Treating the rare disease MPS I is a challenge. MPS I, caused by the deficiency of a key enzyme called IDUA, eventually leads to the abnormal accumulation of certain molecules and cell death. 

The two main treatments for MPS I are bone marrow transplantation and intravenous enzyme replacement therapy, but these are only marginally effective or clinically impractical, especially when the disease strikes the central nervous system (CNS). Using an animal model, a team from the Perelman School of Medicine at the University of Pennsylvania has proven the efficacy of a more elegant way to restore IDUA levels in the body through direct gene transfer. Their work was published this week online in Molecular Therapy.

“The study provides a strong proof-of-principle for the efficacy and practicality of intrathecal delivery of gene therapy for MPS patients,” said lead author James M. Wilson, MD, PhD, professor of Pathology and Laboratory Medicine and director of the Penn Gene Therapy Program. “This first demonstration will pave the way for gene therapies to be translated into the clinic for lysosomal storage diseases.”

This family of diseases comprises about 50 rare inherited disorders marked by defects in the lysosomes, compartments within cells filled with enzymes to digest large molecules. If one of these enzymes is mutated, molecules that would normally be degraded by the lysosome accumulate within the cell and their fragments are not recycled. Many of the MPS disorders can share symptoms, such as speech and hearing problems, hernias, and heart problems. Patient groups estimate that in the United States 1 in 25,000 births will result in some form of MPS. Life expectancy varies significantly for people with MPS I. Individuals with the most severe form rarely live more than 10 years.

The team used an adeno-associated viral (AAV) vector to introduce normal IDUA to glial and neuronal cells of the brain and spinal cord in a feline model. Their aim was to treat the CNS manifestations of MPS at the source. After a single injection of the AAV9 vector expressing a normal feline IDUA gene sequence and various promoters, the investigators collected blood serum and cerebrospinal fluid (CSF) samples from the test animals and from untreated controls.

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