ASGCT Calls for Changes to Synthetic DNA Screening Guidance

This past May ASGCT celebrated its 25th Annual Meeting in Washington, D.C., marking a quarter century of gathering the brightest minds in the cell and gene therapy community together to share knowledge and inspire new discoveries. But ASGCT is much more than its Annual Meeting, of course, and as soon as the posters were packed back into their tubes, the Society turned to another critical endeavor: engaging with the regulators whose rules govern ASGCT Members’ work back at their universities, companies, and hospitals.  

Among several federal guidance documents ASGCT commented on in June was a proposed update to the Screening Framework Guidance for Providers of Synthetic Double-Stranded DNA. Originally created by the Department of Health and Human Services (HHS) in 2010, the existing guidance has served as a series of best practices for users and manufacturers of nucleic acid synthesis technologies. The primary purpose of the guidance is to restrict access to “toxins and agents of concern,” or synthetic biology products that could theoretically be used to create biohazards or weapons. At the same time, the guidance aims to not limit the availability of these tools for their justified use in biomedical research and development intended to benefit humankind.  

In the 10 years since the initial guidance was issued, nucleic acid synthesis technologies have advanced to a remarkable degree. From vaccines to agriculture to industrial use, and certainly in the gene and cell therapy field, synthetic oligonucleotides increasingly underpin scientific research and development. For that reason, it was a priority for ASGCT to weigh in on proposed revisions to the screening framework guidance, which expands on the older guidance to counter an evolving reality: that it is easier today than ever before to assemble genes from component oligos by end users, bypassing commercial gene synthesis. Hence, the new guidelines expand screening to include ssDNA oligos (i.e., components) and not just long assembled dsDNA constructs (i.e., genes). The intent of this screening in helping to protect patient safety is well appreciated. 

ASGCT’s comments on the proposed update to the screening framework addressed several key areas of prospective changes, including:  

1. Expanding the definition of sequences of concern beyond the sequences unique to agents on the select agents and toxins list and Commerce Control List. ASGCT recommended that HHS consider the creation of a single official list that includes full sequences of concern, not only names, which can serve as a centralized, curated, and authoritative resource and help ensure that screening entities are able to keep up the expanding universe of such agents. 

2. Expanding the scope of the guidance to include both single and double-stranded forms of both DNA and RNA. The Society agreed that it makes sense, given the advance of relevant technologies, to screen single-strand DNAs in addition to double-strand versions (currently set at 200 base pairs or longer length), and to screen DNA oligo sequences as short as 50 bases long. However, the Society disagreed that it is necessary or useful to apply that screening framework to short single-strand RNAs, as they are not readily used for gene assembly. Additionally, the proposed new guidance included expanded screening down to 20 base length for oligo synthesis at 1 micromole or greater scale. ASGCT expressed concerns that screening oligonucleotides at 20 base length would present a significant burden to providers and users, as it would be very common to turn up a large number of homologies leading to false positive identifications. If implemented, this new screening requirement would introduce potentially long delays in fulfilling orders to manufacture larger scale oligos while use intent was verified between supplier and end user. Further, non-synthetic gene assembly is not facilitated by large scale synthesis so adding this screening requirement would not improve security. 

3. Reducing the burden on synthetic oligonucleotide providers by recommending that customers preemptively provide information to verify their legitimacy when ordering synthetic oligonucleotides that they know contain sequences of concern. ASGCT noted that the new recommendations on this point would be useful, but shared our Members’ experience that customers seem unlikely to provide the suggested information under real world conditions, i.e. to preemptively provide this information at the time an order is placed and instead were more likely to respond with these details only when faced with regulatory delays after their sequence order was a screening “hit.” 

4. Providing best practices to manufacturers of benchtop oligonucleotide synthesis equipment. ASGCT recognized the intent behind these changes, but again questioned whether the application in real-world settings will be effective; legitimate researchers and institutions may have complex purchasing and use arrangements that would make it extremely difficult for manufacturers of synthesizers to confirm and continuously track the end user’s intent.  

As technologies develop and expand, the regulatory frameworks governing them must adapt with them. ASGCT’s strategic priorities include a commitment to educate the decisionmakers who craft science policy and facilitate Member access to those conversations. To that end, ASGCT will continue to be a trusted voice collecting and disseminating today’s exciting science and tomorrow’s opportunities – whether that’s on Capitol Hill, at the Annual Meeting, or anywhere else our Members’ voices can make an impact.  

Dr. Giangrande is vice president of platform and discovery sciences biology at Wave Life Sciences, and currently serves as treasurer of ASGCT’s Board of Directors.  

The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of Wave Life Sciences.