Replacing defective genes or cells with healthy ones has been a goal of modern medicine for decades. And while that aspiration may have seemed simple in principle, the practical path toward realization has been longer and more complex than ever imagined. But now, the initial wave of gene and cell therapies has reached the clinic, with remarkable health benefits for a subset of patients that affirms the potential of these precision medicines for more widespread applications. With scores of gene and cell therapies now under development, the field stands at a major crossroads.
At Mass General Brigham, our faculty are at the forefront of this extraordinary revolution. As part of a world-leading health care system that spans the full spectrum of the biomedical research enterprise and works collaboratively with industry to fuel innovation, Mass General Brigham scientists and physicians are working to bring the next generation of gene and cell therapies to the clinic. We highlight a few of their stories here, ranging from rare, genetic diseases to more common conditions that lack effective treatments.
Luk Vandenberghe, PhD, the Grousbeck Family Chair of Gene Therapy at Massachusetts Eye and Ear and an associate professor of ophthalmology at Harvard Medical School, has built his career studying one of the molecular workhorses of gene therapy, the adeno-associated virus (AAV). Although this viral vector is the predominant delivery agent for the handful of gene therapies now used in the clinic, its biology is not deeply understood.
“It really is a black-box therapeutic,” said Vandenberghe. “We don’t yet know why different AAVs do what they do.”
To close these knowledge gaps, his lab has been systematically comparing various AAVs found in nature and designing new ones from first principles using computational tools. Several years ago, the researchers discovered that one of these in silico AAVs infected an unexpected group of cells: The sensory cells in the inner ear, called hair cells. These cells carry out highly specialized functions in the ear that are essential for normal hearing. When hair cells malfunction or degenerate, the result is hearing loss and eventually, total deafness.
The unusual affinity of the Vandenberghe’s computer-generated virus, known as Anc80, meant that the researchers could uniquely target hair cells with gene therapies. “Hearing is one of our major forms of communication with the outside world,” said Vandenberghe. “Unfortunately, its loss can be very debilitating and isolating.”
While there have been some recent breakthroughs in treating hearing loss, such as cochlear implants, “These seem fairly rudimentary for 21st century biomedicine,” he said.
Now, Vandenberghe and his colleagues are applying their viral discoveries toward the development of gene therapies for hearing loss. They are beginning with rare genetic forms of hearing loss, such as those due to mutations in a gene called otoferlin, as well as other genes. The team hopes to begin clinical trials early next year.
Vandenberghe believes the environment at Mass General Brigham helps propel his work. “We often underestimate the complementarity that exists within this healthcare system,” he said. “[Mass General Brigham] is arguably the largest organization of its kind and it really goes from soup to nuts — from basic research to clinical care. For scientists, it’s like a playground, and the challenge is ours to figure out how to best use it to serve patients.”