Dr. Raymond Wang, M.D.

Intra-articular Enzyme Replacement Therapy
in a Canine Model for Mucopolysaccharidosis Type I

Dr. Wang's project aims to determine:

1) if intra-articular enzyme replacement therapy is safe and well-tolerated in a canine model of mucopolysaccharidosis type I and

2) if intra-articular enzyme replacement therapy results in reduced lysosomal storage in joint tissue in the canine model of mucopolysaccharidosis type I.

Treatment, whether with hematopoietic stem cell transplantation or with intravenous enzyme replacement therapy (ERT) using recombinant human iduronidase (rhIDU), has revolutionized the lives of individuals with MPS1 and their families. Now, those with MPS1 are surviving and thriving through childhood and beyond, with rescue of cognitive outcomes and significant reduction in upper respiratory tract symptoms, hepatosplenomegaly, exercise intolerance, and other somatic symptoms.

Despite these advances in therapies for MPS1, significant limitations in efficacy still exist. Orthopedic complications are especially problematic for long-term survivors. Unfortunately, iduronidase delivery into cartilage and joints is limited by the lack of blood vessels in those tissues. Consequently, cervical spinal cord stenosis, spinal kyphosis, hip dysplasia, and restriction of joint mobility continue to progress, causing significant impairment of quality of life. Patients with MPS1 must endure continued orthopedic surgeries to palliate or correct these complications.

As intrathecal enzyme delivery methods are being explored for the treatment of cervical spinal stenosis and other central nervous system manifestations of MPS1, we propose intra-articular delivery of enzyme into major joint spaces to directly treat these under-remedied tissues. However, no human trials of this novel modality have been conducted. Therefore, in order to secure approval from the United States Food and Drug Administration to conduct human intra-articular ERT trials, animal safety trials must first be conducted. Our project would represent the first proposal for evaluation of intra-articular ERT in MPS1.

A canine model of MPS1 has previously been used to demonstrate the safety and efficacy of both intravenous and intrathecal enzyme replacement therapy with rhIDU. We will be studying adult dogs to reduce the variability in synovial tissue lysosomal storage and glycosaminoglycan content introduced by growth in puppies through the
study. We believe this choice is also in congruence with the human target population; intra-articular therapy will most likely be used in MPS1 patients with existing joint disease, not as a preventative measure. This study will serve as in important first step towards human intra-articular ERT trials.