Scientific Abstract 
SCIENTIFIC ABSTRACT 
Hunter syndrome is a rare (1/100,000 births), lethal, X-linked disorder 
of glycosaminoglycan (GAG) metabolism resulting from defective iduronate-2- 
sulfatase (IDS) enzyme activity and the consequent systemic accumulation of 
heparan sulfate and dermatan sulfate within lysosomes. As a model for 
mucopolysaccharidosis (MPS) storage diseases, Hunter syndrome is associated 
with global pathophysiology which sometimes includes the central nervous 
system (CNS). Death usually results from obstructive respiratory disease 
and/or complex cardiac involvement. Patients with the "mild form" experience 
only the somatic disease and survive to age 30 - 40 years. Conventional 
therapy is symptomatic and limited to palliative procedures (eg, herniorrhaphy, 
tracheostomy) which have virtually no impact upon the ultimate lethality of the 
disease. Allogeneic bone marrow transplantation (BMT) for patients with MPS 
diseases has been shown to provide a continuous source of enzyme and 
produces metabolic correction in many tissues as evidenced by reduction of 
urinary GAG excretion, disappearance of lysosomal inclusions from the liver, 
and amelioration of respiratory disease. However, several factors limit the 
application of BMT including the high morbidity and mortality of the 
procedure, lack of histocompatible donors, and tremendous cost of treatment 
($200,000 - $1,000, 000/patient). These limitations now motivate exploration 
of gene therapy. Preclinical studies suggest that retroviral -mediated insertion 
and expression of the human IDS gene in hematopoietic cells will prove to be a 
feasible, safe, and efficacious means of treating patients with mild Hunter 
syndrome. This phase I /phase II trial will use the clinically-proven retroviral 
gene delivery system (ie, LXSN) to assess the therapeutic effect of expressing 
recombinant IDS in 4 patients (2 adults and 2 children) with the mild form of 
Hunter syndrome. Eligibility criteria will include clinical features, biochemical 
abnormalities, and identification of the specific gene mutation, to identify those 
individuals with genotypes characteristic of the mild form of Hunter syndrome. 
Peripheral blood lymphocytes (PBL) will be harvested by apheresis and then 
stimulated with anti-CD3 antibody and maintained in culture with IL-2 to 
expand T-lymphocyte populations. Utilizing L2SN (IND #5370, a therapeutic 
retroviral vector designed for insertion and expression of the IDS gene), PBL will 
be transduced ex vivo and then infused on a monthly basis. Subsequent 
studies will determine the frequency of PBL transduction and the half-life of 
infused cells. Evaluation of patients will include measurement of blood levels 
of the recombinant IDS enzyme, assessment of metabolic correction (ie, urinary 
GAG levels), clinical response of the disease (ie, liver and spleen volume, 
pulmonaiy function tests, echocardiography, EKG), and monitor for potential 
toxicities. Although patients with mild Hunter syndrome are characterized by 
normal intellect, this study will also assess GAG deposition in the CNS by 
magnetic resonance imaging. In summary, this phase I/phase II study is 
anticipated to demonstrate the safety of L2SN-mediated gene therapy and 
provide a preliminary evaluation of clinical efficacy. 
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Recombinant DNA Research, Volume 20 
