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MIT Better World

By Leda Zimmerman

“With recent, historic advances from MIT labs, it is clear we’re now creating and rapidly expanding a genetic toolbox leading to new treatments,” says Robert Desimone, McGovern director and the Doris and Don Berkey Professor of Neuroscience.

Among the milestones: In December 2023, the FDA approved Casgevy, the very first genome-editing therapy for sickle cell anemia based on the CRISPR-Cas9 technology developed by McGovern scientist and James and Patricia Poitras Professor of Neuroscience Feng Zhang. Gene replacement therapy from fellow McGovern scientist Guoping Feng, the James and Patricia Poitras Professor of Brain and Cognitive Sciences at MIT, will soon enter clinical trials for patients with a debilitating neurodevelopmental disorder. More gene-based remedies are on the way for diseases and disorders resistant to other treatments, fueled by basic discoveries from McGovern, the Broad Institute of MIT and Harvard, and allied research groups.

“These are really big home runs,” says Desimone.

A DNA sequencing game changer

Eleven years ago, Feng Zhang shook up the biomedical world with news that he had adapted a genetic defense mechanism found in bacterial immune systems to snip out and repair DNA sequences in eukaryotic (animal and plant) cells.

“Researchers had been sequencing and identifying many different genetic mutations associated with very severe conditions, and there was this tantalizing idea that we could go into cells and fix them with CRISPR-Cas9, restoring mutations back to what their natural sequences should be,” says Zhang.

Sickle cell disease results from a single-base pair mutation in the DNA of hemoglobin protein in red blood cells. The cells can’t effectively move oxygen through blood vessels, often causing excruciating pain. Casgevy uses Zhang’s gene-editing technology to repair the mutation in patients’ blood stem cells and restore production of normal hemoglobin.

“This is the first time my research has moved into the world to relieve people’s suffering, but I hope not the last,” says Zhang. “It’s incredibly rewarding and motivating as we try to advance CRISPR-based and other molecular technologies to treat many additional diseases.”

Since 2013, Zhang and fellow researchers have refined gene-editing techniques to enable more precise targeting, editing, and replacement of DNA sequences, whether single bits of genetic code, or extremely long strands responsible for generating many proteins. Some of these innovations are now poised for clinical trials in such difficult-to-treat diseases such as muscular dystrophy, Alpha-1 antitrypsin deficiency (a condition that can spark chronic obstructive pulmonary disease and cirrhosis of the liver), and high cholesterol linked to cardiovascular diseases.

Barriers to progress remain

As significant as these advances are, formidable hurdles remain before gene therapy becomes an established, ubiquitous medical tool. “You can have this wonderful gene-editing system like CRISPR but the question is how you get it to the cells where it’s needed,” says Desimone. “Delivery is a giant problem.”

Professor Guoping Feng. Photo: Tony Luong

Perhaps nowhere is this issue more apparent than in neurological diseases and disorders. “For people working on therapies for the brain, the big challenge is getting past the blood-brain barrier (BBB),” explains Feng. This membrane, evolved to protect the brain from infection and regulate the supply of vital chemicals and nutrients to the organ, proves a formidable shield. “Scientists have spent more than a century trying to figure out how to get even small molecules through,” he says.

A scientist’s journey

After two decades of meticulous research, Feng’s work is paying off. He is pioneering a gene-based therapy that doesn’t simply ameliorate but, if successfully demonstrated in humans, could actually reverse a kind of autism, identified in nearly 30,000 Americans, that is caused by a single mutation in the SHANK3 gene and causes severe cognitive, social, and motor skill deficiencies.

The breakthrough involves both a bold idea for replacing the flawed SHANK3 gene and an ingenious solution for delivering this remedy past the BBB and directly to neurons.

“Our first version for packaging this technology was far too large,” he says. “We came up with a mini-SHANK3 suite that we believe will lead to a dramatic improvement in patients.” With support from the Hock E. Tan and K. Lisa Yang Center for Autism Research, Feng genetically engineered the SHANK3 mutation in animal models using CRISPR-based technology. With marmosets, a small primate and ideal stand-in for humans, his gene-correction therapy greatly reduced SHANK3 symptoms, restoring the animals’ cognitive, behavioral, and motor functions with no side effects, even after two years.

Based on the safety and efficacy of these and other studies, the FDA approved JAG201, the SHANK3 minigene package licensed from Feng’s lab by Jaguar Gene Therapy, for human trials starting in 2024. If the treatment works as planned, says Desimone, “It could mean that someone doesn’t need to be institutionalized, or could live at home or in the community, which would be huge.”

Next steps

While this treatment was many years in the making, Feng sees the next gene therapies arriving at a quickening pace.

“Genome editing took a long time to refine, but applying each development to a new disease treatment will be much shorter because we have the basic platforms now,” says Feng. “Our experience using CRISPR and AI to model the genetics and cellular systems, design and test the delivery systems, will dramatically reduce time to treatment.”

Complex neurological disorders

Major challenges lie ahead for researchers hoping to gain traction on many other neurodevelopmental disorders, as well as dementia and mental illnesses like schizophrenia and depression. Here, they must identify and fix multiple genes rather than a single mutation, determine the impacts on a panoply of proteins these genes express, and then find a method for deploying their therapeutic payload exactly where it is needed, without unwelcome side effects.

“We need to get to the next step, which is scaling up our therapies and achieving targeted delivery of editing enzymes,” says Victoria Madigan, a postdoctoral fellow at the McGovern Institute. Madigan specializes in a class of protein structures called capsids—protective shells that can encase genetic material and transfer it from cell to cell.

“It’s always a good idea to learn from Mother Nature,” she says. “I’m studying a family of capsids that are naturally found in the human genome and are produced in great volumes by neurons in the central nervous system, trying to learn how we can make them effective gene delivery modalities,” she says.

Madigan and fellow researchers are bent on modifying capsids to carry ever-more-complex gene-editing cargo that will produce only those proteins that impact the target disorder. Their vision is to rewire genetic machinery that could restore function or even head off the degenerative effects in patients with such diseases as Huntington’s and Parkinson’s.

Other McGovern and MIT labs are exploring different mechanisms for accurate delivery of therapies for multigene diseases. One approach involves coating the gene-altering packages in lipid nanoparticles, along the lines of those used to make the Covid-19 mRNA vaccines. Researchers at the Zhang lab developed a microbial syringe system and co-opted it to deliver gene-editing enzymes. “It functions on the molecular level just like a real syringe, with a spring-loaded mechanism that shoves the proteins right into the cell,” says Zhang. Biotech firms have already expressed an interest in this early-stage microdevice for treating disorders in the kidney and brain.

“As molecular biologists, we focus on the basic technology platform, trying to make that as robust and widely applicable as possible, so many groups can apply it to whatever disease they have expertise in,” says Zhang.

Researchers in the field express genuine optimism about what comes next. “I think we’re just going to see so much happen in the next 10 years,” says Madigan. “CRISPR-Cas9 has taken off and become useful for so many different things. I’m very hopeful that we can have substantial impacts on human health.