JAX researchers alleviate symptoms of ultra-rare genetic disease

In two new papers, researchers from The Jackson Laboratory (JAX) report the successful use of two approaches -- gene therapy and bone marrow transplantation – to alleviate symptoms of multiple sulfatase deficiency (MSD), an ultra-rare genetic disease with no cure. The studies, carried out in mice, not only offer new hope to children with MSD and their families but can also help researchers better understand common diseases with related genetic mutations.

“This work provides multiple new approaches – which might turn out to be complementary to each other – to treating MSD,” said Maximiliano Presa, senior study director at the JAX Rare Disease Translational Center, which accelerates pre-clinical research on rare, understudied and underfunded conditions like MSD. “For a complex disease like this, we cannot rely on only one approach.”

The gene therapy approach is now moving toward human clinical trials as part of a private-public partnership operated by the Foundation for the National Institutes of Health (FNIH).

Focus on a Rare Disease

Babies born with MSD have an average lifespan of 13 years and there are currently no treatments to slow or stop its progression. MSD is caused by mutations in the SUMF1 gene, which encodes a protein that cells require to break down complex sugars and fats. Sugars and fats accumulate inside cells, eventually keeping the cells from functioning correctly. Depending on which mutation a patient has in the SUMF1 gene, this accumulation can impact the brain, liver, skin, and skeleton and symptoms can include seizures, developmental delay, and movement problems.

Presa, working in the laboratory of Cat Lutz, wanted to spearhead new approaches to treating MSD.  These efforts were funded by both the United MSD Foundation and a grant from the Jax Center for Precision Genetics, which leverages advanced genetic tools and techniques, like CRISPR/Cas9 and other methods, to create mouse models for studying rare diseases. The JAX Center for Precision Genetics is sponsored by the National Institutes of Health.

“So many families we work with in the Rare Disease Translational Center are facing devastating diagnoses, many of which are certainly fatal and with no treatment options.  New therapeutic approaches offer hope to these families, and our genetically engineered mice are a perfect model to test these cutting-edge therapeutics,” said Lutz, who is the vice president of the Rare Disease Translational Center.

Testing New Bone Marrow

In a study published in the October 25 issue of Communications Medicine, Presa, Lutz and their collaborators investigated using bone marrow transplant to treat MSD. This approach involves replacing a patient’s bone marrow with donor bone marrow cells containing a functional SUMF1 gene. If successful, donor cells with functional SUMF1 gene can move around the body and produce active sulfatases. The sulfatases can then be taken up by other patient cells and help them to dispose of toxic metabolites. This is an effect called cross-correction.

Using a mouse model, developed at JAX, with the same SUMF1 mutation found in some MSD patients, the team found that a bone marrow transplant restored the once dysfunctional proteins and furthermore, reduced the toxic buildup of sugars and fats in peripheral organs such as the liver and heart, lowering levels of inflammation and cell damage. However, the treatment had little effect on the brain, where many MSD symptoms originate. This is, in part, due to the challenge of coaxing cells to cross the blood-brain barrier.

“It is possible that some donor cells were migrating to the brain, but we didn’t see enough change to molecules in the brain to be confident that there was much of an effect,” explained Presa. “This is something that we have to continue to explore ways to overcome.”

Replacing a Defective Gene

In the second study, published January 27 in Communications Medicine, Presa and Lutz’s group developed a more effective gene therapy for MSD, targeting the brain. Gene therapy delivers a healthy gene by putting the DNA encoding the gene inside a delivery system – usually small viral shells – that can move throughout the body and inject their contents into the body’s cells.

Previous attempts required multiple treatments and yielded mild results. In the new approach, which delivered the gene therapy through the cerebrospinal fluid, mice treated at one week of age showed significant improvements: extended lifespans (from 30 days to over 18 months) and reduced neurological symptoms.

“They were not only able to survive longer, but their neurological symptoms were nearly gone,” said Presa. “It was really remarkable to see this rescue.”

The impact of the gene therapy on brain cells, Presa noted, is long-lasting because they are cells that are not frequently replaced. However, effects on organs like the liver may be less durable due to cell turnover. Moreover, the therapy demonstrated that even a small percentage of brain cells – around 10 percent -- with low levels of functional SUMF1 can improve symptoms.

“This is an important lesson,” he said. “We don’t need incredibly high doses of gene therapy in the brains of children to have an impact for MSD.”

Toward the Clinic

Neither approach tested in mice by the JAX team offers an immediate standalone cure for MSD, nor is likely to completely reverse the disease for life. While the gene therapy is more effective in the brain and nervous system, the bone marrow transplant serves as a foundational step toward developing more advanced cell-based therapies that could better target and treat other organs. Eventually, researchers may decide to test the two treatments in tandem.

“In the future, combining a gene therapy and a cell therapy may be the way to assure a persistent rescue,” said Presa. “There are also other types of gene therapy and gene editing that are still in the very early research phases but could eventually be complementary to these treatments.”

The gene therapy approach to treat MSD developed by the JAX team was, in 2023, selected as one of eight rare disease therapeutics to be included in a FNIH clinical trial portfolio. This will help streamline the approval pathway for the first human clinical trials of the treatment and help bring new treatments to patients.

Parents of children with MSD – like Amber Olsen, whose daughter Willow was born with MSD, and Alan Finglas, whose son Dylan was born with the disease – have become advocates for MSD research and worked with scientists around the world to advance pre-clinical and clinical trials. Olsen and Finglas, through their involvement in the United MSD Foundation, inspired the recent studies at JAX.