Enzyme Replacement Therapy for Hurler
Enzyme replacement therapy to enhance transplant outcomes for patients with Hurler Syndrome.
The mucopolysaccharidoses (MPS) are a category of rare metabolic diseases characterized by the lack of certain lysosomal enzymes necessary to break down cellular material. In severe MPS Type 1, or Hurler syndrome, a deficiency of alpha-L-iduronidase activity causes excessive macromolecular glycosaminoglycans (GAGs). Accumulating GAGs lead to the complications of Hurler syndrome including orthopaedic abnormalities, heart problems, corneal clouding, hearing difficulties, airway crowding and a decline in neurologic functioning. Historically, Hurler syndrome was lethal with a life expectancy of less than 10 years.
University of Minnesota has been at the forefront of major treatment innovation for Hurler syndrome since performing the first allogeneic blood and marrow transplant (BMT) in the United States for a child with the disease in 1981. Based on the principle of metabolic cross-correction provided by normal, donor-derived leukocytes, BMT was the first treatment to stabilize disease and increase life expectancy for Hurler patients.
Pharmacologically available intravenous enzyme replacement therapy (IV ERT) with Aldurazyme was approved for Hurler syndrome in 2003. Unfortunately, the intravenously administered enzyme cannot cross the blood brain barrier, so it does not slow the progression of neurologic impairment. In 2004, a new approach combining enzyme replacement followed by allogeneic BMT was pioneered at the University of Minnesota. BMT can halt cognitive decline in Hurler patients as healthy donor-derived monocytes migrate and differentiate into long-term microglial residents in the brain, but this process can take several months. During this time, a patient’s cognitive function may continue to decline. Hurler patients lose a median of 15-17 points on the developmental quotient scale during the BMT process before stabilizing.
A clinical trial available only at the University of Minnesota examines the use of intrathecal Aldurazyme to deliver the enzyme directly to the central nervous system during the peri-transplant period. The goal is to provide the missing enzyme to the brain while the migration of microglia cells is ongoing. Enrolled patients receive four total doses (two pre-transplant and two post-transplant) of the intrathecal enzyme at pre-determined intervals. The primary study endpoint is cognitive function two years after BMT. To date, no additional toxicities have been associated with intrathecal enzyme administration.
Ongoing clinical research at the University of Minnesota is also exploring the use of IV ERT in Hurler patients who have previously undergone BMT. While BMT can significantly improve both cognitive and non-cognitive aspects of Hurler syndrome via metabolic cross-correction, many patients continue to suffer from potentially debilitating orthopaedic problems post-transplant. Physicians believe that these orthopedic symptoms persist because the bones and growth plates do not receive adequate concentrations of donor leukocyte-derived enzyme. This trial aims to demonstrate that enhancing the amount of enzyme available post-transplant via IV ERT will decrease the incidence and severity of orthopaedic and other complications related to Hurler syndrome.
Our comprehensive care team, including world-renowned specialists in BMT -- neurologists, endocrinologists, neuropsychologists, cardiologists and orthopaedic specialists -- is available for assessment and consultation. The team works together to create an individualized monitoring and treatment plan for each patient. To learn more about the Inherited Metabolic Disorders Comprehensive Care Program at University of Minnesota Masonic Children’s Hospital, contact Paul Orchard, MD, Weston Miller, MD, Troy Lund, MD, or call Patty Kleinke with the BMT Program office at 612-273-0857 or 888-601-0787 (toll free).