53818 
ffedeod Renter t Vcrl. aa, No. COO / Monday, October T8. tM3 r Notfoe* 
Expenmmfts involving germs coding for 
toxin anolacifles 'with an LDjo-dT <100 
mi c ro gram s Tintl >100 xianogranis per 
kilogram body weight require 
registration with ORDA and IBC 
epproval prior .to initiating -the 
experiments. A list of toxin molecules 
classified «s to LDso is available from 
ORDA. Testing prooedures tor 
determining toxicity of toxin molecules 
not on-tbe'list are available from ORDA. 
The resiihs oTauchtests-sballbe 
forwarded to ORDA.which will consult 
with -ad hoc -experts, prior to inclusion 
of ( fhemdlecttles onthe'list tsee Section 
IV-C-l-V^ZH®)) 1 * '* 
■"AppendixE-tIL'Containment 
Conditions TorCloning'ToxinMolecule 
Genes in *Organi sms “Other Than E. coli 
K-TC. 
“Tlequests involving *the *cloning of 
genes coding fbrnrolecules toxic for 
vertebrates atan LDso oTlessthan 100 
nanograms •perkflogram body weight in 
host-vectoraystems -other than E. coli 
K— 12 will devaluated “by NIH (ORDA) 
in consultation with -ad hoc-toxin 
expertslsee ‘Sections TEI-® andTV^C-1- 
b-(3Hf). 
"Appendix F-IV. Specific Approvals. 
“An -updated Li stof experiments 
involving the .deliberate formation nf 
recombinant -DN A containing genes 
coding for toxins lethal for vertebrates at 
an LD jo ofiless than 100 nanograms per 
kilogram body weight 1 b available from 
the Office ofReconibinantDNA 
Activities, National Institutes of Health , 
BuiMrqg 51, 'Room ABll.'Bethesda. 
Maryland 20892;” 
Appendix F-W-A through Appendix 
F-TV-K wmfld'be deleted. (A list of 
these specific approvals will be 
maintained in ORDA;) 
This request was reviewed and 
recommended for approval as proposed 
during |he RAC -meeting of September 
9-10. 1993,‘by.a.vdte of 16. in favor, 0 
opposed, and no abstentions. 
I accept this recommendation, and 
Sections "HI, TV, "V andAppendixC and 
F of the NIH Guidelines will be 
amended accordingly. 
II. Summaryef Actions 
A. Major Amendment to Appendix G- 
XXVUlo the NIH Guidelines 
AppendixO-KXVII will read as 
follows: 
"AppendixD-XXVIL 
"Drs. (Philip Oreenberg and Stanley -R. 
RiddelloflheiRred Hutchinson Cancer 
Research Center, Seattle, Washington, 
may conduct gene transfer ^experiments 
on 15 hnman immimodeficiencyvirus 
(HIV) setoposilrvs patients flfi-45 years 
old) -undergoing allogeneic hone marrow 
transplantation sfbr condiodgkin *5 
lymphoma and 15 HIV**ero positive 
rjatientsKlB-CO'yeersold) who do not 
have acquired immunodeficiency 
syndrome ;(A3DS)«relaled lymphoma and 
who are not undergoing bone marrow 
transplantation to evaluate “the safety 
and efficacy nf HlV-speclfic'cytotoxic T 
lymphocyte (CIX) therapy. CTL will be 
transduced with e retroviral -vector 
(HyTK) encoding a gene (hat is a fusion 
pr^uctnf thehygromycin 
phosphotransferase genefHPH) and *the 
herpes simplex vims thymidine ianase 
(HS V-TK) gene.Tbis vector will deliver 
both a marker gene and an {(bistable 
gene in these Tcellxloneslnthe event 
that patients develop side effects as a 
consequence of CTL "therapy. Data will 
be correlated over time, looking at 
multiple parameters oTHIV disease 
activity. The objedtivesdT these .studies 
include evaluating (he. safety and 
toxicity-dTCTL therapy, determining the 
duration ofln vivo. survival -dfiHIV- 
specific CTL clones, and determining if 
ganciclovir therapy can eradicate 
genetically modified, adoptively 
transferred UTL cells." 
