Findings offer hope for patients with the rare and devastating disease
PHILADELPHIA, March 11, 2025 /PRNewswire/ — In a preclinical study, researchers at Children’s Hospital of Philadelphia (CHOP) demonstrated a novel gene therapy with potentially increased effectiveness and safety for the treatment for metachromatic leukodystrophy (MLD), a rare disease in young children characterized by the deficient activity of a critical enzyme. Without effective treatment, MLD leads to rapidly declining neurological skills in young children and is potentially fatal. The promising findings were published in print today in the journal Molecular Therapy Nucleic Acids.
In MLD, patients lack a properly functioning arylsulfatase A (ARSA) enzyme, preventing them from breaking down sulfatides, or fatty substances, that help maintain healthy nerve function. Over time, this toxic buildup injures the myelin, a protective layer of proteins that surrounds our nervous system. Affecting about one in 40,000 individuals in the United States, this progressive disease causes issues with movement and speech. Most children eventually lose the ability to walk and talk, and death can occur between 10 and 20 years after diagnosis.
The current Food and Drug Agency (FDA) approved MLD gene therapy introduces a functional ARSA gene into a patient’s own hematopoietic stem cells with the goal of fixing the genetic problem. However, not all patients are eligible, which leaves many people with MLD unable to receive the transformative treatment, including children with the late juvenile form of the disease.
This led Stefano Rivella, PhD, a senior study author and research faculty member in the Division of Hematology, and his team at CHOP to explore how to better serve the whole MLD population using recent advances. Newer vectors produce the missing enzyme at higher levels, which may improve safety and efficacy and potentially decrease cost.
“Combining autologous hematopoietic stem cell transplant (HSCT) with a more powerful lentiviral (LV) based gene therapy has a greater potential to treat different manifestations of MLD,” said first study author Lucas Tricoli, PhD, a research associate scientist at Children’s Hospital of Philadelphia. “We’ve shown that achieving the optimal balance between high enzyme production for therapeutic efficacy and maintaining a low VCN is essential in order to maximize the clinical benefit while minimizing risks and costs.”
In this study, researchers in the Rivella Laboratory collaborated with researchers in the Division of Neurology and the Leukodystrophy Center at CHOP to find better and more effective treatments. By generating novel lentiviral vectors, microscopic delivery systems for inserting therapeutic genes, they increased the production of ARSA cellular DNA at single integration, optimizing ARSA gene expression and enhancing safety.
They also used the smallest amount of viral vector possible in both preclinical and human hematopoietic stem cells. This is important because, while it improves the likelihood of reaching targeted cells, it does minimize potential side effects, including adverse off-target outcomes, and reduces the risk of accidentally causing harmful changes, like turning on cancer-causing genes.
Researchers found that the top-performing vector (EA1) showed at least four times more ARSA activity than the currently FDA approved vector and a superior ability to secrete vesicle- associated ARSA, a critical modality to transfer the functional enzyme from lentiviral modified microglia to other brain cells. Because of these advances, the researchers hope that future clinical trials will be able to evaluate expanding eligibility for MLD gene therapy.
“Taking this approach is crucial for the translational success of the therapy from preclinical models to human trials because our goal is to evolve this research into safe and effective treatment for patients,” said Rivella.
The research team is currently in the process of applying for an Investigational New Drug (IND) application with the FDA to start a new trial to confirm safety and efficacy in human patients before it can become the new standard of care for MLD.
“We need to continue to work to develop effective and accessible therapies for MLD,” said Adeline Vanderver, MD, a senior study author, attending physician in the Division of Neurology and Program Director of the Leukodystrophy Center at Children’s Hospital of Philadelphia. “Through innovation, our research aims to advance better standards of care for affected children and their families worldwide.”
The researchers also collaborated with Rebecca Ahrens-Nicklas, MD, PhD, an attending physician with the Metabolic Disease Program and the Division of Human Genetics at CHOP, Laura Adang, MD, PhD, an attending physician in the Division of Neurology at CHOP, Frederic D. Bushman, PhD, a professor of microbiology at the University of Pennsylvania, Stephanie Hurwitz, MD, PhD, a postdoctoral fellow in the Department of Pathology and Laboratory Medicine, Peter Kurre, MD, Director of the Pediatric Comprehensive Bone Marrow Failure Center at CHOP and Sunetra Sase, PhD, a postdoctoral fellow in the Leukodystrophy Center at CHOP.
This study was supported by Digestive and Kidney Diseases Institute of the National Institutes of Health (R01 DK133475, R01 DK095112), Institute for Translational Medicine and Therapeutics (ITMAT), Irish Health Research Board-Health Research Charities Ireland (HRCI-HRB), Acceleration-Seed program/CHOP and The Sickle Cell and Red Cell Disorders Curative Therapy Center (CuRED) Frontier Program, Molecular Therapies for Inborn Errors of Metabolism-Frontier Program (R01-HL164633), Calliope Joy Foundation (R38-HL143613-04) and Kamens chair in translational neurotherapeutics.
Tricoli et al. “Effective Gene Therapy for Metachromatic Leukodystrophy Achieved with Minimal Lentiviral Genomic Integrations.” Molecular Therapy Nucleic Acids. Online January 24, 2025. DOI: 10.1016/j,omtn.2025.102464.
About Children’s Hospital of Philadelphia:
A non-profit, charitable organization, Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey, as well as the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia. In addition, its unique family-centered care and public service programs have brought Children’s Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit https://www.chop.edu.
Contact: Jennifer Lee
Children’s Hospital of Philadelphia
(267) 426-6084
[email protected]
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