Driven to Solve Devastating Rare Diseases

cell under a microscope

Gene and cell therapy at a crossroads

After glimpsing the promise of gene and cell therapy, Mass General Brigham researchers are now enhancing the technology to drive new treatments for rare and common diseases

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 healthcare 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.


Susan Slaugenhaupt, PhD, the Scientific Director of the Mass General Research Institute, first began working on a rare genetic disease called mucolipidosis IV (ML4) in the late 1990’s as a junior faculty member at MGH. At the time, very little was known about the condition, which results in early motor and cognitive delays, followed by loss of sight, and eventually, death, often in the third or fourth decade of life.
In 2000, Slaugenhaupt and her colleagues made a transformative discovery: they identified the culprit gene. That gave them a critical handle on the molecular roots of the disease, one of about 40 so-called lysosomal disorders that together represent the most common cause of neurodegenerative disease in children. Still, there remained many questions about the biology of ML4 and if — and how — a gene therapy strategy should be crafted.

“This is a very slowly progressing neurological disease, which, from a research perspective makes it a very difficult nut to crack,” said Slaugenhaupt, who is also a professor of neurology at HMS. “We’re committed to cracking it because of our deep relationship with the ML4 patients and their families.”

Yulia Grishchuk, PhD, an assistant professor of neurology at MGH, who trained as a postdoctoral fellow in Slaugenhaupt’s lab, is now carrying the project forward in her own lab. Her focus: to not only unlock the biology of the disease but also fix it.

In 2016, she began developing a gene therapy approach for treating ML4. Now, after several years of rigorous pre-clinical studies, Grishchuk and her colleagues are looking for an industry partner to help carve a path toward clinical translation.

“Overall, working in the rare disease space has posed hurdles at every level: getting grants, publishing papers, and finding commercial partners to collaborate with us and help sustain the translational work,” said Grishchuk.

Despite these hurdles, she remains deeply focused on studying ML4 and getting an effective treatment to the patients who need it.

“I started working on ML4 because of its underlying biology and my own background in lysosomes and neurodegeneration,” said Grishchuk. “But after getting to know the ML4 community and the patients who suffer from the disease, they are what drive me.”

Jeannie Lee, MD, PhD, a molecular biologist at MGH and professor of genetics at Harvard Medical School, is studying another devastating rare disease, known as Rett syndrome. She and her colleagues are pioneering a novel form of epigenetic therapy for the condition, which is a rare, X-linked disorder that affects roughly 1 in 10,000 girls. Rett syndrome is particularly devastating because the girls appear normal for the first year or two of life, and then begin to deteriorate rapidly, losing language and motor skills, and developing behavioral and cognitive difficulties. Eventually, they require constant, lifelong care. Unfortunately, there are no treatments for these patients.

The gene responsible for Rett syndrome is called Mecp2, and affected girls carry one defective copy and one healthy copy. Ordinarily, that healthy copy might suffice, but since it sits on the X-chromosome, it is rendered inactive about half the time. That’s because females randomly inactivate one of their X chromosomes in cells throughout the body as a way to cope with the double dose of genes from the two X chromosomes — males, by comparison, have just one X chromosome. So, in females with Rett syndrome, roughly 50 percent of their cells allow the healthy copy of Mecp2 to remain active, while the other 50 percent choose the damaged copy — an unlucky role of the dice that sets the disease in motion.

“Mecp2 is used within the cells that make it, so while some cells have a fully functioning gene, their activity can’t help other cells in which the healthy copy of Mecp2 is inactive,” explained Lee.

She has studied X-inactivation for 25 years and her laboratory discovered many of the core molecular components. Lee and her colleagues realized that the answer to treating Rett lies in the bodies of the affected girls. “In the cells that are sick, there is a normal copy of Mecp2, it’s just locked up on the inactive X chromosome,” said Lee. “But what if we could reactivate it?”

That reversal requires a novel kind of gene-based therapy, known as an epigenetic therapy, which relies on two key elements: an antisense oligonucleotide that targets one of the essential factors within the X-inactivation machinery and silences it, and an inhibitor of an epigenetic process known as DNA methylation. Together, these factors can help target Mecp2 and turn it back on. “What we’ve learned is that it doesn’t take 100 percent of Mecp2 function to have an impact, based on various mouse studies, so even just a little bit of reactivation might make a big difference for Rett patients.”

Lee and her colleagues have spent several years developing and vetting their approach in animal models and are now looking for an industry partner to embark on clinical translation. They are also working to adapt their approach for other X-linked disorders. “We’re pressing ahead,” said Lee. “We know we can get this therapeutic cocktail to work in human cells. Now the question is can we get it to work in Rett patients.”

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