in patients with Gaucher disease. The measurements to be made monthly are physical exam, 
white count, hemoglobin, platelet count, serum non-tartrate inhibitable acid phosphatase, 
and serum angiotensin converting enzyme. Measurements to be made every six months are MRI 
of liver and spleen for size, x-ray films and scans of long bones and pelvis, and biopsy 
of the bone marrow. An overview of the study is diagramed in figure 22. 
B. SELECTION OF STUDY CANDIDATES 
Patients with an enzyme assay proven diagnosis of Gaucher disease will be recruited 
from clinics at the University of Pittsburgh and from referrals. They will be informed of 
the risks and inconveniences of the study by Dr. Barranger. They will be required to sign 
a consent form. Either of two types of patients will be selected for study. One type of 
patient is the enzyme treated patient, the other is the patient with evident disease not 
currently treated with enzyme. In the enzyme treated patient, the criterion of response 
to gene therapy is the ability to reduce the dosage of gl ucocerebrosidase without clinical 
deterioration as assessed by clinical parameters. Therefore, to be eligible for the study, 
these enzyme treated patients 1) must have had significant signs and symptoms of Gaucher [ 
disease prior to the initiation of therapy with gl ucocerebrosidase enzyme infusions and 2) 
have responded to treatment in a measurable way. The specific criteria of improvement in 
response to enzyme are: 
1) An increase in hemoglobin of 2gm/dl 
2) An increase in platelet count of 50% 
3) A decrease in spleen size of at least 25% or 
a decrease in liver size of at least 25% 
4) An improvement in MRI or X-ray of the bones 
5) A 50% decrease in non-tartrate inhibitable acid phosphatase 
6) A 50% decrease in angiotensin converting enzyme 
The patient would be judged to have a positive response to gene therapy if these 
improvements are maintained for 1 year following the cessation of enzyme therapy. The 
schedule of planned enzyme dosage reduction is 50% at the start of the study, an additional 
50% reduction at three month intervals times three, then discontinuation of enzyme. If the 
patient deteriorates as assessed by clinical exam and laboratory studies, enzyme therapy 
will be reinstituted. Since patients change slowly over a period of months after enzyme 
withdrawal, this plan should be safe. The second type of patient eligible for the study 
is the previously untreated patient with evident disease, but in whom immediate enzyme 
therapy would not be life-saving. These patients will have measurable clinical signs and 
symptoms, but would not die from their disease within two years if not treated with enzyme. ! 
To be eligible for the study, these candidates must have two of the following signs or 
symptoms: 
1) Splenomegaly or Hepatomegaly 
2) Anemia with a hemoglobin < llg/dl 
3) Thrombocytopenia with a platelet count < 90,000 
4) Disabling bone pain with degenerative changes on X-ray films 
5) Pulmonary compromise with clubbing and hypoxemia (Pa02 < 70) 
6) Biopsy proven cirrhosis and elevation of hepatic parenchymal enzymes 
7) Esophageal variceal bleeding 
Ineligibility 
No patient is eligible to participate in the study without a proven deficiency of b 
gl ucocerebrosidase. Each patient must have clinical evidence of significant disease as f 
described above. To participate, a patient must be able to tolerate physical examination, £ 
blood drawing not to exceed 5% of blood volume, x-rays, nuclear magnetic resonance imaging s 
and electrocardiography. No patient with malignancy, positive HIV serology or f 
cardiorespiratory instability will be accepted into the study. Pregnant women will not be ? 1 
accepted into the study. Women will be advised not be become pregnant during the study. 
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Recombinant DNA Research, Volume 17 
