop new tools for the manipulation of DNA, RNA, and cellular states. They call this suite of next-generation gene editing tools the “cellular engineering toolbox.”

“These tools have the ability to push our understanding of complex systems, provide novel diagnostic insights, and enable new platforms of therapeutics,” said Gootenberg, whose primary appointment is at BIDMC and has a secondary appointment at the Brigham. “We are enthusiastic about applying these tools to multiple areas, including cellular fate, aging, and genetic disease.”

Their background in gene editing and technology development positions them to make innovative contributions to this area of research at the Brigham.

“It’s exciting to be at the Brigham for a few reasons,” said Abudayyeh. “Not only are we able to continue our own research, but we’re able to collaborate with disease experts who can help us understand how the technologies we create can be applied to a variety of diseases.”

Working together, they are developing programmable gene editing and insertion technologies, such as CRISPR and Programmable Addition via Site-specific Targeting Elements (PASTE). PASTE is a molecular biology tool that can cut flawed genes in DNA and insert new ones safely. The tool builds on the CRISPR gene editing system by combining the DNA-cutting enzyme Cas-9 with other DNA modification enzymes, to target specific landing sites and insert large pieces of DNA, such as entire genes, into the genome. PASTE offers several advantages over CRISPR because it allows researchers to integrate much larger stretches of DNA without introducing double-stranded DNA breaks, enabling a single therapy that can treat any mutation the patient might have.

“In the field, people are always asking ‘what’s the next CRISPR?’,” said Gootenberg. “We still work with CRISPR-based and gene editing technologies, but we also use them as a framework to accelerate science by learning about natural biology to help us develop other tools, which is always a fun process.”

Advancing Care Using Advanced Delivery Materials

Natalie Artzi, PhD

As an innovator, Artzi is developing new ways to deliver gene and cell-targeted therapeutics for patients effectively. Specifically, she and her team are interested in utilizing materials and nanostructures that are tissue- and cell-responsive to deliver drugs, increasing the efficacy of drug delivery and minimizing systemic side effects. The size of nanoparticles allows them to break through biological barriers, enter cells more readily and prevent the drug from degrading and therefore improving the effectiveness of the therapeutic. Nanoparticles are also versatile and precise and can be used across multiple disciplines of medicine and science.

Artzi’s lab is using advanced delivery materials, including hydrogels for local delivery, microneedle patches for transdermal delivery and targeted nanostructures. The materials vary in scale, allowing them to target specific genes, cells, or organs.

Artzi’s passion and tenacity help her to create these materials and provide a framework for future treatments.

“It’s not uncommon for drugs that are developed for certain diseases or conditions, such as cancer or inflammatory diseases, to exert nonspecific off-target effects,” said Artzi. “In the example of cancer, cytotoxic therapies, such as chemotherapy, may kill cancer cells and healthy cells found throughout the body. Using materials tailored to the scale of our targets, we can effectively treat the patient without it affecting other systems in the body.”

Historically, glioblastoma has been difficult to treat because the blood-brain barrier prevents drugs from getting to the location of the tumor cells. To overcome this challenge, her lab has developed a therapeutic material for patients with glioblastoma that can be sprayed or injected into the tumor resection cavity during surgery to activate and train the immune system to eradicate cancer cells specifically and generate long-lasting anti-tumor immune therapy. The material effectively targets the cancer cells without spreading to other parts of the body. This development addresses chemotherapy and other emerging drug’s inability to cross the blood-brain barrier in an appropriate dose and their lack of retention in the brain required to exert their effect.

“At the Brigham, I’m surrounded by scientific and clinical collaborators who are motivated to create gene and cell targeting materials to improve patient outcomes,” said Artzi. “We are eager to create solutions to complex problems. We’re fortunate to be in a place where we’re able to apply these solutions to patients and see the impact.”

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