B. Addition of Appendix :D-LVI1 to the 
NlHGuidelmes 
The followingsection is added to 
AppendixD: 
"Appendix D-L'VII. 
"Drs. Richard C. Boucher and Michael 
R. Knowles ofthe University of North 
Carolina, Chapel Hill. North Carolina, 
may conduct experiments on 9 patients 
(18 years old orgreater) with cystic- 
fibrosis “to test for thesafetynnd efficacy 
of and El --deleted' recombinant 
adenovirus contairrfngfhe-cystic fibrosis 
transmenfbrane conductance regulator 
(CFTR) CBN A, AdCB-CFTR. A single 
doseoflO®, 3x10® orl0»* pfu/ml will 
be administered totbe-nasal cavityof 3 
patients in-each dosegroup. Patients 
will be monttored'-by nasal lavage end 
biopsy to assess safety and rest oration of 
normal epithelial function;” 
C. ^Addition of Appendix 'D-LVU1 to . the 
NIH Guidelines 
The following section isefltiedto 
AppendixD: 
“Appendix D-LATD. 
" Dr. Joyce A. O’Shaughnessy df the 
National “Institutes of Health, LBethesda. 
Maryland, may conduct experiments *on 
18patients"(l&--60 years -old) with 'Stage 
IV breast -cancer who have achieved® 
partial or complete vesponse'to 
induction chemotherapy. This study 
wifi determine the feasibility *of 
obtaining engraftmentdf<IB34{'t J ) 
hematopoietic stem cells transduced by 
a retroviral vector.'-GfMD.and 
expressing * cDNAforthe human multi- 
drug resistance-1 fMDR-l)gene 
following high dosechemotherep>y,‘Bnd 
whether the transduoed MBR-lgene 
confers drug resistancelohematopoietic 
cells and functions as in in vivo 
dominant selectable marker. Patients 
will ‘be monitored for evidence of 
myeloprotection and presence of -the 
transduced MDR-1 gene.” 
D. Addition of Appendix D-LIX lo the 
NIH Guidelines 
The following section is added lo 
AppendixD: 
"Appendix D-UX. 
‘Drs. ‘Larry E. Kun.R. A.ISanford. 
Malcolm Brenner, and .Richard L. 
Heideman df St. "Jude Children's 
Research 'Hospltil.'Meiqp’his, 
Tennessee, .and Dr.'EdwardH. Oldfield 
of the National Institutes df Health, 
Bethesda, Mainland, may conduct 
experiments on0paitentsl3-r21 years 
old) with progressive or recurrent 
malignant supratentorial tumors 
resistant to .standard therapies. Mouse 
cells producing the retroviral vector 
containing the herpes simplex 
thymidine "kinase gene (GlTKSVNa) 
will be instilled into the tumor areas via 
multiple stereotacticalLy placed 
cannulas. Patients will .be treated with 
ganciclovir to eliminate cells. expressing 
the transduced gene. Patients wfll be 
monitored ior central nervous system, 
hematologic, renal nr other toxici ties, 
and lor anti-tumor responses by 
magnetic resonance imaging studies." 
E. Addition of Appendix D-iXtothe 
NIH Guidelines ‘Regarding Seniliki 
Forest Virus 
The following section is added , to 
AppendixD: 
‘lAppendix-D-LX. 
"The physical containment level may 
be reduced from Biosafety Level 3 to 
Biosafety Level 2 tfor-a Semliki Forest 
Virus (SFV) vector expression systemof 
Life Technologies, Inc. . Gaithersburg, 
Maryland. ” 
F. Amendment to Section JI1 and 
A ppendix D.oJ the NIH Guidelines 
Regarding Actions Taken Under the 
Guidelines 
Section III-A and Appendix D -will 
read as follows: 
“Section -fll-A— -Experiments that 
Require -RAC (Re vie w.and iBC Approval 
Before (Initiation. 
"* * • Specific experiments already 
approved in 'this -section maybe 
obtained from -the©ffioe of 
Recombinant DNA Activities, National 
Institutes of Health. Building Bl.Ttoom 
4B11. Bethesda, Maryland '20892."’ 
"AppendixD — Actions Taken Under 
tbe-Guidelines. 
[502] 
Recombinant DNA Research, Volume 18 
