Bio-ARROW - SmartForm - Recombinant Synthetic DNA/RNA Materials

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Drug Resistance

Antibiotics, herbicides, etc. that are used for selection purposes, even if they are not used to treat infections, should be included in this section.

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Drug Resistance Trait-Compromise

The deliberate transfer of a drug resistance trait to a microorganism when such resistance could compromise the ability to control the disease agent in humans, veterinary medicine, or agriculture requires NIH Director approval and is considered a "Major Action" under the NIH Guidelines: https://osp.od.nih.gov/biotechnology/faqs-about-major-actions-under-section-iii-a-of-the-nih-guidelines-for-research-involving-recombinant-or-synthetic-nucleic-acid/ .

A therapeutically useful drug must be recognized in the scientific literature as a useful drug in vivo. The drug does not have to be the "first line" agent. A drug can be useful to treatment event if its use is limited to the treatment of a specific patient population, such as children or pregnant women, or primarily used outside of the U.S. where alternative drugs are not available.

To determine if a particular drug is considered a therapeutically useful drug, consult the following references:

Up to Date Online:  http://www.uptodateonline.com/utd/index.do
Johns Hopkins ABX Guide: http://www.hopkins-abxguide.org/
Red Book: Report of the Committee on Infectious Diseases: http://redbook.solutions.aap.org.ezproxy.library.wisc.edu/
Sanford Guide to Antimicrobial Therapy: http://search.library.wisc.edu/catalog/ocm37280724
Principles and Practice of Infectious Diseases:  http://search.library.wisc.edu/catalog/ocn370605770
Principles and Practice of Pediatric Infectious Disease: https://search.library.wisc.edu/catalog/9910053220302121

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Genome Editing and Gene Drives

There are certain configurations of genome editing components that have the potential to create a gene drive.  Gene drives are a risk to the environment, not the researcher.  Gene drives occur when alleles are inherited more often in populations than expected from Mendelian segregation.  Even though gene drives can speed up the time it takes to create mutant lines in the lab, there can be severe consequences if these lines are not contained.  If lines become cross-contaminated in the lab, you risk introducing the mutant allele in unwanted lines.  If a line containing a gene drive is released to the outside environment, the mutant allele can become well established in the natural population.  Depending on the mutation, this can have devastating results.

It is therefore extremely important to keep the genome editing components separated to reduce the risk of creating a gene drive.  Even if the components are on separate constructs, some organisms have a tendency for several transforming DNAs to integrate into the same location (tandem copies) within the genome, thus creating the potential for creating a gene drive.  If there is potential for creating a gene drive, a minimum of two confinement strategies should be used.   This can include performing experiments in areas without potential wild mates, using a laboratory strain that cannot reproduce with wild organisms, or using increased physical barriers to contain the strain in the laboratory.  Organisms that have the potential to carry a gene drive should also not be shipped to protect against a release to the environment.  For additional information regarding safety concerns and recommendations of gene drives, please see the following article: Akbari, O.S., et. al. Science 340: 927-929 (2015).

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Genes and DNA/RNA Fragments

Examples of how to enter genes fragments used to knock-down or silence genes.

 

Genes and DNA/RNA fragments

Gene source

Gene Protein

Gene Use

DNA carried on a vector that is introduced to knock-down or silence a gene

Fragments of gene X

Genus and species the gene fragment originated from

Describe the function of the gene you are knocking down or silencing

 Knock down or silence

siRNA

Fragments of gene X

Synthetic

Describe the function of the gene you are knocking down or silencing

Knock down or silence
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Construct: Construct Risk Attenuation

Plasmids that are non-conjugative or non-mobilizable lack the nic/bom elements required for mobility. Plasmids that lack F factors are considered nonconjugative (see http://en.wikipedia.org/wiki/F-plasmid for more information).

Agrobacterium plasmids that are disarmed lack the tumor inducing genes needed for pathogenicity.

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Human Subjects Status and Documents - RAC Review Status

The Recombinant DNA Advisory Committee (RAC) is a federal advisory committee that provides recommendations to the NIH Director related to basic and clinical research involving recombinant or synthetic nucleic acid molecules. https://osp.od.nih.gov/biotechnology/recombinant-dna-advisory-committee/.   Clinical trials involving the administration of recombinant or synthetic nucleic acid molecules require RAC review if any of the following three criteria are met:
  1. The protocol uses a new vector, genetic material, or delivery methodology that represents a first-in-human experience, thus presenting an unknown risk.
  2. The protocol relies on preclinical safety data that were obtained using a new preclinical model system of unknown and unconfirmed value.
  3. The proposed vector, gene construct, or method of delivery is associated with possible toxicities that are not widely known and that may render it difficult for oversight bodies to evaluate the protocol rigorously.
If UW-Madison serves as an additional trial site or if the trial is specially exempted from RAC review as noted in Appendix M-VI-A of the NIH Guidelines: https://osp.od.nih.gov/biotechnology/nih-guidelines/  then RAC review is not required.  If you have questions about the vaccine exemption, consult the FAQ guide: https://osp.od.nih.gov/biotechnology/faqs-on-the-nih-guidelines-vaccine-exemption/.

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Human Subjects Status and Documents – Appendix M

Responses to Appendix M-IA should be uploaded: https://osp.od.nih.gov/wp-content/uploads/NIH_Guidelines.html#_Toc446948491

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Human Subjects Status and Documents – Adverse Events

PIs must submit a report on (1) any serious adverse event that is both unexpected and associated with the use of the gene transfer product (i.e., there is reasonable possibility that the event may have been caused by the use of the product; investigators should not await definitive proof of association before reporting such events); and (2) any finding from tests in laboratory animals that suggests a significant risk for human research participants including reports of mutagenicity, teratogenicity, or carcinogenicity. Some adverse events require reporting as soon as 7 days after the event.

Please see http://osp.od.nih.gov/sites/default/files/NIH_Guidelines.html for more information.

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Still have questions? Call the Office of Biological Safety (OBS) at 608-263-2037. We are happy to help!!