Lymphocyte Gene Therapy for Mild Hunter Syndrome 
This phase I/phase n trial will use the clinically-proven retroviral gene delivery system 
(i.e., 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 as recently 
pioneered in this laboratory, 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 according to standard methods. Utilizing L2SN (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 
(i.e., urinary GAG), clinical response of the disease (i.e., liver and spleen volume, pulmonary 
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 central nervous system 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 preliminary evaluation of clinical efficacy. 
2.2 Hunter Syndrome 
Hunter syndrome is an X-linked recessive inborn error glycosaminoglycan (GAG) 
metabolism resulting from deficiency of lysosomal iduronate-2-sulfatase (IDS) (1-3). In normal 
individuals IDS cleaves a 2-sulfate moiety from terminal iduronic acid residues in dermatan 
sulfate and heparan sulfate. Thus, deficiency of IDS activity in patients with Hunter syndrome 
results in systemic accumulation of GAG species heparan sulfate and dermatan sulfate. 
2.2.1 Severe Hunter Syndrome 
Most children with Hunter syndrome have a relatively "severe" form with early somatic 
abnormalities including skeletal deformities (dysostosis multiplex), hepatosplenomegaly, and 
progressive cardiopulmonary deterioration. A prominent feature is the presence of brain damage 
initially evident as developmental delay and hyperactivity but which progresses to mental 
retardation and eventually to dementia. Patients with severe Hunter syndrome die before age 15 
usually as a result of obstructive airway disease or cardiac failure (4,5). Because this therapeutic 
approach (i.e., ex vivo lymphocyte gene therapy) may not have significant effect on the brain, 
patients with severe Hunter syndrome will not be eligible for entry into this study. 
2.2.2 Mild Hunter Syndrome 
Patients with the "mild" form of Hunter syndrome may survive into adulthood with 
attenuated somatic complications and often without mental retardation (4, 5). However, even 
those with the mild form become physically debilitated, incur severe cardiopulmonary disease, 
and die early in life, typically between 20 to 40 years of age (4, 5). Patients with mild Hunter 
syndrome will be eligible for this protocol and successful treatment may be life-saving for such 
patients. 
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