Advancements in Treating Mucopolysaccharidosis Type I: From Enzyme Replacement to Cutting-Edge Therapies

The Revolutionary Impact of Enzyme Replacement Therapy

The introduction of ALDURAZYME (laronidase) in 2003 marked a pivotal moment in MPS Type I treatment. As the first FDA-approved enzyme replacement therapy (ERT) for MPS I, ALDURAZYME provides patients with a recombinant form of human alpha-L-iduronidase, administered weekly through intravenous infusions.

Clinical studies have demonstrated that regular ALDURAZYME infusions can substantially reduce urinary GAG levels, improve pulmonary function, enhance exercise capacity, and increase joint mobility. For patients with Hurler-Scheie and Scheie syndromes (the attenuated forms of MPS I), ERT has become an essential therapeutic strategy that can significantly slow disease progression and improve quality of life.

Despite these benefits, ERT has important limitations. The enzyme cannot effectively cross the blood-brain barrier, which means it has minimal impact on the central nervous system manifestations of the disease. This limitation is particularly significant for patients with Hurler syndrome, the most severe form of MPS I, which is characterized by progressive cognitive impairment.

Hematopoietic Stem Cell Transplantation for Severe Forms

For patients with the severe Hurler phenotype, Hurler syndrome treatment typically involves hematopoietic stem cell transplantation (HSCT). When performed early in life, ideally before the age of two years, HSCT can preserve cognitive function by providing a source of enzyme-producing cells that can cross the blood-brain barrier.

The current standard of care for many children with Hurler syndrome involves a combination approach—initiating ERT to stabilize the child's condition, followed by HSCT. Post-transplantation, many clinicians continue ERT to maximize systemic benefits while the transplanted cells establish enzyme production.

This combination strategy represents a significant advancement in addressing both the neurological and somatic manifestations of MPS I. However, HSCT carries substantial risks, including graft-versus-host disease and transplant-related mortality, highlighting the continued need for safer and more effective therapies.

The Frontier of Gene Therapy

The most exciting developments in the MPS I treatment landscape involve gene therapy approaches. Unlike ERT, which requires lifelong administration, gene therapy aims to provide a durable solution by enabling the patient's own cells to produce the missing enzyme.

Current clinical trials are exploring several innovative approaches:

Ex vivo autologous stem cell gene therapy, which involves harvesting a patient's own hematopoietic stem cells, genetically modifying them to express functional alpha-L-iduronidase, and reinfusing them
In vivo gene therapy using adeno-associated viral vectors to deliver the functional IDUA gene directly to target tissues
Genome editing technologies to correct the underlying genetic mutation

Early clinical results have been promising, with some patients demonstrating sustained enzyme expression, reduced GAG levels, and clinical improvements following a single treatment. These approaches hold the potential to overcome the limitations of current therapies by providing continuous enzyme production throughout the body, including the central nervous system.

Comprehensive Management and Supportive Care

While breakthrough molecular therapies continue to evolve, comprehensive management of MPS I still requires a multidisciplinary approach. Patients benefit from coordinated care involving specialists in cardiology, pulmonology, orthopedics, neurology, ophthalmology, and other disciplines.

Supportive interventions—including physical therapy, occupational therapy, speech therapy, and orthopedic surgeries—remain essential components of patient care. Additionally, emerging anti-inflammatory therapies and substrate reduction approaches are being investigated as complementary strategies to address the complex pathophysiology of MPS I.

Looking Toward the Future

The therapeutic landscape for MPS I continues to evolve rapidly. Current research focuses on developing enhanced enzyme formulations with improved central nervous system penetration, optimized gene therapy vectors, and combination approaches that target multiple aspects of disease pathology.

For patients and families affected by this challenging disorder, the pace of innovation offers unprecedented hope. While challenges remain, the transformation of MPS I from an untreatable condition to a manageable disease represents one of modern medicine's most significant achievements in addressing rare genetic disorders.