Recombinant DNA Advisory Committee - 06/7-8/93 
X. ADDITION TO APPENDIX D OF THE NIH GUIDELINES REGARDING A HUMAN 
GENE THERAPY PROTOCOL ENTITLED: GENE THERAPY FOR GAUCHER 
DISEASE: EX VIVO GENE TRANSFER AND AUTOLOGOUS TRANSPLANTATION 
OF CD34( + ) CELLS/DR. BARRANGER 
Review-Dr. Haselkorn 
Dr. Walters called on Dr. Haselkorn to present his primary review of the protocol 
submitted by Dr. John A. Barranger of the University of Pittsburgh, Pittsburgh, 
Pennsylvania. Dr. Haselkorn stated there are two protocols being presented at this RAC 
meeting for the treatment of Gaucher disease; therefore, there are several general 
comments that apply to both protocols. Gaucher disease is an ideal genetic disorder for 
gene therapy. It is likely that positive results could be obtained similar to those reported 
for the ADA protocol, with the added feature that Gaucher disease is a much more 
prevalent disease. Gaucher disease results from an accumulation of glucocerebroside in 
macrophages due to a deficiency in the glucocerebrosidase (GC) enzyme. Type I is the 
most prevalent form of Gaucher disease resulting in less than 25% of the normal level of 
enzyme activity in homozygotes. The rarer forms of the disease, Types II and III, also 
involve the central nervous system and can result in early death. Current therapy 
involves purified GC enzyme; however, this treatment is extremely expensive which 
justifies gene therapy as a viable alternative. 
Dr. Haselkorn explained that in this proposal G-CSF will be used to mobilize CD34( + ) 
cells in the peripheral blood. In turn, these stem cells will be harvested and transduced 
with retrovirus vectors encoding the absent GC enzyme. The hypothesis is that GC will 
enter the macrophages and alleviate the lipid storage condition. The investigators 
propose to treat the first two patients without bone marrow ablation. If these two 
patients engraft without prior ablation, the remaining patients will be treated similarly. 
If these two patients do not engraft, then the remaining patients will receive low doses of 
Cytoxan to produce partial myeloablation. He asked questions concerning the choice of 
cells, the collection and transduction of cells, the level of gene expression, the necessity 
of marrow ablation, and how the two different vectors proposed for the two different 
Gaucher disease protocols compare. 
Review-Ms. Grossman 
Ms. Grossman stated that the investigators have submitted inadequate data 
demonstrating GC expression enzyme using the proposed vector in the human target 
cells. She questioned whether the transduced cells will engraft without myeloablation. If 
myeloablation is necessary, does the potential risk justify the use of gene therapy since 
an effective alternative therapy is available? 
[562j 
Recombinant DNA Research, Volume 17 
