6. POTENTIAL RISKS & RISK MANAGEMENT PROCEDURES 
6.1 Toxicity Criteria & Reporting of Adverse Effects 
A. Monitoring of adverse effects . Subjects will be clinically evaluated at frequent 
intervals as detailed above (PROJECT PROTOCOL). All side effects will be graded using 
standard criteria (see attached). Subjects with recurrent grade 3 or greater toxicity 
will be removed from the protocol and replaced by another subject. If recurrent grade 
three toxicity is observed in more than one subject, the trial will be suspended. 
B. Reporting of Adverse Effects . Adverse reactions will be reported to the UCSD Human 
Subjects Committee and in writing within 10 working days to Investigational Drug 
Branch, P.O. Box 30012, Bethesda, MD 20824, Phone 301-496-7957, and include all 
fatal events, all life-threatening events (Grade 4) which may be due to drug 
administration, or the first occurrence of any previously unknown clinical event 
(regardless of grade). 
6.2 Potential Risks of Gene Therapy with Ribozymes 
A. Insertional mutagenesis . Retroviruses insert randomly in the genome and the 
theoretical risk exists that transduction of lymphocytes with a retroviral vector could 
give rise to a clone or clones of malignant cells. This risk is considered low, however (2, 
1 0,24,42,55). 
B. Toxicity specific to the ribozvme . There is an even smaller, wholly theoretical risk 
that the ribozyme could cleave or have anti-sense activity against the mRNA of an 
unknown gene having tumor-suppressor activity and thus cause malignancy. Even 
accounting for wobble at certain bases, the probable frequency of a sequence homologous 
to the leader-sequence ribozyme can be calculated to be about one per eukaryotic genome. 
Since only a small percentage of the genome is expressed and an even smaller portion of 
such messages can be expected to have tumor-suppressor activity, the likelihood of 
carcingenesis resulting from cleavage of a human mRNA is vanishingly small. 
Carcinogenesis has not been apparent in previous human gene therapy trials (2,42,55); 
this risk, which is discussed in more detail above in OBJECTIVES AND BACKGROUND, is 
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