3) A decrease in spleen size of 25% 
4) A decrease in liver size of 25% 
5) An improvement in MRI or X-ray of bone 
6) A 50% decrease in serum non-tartrate inhibitable acid phosphatase 
7) A 50% decrease serum angiotensin converting enzyme 
8) An improvement in bone marrow morphology 
Group B Patient : Enzyme Treated 
Maintenance of improved clinical status without deterioration of one (1) year 
following the cessation of enzyme therapy. 
N. ASSESSMENT OF RISK/BENEFIT 
Gaucher disease is a progressive disorder. Most patients coming to medical attention 
suffer disability and a shortened life span. Allogeneic bone marrow transplantation is an 
option for only a few patients who have a matched sibling donor. Moreover, the risks of 
classical BMT are unacceptably high for many patients. Enzyme therapy ameliorates the 
disorder. However, it is not a permanent treatment, requires a life-long commitment to 
infusions of enzyme, and is very expensive. Gene therapy is a potential cure for the 
disease. If these initial studies are successful, they could provide treatment for 
essentially every patient with the disease. Without the need for myeloablation, the risks 
of gene therapy would be, in comparison to the potential benefit, very small. If partial 
myeloablation is required, the risk will be higher, but should be acceptable for patients 
with evident clinical disease. If complete myeloablation is necessary to achieve a 
satisfactory response, gene therapy would be reasonable only for the severely affected 
patient. The study proposed in this application will evaluate these possibilities. 
The risk of malignancy to which the patient is put from the presence of replication 
competent retrovirus has now been estimated by a study in monkeys' 931 . It is clear that this 
risk is unacceptable. The risk of malignancy from replication defective retroviral vectors 
has not been estimated completely and will require many years of study to assess. To date, 
no malignancies have been reported in animal or human experiments employing replication 
defection retroviral vectors. With appropriate caution to avoid the introduction of RCR 
into patients or their cells, this risk should be minimized. In this application, we will 
take every precaution to detect the presence of RCR. 
If the proposed studies are successful, they will have a significant impact on the ' 
treatment of Gaucher disease as well as a variety of other less common lysosomal storage 
diseases. Some of these can be treated with gene transfer to bone marrow stem cells. In 
others, development of vectors to target genes to other pathobiol ogical ly important cells 
will be required. If the proposed studies fail, they could provide guidance on how the 
approach might be improved. 
The risks of the procedures are discussed below. 
N. 1 Contamination 
Preparation of PBSC from blood will be performed in Dr. Ball's laboratory as is 
currently being done in a sterile fashion for studies of PBSC transplantation in cancer 
patients in IRB approved protocols. Transduction of PBSC will take place in a newly 
constructed Human Gene Therapy Application Laboratory in the Center for Biotechnology and 
Bioengineering. This laboratory will receive FDA approval for production and use of vectors 
to transduce cells for human gene therapy studies and treatment. This is a special area 
with stringent requirements for control of sterility. The cells used to generate vectors 
and the vector containing supernatants will be certified to be microbiological ly clean and 
safe, and free of helper viruses. 
The R-GC vector is a retroviral vector. It has the same risks associated with it as 
other retroviral vectors currently in use in clinical trials of gene therapy. In theory, 
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Recombinant DNA Research, Volume 17 
