Office of Biotechnology Activities; Recombinant DNA Research: Action Under the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines)

AGENCY:

National Institutes of Health (NIH), PHS, DHHS.

ACTION:

Action under the NIH Guidelines.

SUMMARY:

The NIH Guidelines currently require that recombinant DNA experiments designed to create new transgenic rodents be registered with the Institutional Biosafety Committee (IBC). Specifically, Section III-E-3 of the NIH Guidelines addresses the generation of transgenic rodents that may be housed under biosafety level (BL) 1 conditions and allows the work to proceed simultaneously with registration of the experiment with the IBC. The IBC must then review and approve the experiment. The NIH Guidelines address two pathways for generation of a transgenic rodent: altering the animal's genome using recombinant DNA technology, or breeding one or more transgenic rodents to create a new transgenic rodent (i.e., breeding of two different transgenic rodents or the breeding of a transgenic rodent and a non-transgenic rodent).

On July 20, 2010 the NIH Office of Biotechnology Activities (OBA) published a proposed action (75 FR 42114) to amend Section III-E-3 and to add a new Section to Appendix C (Appendix C-VII) of the NIH Guidelines so as to exempt breeding of almost all transgenic rodents that can be housed at BL1, with the exception of rodents that contain a transgene encoding more than fifty percent of an exogenous eukaryotic virus and transgenic rodents in which the transgene is under the control of a gammaretroviral promoter. After receiving public comment on the proposed changes, OBA is implementing these changes.

FOR FURTHER INFORMATION CONTACT:

If you have questions, or require additional information about these changes, please contact OBA by e-mail at oba@od.nih.gov, telephone, 301-496-9838 or mail to the Office of Biotechnology Activities, National Institutes of Health, 6705 Rockledge Drive, Suite 750, MSC 7985, Bethesda, Maryland 20892.

Background: Section III-E of the NIH Guidelines addresses experiments for which IBC registration is required at the time the research is initiated. Experiments covered in this section of the NIH Guidelines are considered to be of low biosafety risk and although IBC review and approval is still required, such approval need not be obtained prior to initiating the research. This is in contrast to all other experiments described in the NIH Guidelines for which IBC review and approval is required prior to initiation of the experiment.

Under the NIH Guidelines (Section III-F-6), certain experiments can be exempted from the NIH Guidelines if they do not present a significant risk to public health or the environment and the NIH Director approves this action. These exemptions are delineated in Appendix C of the NIH Guidelines.

Currently, the purchase or transfer of transgenic rodents that require BL1 containment are exempt from the NIH Guidelines under Appendix C. This action would extend that exemption to most experiments that involve the generation of transgenic rodents by breeding, as long as the transgenic rodents can be appropriately maintained under BL1 conditions. The rationale for this change is that three decades of working with and breeding transgenic rodents have demonstrated that the overwhelming majority of experiments involving breeding of transgenic rodents that can be housed under BL1 conditions results in progeny that can also be housed under BL1 conditions. Thus these breeding experiments do not pose an appreciable risk to human health or to the environment. In addition, while registration with the IBC is not a significant burden, the total number of registrations required can constitute a significant collective administrative burden on the IBC and researchers that does not appear to be commensurate with the very low biosafety risk.

There are still two categories of breeding experiments for which IBC registration will be required in order to ensure that a risk assessment is conducted and that the resulting rodent is disposed of appropriately:

(a) Breeding experiments involving transgenic rodents that contain more than 50 percent of the genome of an exogenous eukaryotic virus from a single family, in order to prevent inadvertent reconstitution of an exogenous virus in the resultant transgenic rodent; and

(b) breeding experiments in which the transgenic rodent's transgene is under the control of a gammaretroviral long terminal repeat (LTR), in order to address the small risk of recombination with endogenous retroviruses which could potentially result in mobilization of the transgene via a replication-competent mouse retrovirus.

As the risk of recombination and possible transmission to humans is more likely with gammaretroviral LTRs (e.g., murine leukemia virus, feline leukemia virus, xenotropic murine leukemia-related virus), the requirement for registration is limited to rodents containing a transgene under control of these LTRs.

OBA received nine comments in response to the July 20, 2010 Federal Register notice of proposed changes. All were supportive of the change and emphasized that the current registration requirements impose a significant administrative burden on IBCs that is not necessary to protect public health, laboratory workers or the environment. One comment noted that making these experiments exempt would free up valuable resources (time and money) for their IBC, Institutional Animal Care and Use Committee, and researchers. One comment asked for clarification regarding how to assess whether breeding a transgenic rodent containing a partial gammaretroviral LTR sequence must be registered with the IBC. The key issue is not the percentage of the LTR sequence, but rather whether it is functional or not, i.e. whether there is sufficient LTR sequence to direct the expression of a transgene.

The following changes will be made to Appendix C of the NIH Guidelines:

Appendix C-VII. Generation of BL1 Transgenic Rodents via Breeding

The breeding of two different transgenic rodents or the breeding of a transgenic rodent and a non-transgenic rodent with the intent of creating a new strain of transgenic rodent that can be housed at BL1 containment will be exempt from the NIH Guidelines if:

(1) Both parental rodents can be housed under BL1 containment; and

(2) Neither parental transgenic rodent contains the following genetic modifications:

(a) Incorporation of more than one-half of the genome of an exogenous eukaryotic virus from a single family of viruses; or

(b) Incorporation of a transgene that is under the control of a gammaretroviral long terminal repeat (LTR); and

(3) The transgenic rodent that results from this breeding is not expected to contain more than one-half of an exogenous viral genome from a single family of viruses.

The current Appendix C-VII and Appendices C-VII-A through C-VII-E will be renumbered to Appendix C-VIII and Appendices C-VIII-A though C-VIII-E, respectively.

For clarity the following is added to Section III-E-3.

Section III-E-3-a. Experiments involving the breeding of certain BL1 transgenic rodents are exempt under Section III-F, Exempt Experiments (See Appendix C-VII, Generation of BL1 Transgenic Rodents via Breeding).