5S800 - 
Federal Register / Vol. 56, No. 225 / Thursday, November 21, 1991 / Notices 
DEPARTMENT OF HEALTH AND 
HUMAN SCRYICES . 
| National Institutes of Health 
Recombinant DNA Research; Action 
j Under the Guidelines 
agency: National Institutes of Health, 
PHS. DHHS. 
action: Notice of action under the NIH 
. Guidelines for Research Involving 
Recombinant DNA Molecules. 
summary: This notice sets forth an 
action to be taken by the Director, 
| National Institutes of Health (NIH), 
under the May 7, 1986, NIH Guidelines 
for Research Involving Recombinant 
DNA Molecules (51 FR 16958). 
EFFECTIVE DATE: November 21. 1991. 
FOR FURTHER INFORMATION CONTACT: 
I Additional information can be obtained 
from Dr. Nelson A. Wivel, Director, 
Office of Recombinant DNA Activities, 
Office of Science Policy and Legislation. 
National Institutes of Health, building 
31, room 4B11, Bethesda, Maryland 
20392, (301) 496-9838. 
SUPPLEMENTARY INFORMATION: Today 
an action is being promulgated under 
the NIH Guidelines for Research 
Involving Recombinant DNA Molecules. 
This proposed action was published for 
comment in the Federal Register of 
September 3. 1991 (56 FR 43686), and 
reviewed and recommended for 
approval by the NIH Recombinant DNA 
Advisory Committee (RAC) on October 
7.1991. 
I. Background Information and Decision 
on Action Under the NIH Guidelines 
A. Addition of Appendix D-XXII to the 
NIH Guidelines 
In a letter dated June 7, 1991, Dr. 
James M. Wilson of the University of 
Michigan Medical Center indicated his 
intention to submit a human gene 
therapy protocol to the Human Gene 
Therapy Subcommittee and the 
Recombinant DNA Advisory Committee 
'or formal review and approval. The title 
of this protocol is: “Gene Therapy of 
Familial Hypercholesterolemia." 
This request was published for 
comment in the Federal Register on July 
2. 1991, (56 FR 30398). 
The protocol was reviewed during the 
Human Gene Therapy Subcommittee 
meeting on July 29-30, 1991. Provisional 
approval was granted with the following 
stipulations. It was requested that the 
Principal Investigator provide additional 
data about the quality control of the 
vector system and the characteristics of 
the packaging cell line. In addition, the 
consent form is to be reviewed following 
several requested changes. 
The Human'Gene Therapy 
Subcommittee forwarded the protocol to 
the Recombinant DNA Advisory 
Committee for consideration during the 
October 7-8, 1991, meeting. 
This request was published for 
comment in the Federal Register on 
September 3, 1991 (56 FR 43686). 
During the meeting on October 7-8, 
1991, the Recombinant DNA A.dvisory 
Committee met to review the protocol 
and recommendations from the 
subcommittee. Following the discussion, 
the Recombinant DNA Advisory 
Committee by a vote of 16 in favor, 0 
opposed, and 1 abstention, approved the 
protocol with the following section to be 
added to appendix D: 
“Appendix D-XXII." -- , 
Dr. James M. Wilson of the University 
of Michigan Medical Center can conduct 
a set of experiments on three patients 
with the homozygous form of familial 
hypercholesterolemia, using ex vivo 
gene therapy. This approach will 
attempt to correct the defective function 
within the patient’s liver cells by adding 
the gene that codes for the normal 
receptor for low density lipoprotein 
(LDL). The patient population to be 
treated will include persons with 
symptomatic coronary artery disease 
who have a relatively poor prognosis, 
but who can tolerate a noncardiac 
surgical procedure with acceptable 
risks. Both children and adults will be 
eligible for this therapy. Patients will be 
evaluated over a six week period to 
determine their eligibility in the study 
and to establish metabolic baselines. 
The proposed therapy will be an adjunct 
to the more traditional therapies such as 
plasma exchange and drugs, which will 
be reinstituted six weeks after gene 
therapy. Eligible patients will be 
admitted to the hospital and subjected 
to a two step procedure in which a 
portion of liver is removed on day 0 and 
in which hepatocytes are isolated and 
plated in culture. 
Recombinant retroviruses will be used 
to transduce a normal LDL receptor gene 
into the cultured hepatocytes: these 
transduced hepatocytes will be 
harvested on day three and infused into 
the portal circulation of the patient 
through an indwelling catheter. The 
patients will be evaluated for 
engraftment of gene-corrected 
hepatocytes through a series of 
metabolic studies. Three months after 
gene therapy, a small amount of liver 
tissue will be harvested by 
percutaneous biopsy and analyzed for 
the presence of recombinant derived 
RNA and DNA to document the 
presence of the gene coding for the 
normal LDL receptor. 
I accept this recommendation, and 
appendix D-XXII of the NIH Guidelines 
will be added accordingly. 
II. Summary of Action 
A. Addition of Appendix D-XXll to the 
“ NIH Guidelines" 
The following section is added to 
appendix D: 
“Appendix D-XXII." 
Dr. James M. Wilson of the University 
of Michigan Medical Center can conduct 
experiments on three patients with the 
homozygous form of familiar 
hypercholesterolemia. Both children and 
adults will be eligible for this therapy. In 
an attempt to correct the basic genetic 
defect in this disease, the gene coding 
for the low density lipoprotein (LDL) 
receptor will be introduced into liver 
cells taken from the patient. The gene- 
corrected hepatocytes will then be 
infused into the portal circulation of the 
patient through an indwelling catheter. 
The patients will be evaluated for 
engraftment of these treated 
hepatocytes through a series of 
metabolic studies; three months after 
gene therapy, a liver biopsy will be 
taken and analyzed for the presence of 
recombinant derived RNA and DNA to 
document the presence of the gene 
coding for the normal LDL receptor. 
OMB’s Mandatory Information 
Requirements for Federal Assistance 
Program Announcements (45 FR 39592) 
requires a statement concerning the 
official Government programs contained 
in the Catalog of Federal Domestic 
Assistance. Normally NIH lists in its 
announcements the number and title of 
affected individual programs for the 
guidance of the public. Because the 
guidance in this notice covers not only 
virtually every NIH program but also 
essentially every Federal research in 
which DNA recombinant molecule 
techniques could be used, it has been 
determined to be no* cost effective or in 
the public interest to attempt to list 
these programs. Such a list would likely 
require several additional pages. In 
Recombinant DNA Research, Volume 15 
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