Lymphocyte Gene Therapy for Mild Hunter Syndrome 
potential benefits of a particular therapy (i.e. bone marrow transplant) and need to be considered 
in anticipating gene therapy for Hunter syndrome. 
Several factors limit the use of BMT for treatment of MPS diseases: (i) only 20-30% of 
affected individuals have an HLA-identical sibling donor; (ii) there is a significant mortality 
(approximately 20% mortality using an HLA-identical sibling donor, and 50% mortality using a 
closely-matched non-sibling relative or unrelated donor); (iii) significant risk of complications 
such as graft-versus-host disease; (iv) the procedure is exceedingly expensive owing to prolonged 
hospitalization (ranging $200,000 - $1,000,000 per patient); and (v) there has been a limited 
response in the CNS for some disorders. 
For Hunter syndrome, successfully engrafted children have shown decreased urine and 
hepatic GAG, decreased liver and spleen volumes, and no airway obstruction. We thus propose 
that IDS gene transfer and expression in peripheral blood lymphocytes (PBL1 will similarly 
provide enzyme capable of conferring metabolic correction and amelioration of the life- 
threatening symptoms. 
2.3.2 Enzyme Replacement Therapy 
The MPS diseases have been largely unresponsive to conventional medical intervention 
and currently available treatments (such as tracheotomy, VP-shunt placement, carpal tunnel 
surgery, etc.) are only palliative. As a consequence, these diseases have been prototypes for in 
vitro studies and clinical trials of treatment by enzyme therapy. An approach to therapy was 
suggested when Neufeld and colleagues discovered that "corrective factors" could be exchanged 
between cultured cells (34). It was originally proposed that such enzymes are secreted to the 
extracellular environment and subsequently re-captured and delivered to lysosomes (35). 
However, it has been more recently determined that mannose-6-phosphate receptors mediate 
normal lysosomal enzyme "maturation" by the trafficking and compartmentalization of lysosomal 
proteins through the golgi-endoplasmic reticulum-lysosome (GERL) system; relatively small 
amounts of enzyme actually escape to the extracellular milieu (1). The therapeutic applications of 
exogenous enzyme uptake into lysosomes have become widely appreciated (36). Several means of 
providing replacement enzyme have been studied. However, experimental attempts to treat MPS 
diseases by enzyme therapy have been largely unsuccessful: early trials of infusing normal plasma 
(37), infusion of leukocytes, (38) subcutaneous implantation of amniotic membranes, (39, 40) and 
even liver transplantation (Philipart, personal communication) have sometimes produced 
minimal, salutary effects but failed to demonstrate a response sufficient to merit continued 
therapeutic application. 
In summary, satisfactory systemic therapy is not currently available for Hunter syndrome 
except for relatively high-risk bone marrow transplantation. Enzyme therapy has been 
contemplated but will be limited by the immense cost of producing sufficient quantities of 
enzyme, and potential immune response to injected protein. 
2.4 Gene Therapy 
The success of allogeneic bone marrow transplantation in providing a source of enzyme 
capable of clearing storage materials in some organs and impeding neurological degeneration in 
some diseases has led to the suggestion that MPS diseases may be treatable by the introduction of 
new gene sequences into autologous somatic cells (41). The recent isolation of genes and cDNA 
sequences encoding many of the lysosomal enzymes (2) raises the possibility of applying gene 
transfer and expression to the treatment of MPS diseases. 
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