Recombinant DNA Advisory Committee- 9/12-13/94 
Hunter syndrome. For treatment, lymphocytes will be removed from the patient, grown in 
the laboratory, and exposed to the L2SN vector. The treated lymphocytes will then be 
returned to the subject by intravenous injection. It is hoped that the treated lymphocytes 
will survive in the blood stream for several days or longer and will be able to partially 
replenish the IDS enzyme which is missing. It is hoped that some symptoms of Hunter 
syndrome will be slowed, prevented, or reversed by this treatment. The specific objectives 
of this study are: (1) to determine the amount of IDS enzyme that can be produced in 
the body after injection of transduced lymphocytes; (2) to determine how long the 
modified lymphocytes can survive in the blood stream; (3) to determine if the gene 
modified lymphocytes will reduce the abnormal amounts of glycosaminoglycan storage 
material in urine; (4) to determine if the gene-modified lymphocytes will decrease the 
size of patient’s enlarged liver and spleen, and if treatment will improve heart and 
respiratory functions; and (5) to determine if there are any other effects of this new form 
of treatment, i.e., other improvement and side-effects. 
Dr. Erickson said that children with Hunter syndrome are usually bom looking normal. 
With increasing years, they start to look abnormal, and the disease was given the 
unfortunate name of gargoylism years ago. As the storage material accumulates in the 
internal organs, it affects lung and heart functions. Children usually die by the age of 10; 
but in the mild variant of the disease, these children will survive much longer. This is a 
lysosomal storage disease similar to Gaucher disease, and it is a reasonable target for 
gene therapy. 
The investigator provided preclinical data which shows successful expression of the IDS 
enzyme in the transduced cells, and the enzyme produced by the transduced cells can 
partially correct cells lacking IDS. Dr. Erickson’s major concern was the patient selection. 
Some patients with the mild form of the disease have lived to the fifth decade and have 
reproduced. The "mild" has been used to designate a form of Hunter syndrome with 
normal and sometimes subnormal intelligence. Thus, it is frequently a matter of degree, 
and the choice of patients who would optimally benefit from this therapy is quite critical. 
Mere identification of the particular mutations, as proposed by the investigators, is 
probably not adequate to identify the appropriate cases. Although it may be rare, there 
has been moderate heterogeneity even within a single family. 
Dr. Erickson’s second critique was about the efficacy of this gene therapy. In preclinical 
studies, transduced cells were selected for high IDS expression by G418, and the actual 
proposed protocol, such a selection will not be used. IDS expression on average is about 
50% of the normal level, and it is not certain how much efficacy would be achieved with 
such a level of IDS expression. Dr. Erickson said that bone marrow transplantation 
(BMT), particularly with the cord blood, will be a better alternative. The cross correction 
in reducing the glycosaminoglycan storage with the gene transfer is only about 60%. The 
usual classic correction would need to have a level of 20% reduction. But this protocol is 
a Phase I study, efficacy is not a major endpoint. 
In conclusion. Dr. Erickson said that this vector has been previously approved by the 
RAC, the approach of gene modification of peripheral blood lymphocytes and treating 
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