The Vector
Editorial Team
Karen Bulaklak, PhD – Editor, The Vector
Jon Brudvig, PhD – Associate Editor, The Vector
Jessica Schneller, PhD – Junior Editor, The Vector
Inside This Issue
Leadership Message
Breaking Through
From Molecular Therapy
Society News
Career Center
Public Policy
Industry News
Leadership Message
A Record-Breaking Abstract Collection at the Annual Meeting
Hello ASGCT members,
We’re still a few months out, but I’m very happy to let you all know that the 26th Annual Meeting is already breaking records. We closed out abstract submission with more than 1,750 pieces of research—the largest collection of abstracts we’ve ever received in ASGCT’s history! This exciting news is such a testament to all of you and your efforts that advance our field and keep the bar high. I’m so proud of the important work you’re doing and I’m looking forward to learning about your discoveries in May. Thank you to everyone who sent us your abstracts!
Beginning Monday, Feb. 13, you can submit a late-breaking abstract if you have data that is high impact, groundbreaking, innovative, and newsworthy. The late-breaking deadline is final and is not intended to be an extension of the general submission deadline. Submit your late-breaking research through March 17.
Now that you know this meeting will include more research than ever, make sure you register by Feb. 28 before the rates increase. Lock in your spot so you won’t miss four full days of the latest science, workshops, exhibits, connecting with colleagues, and more. The meeting program is posted here and will be updated weekly. We hope to see you on the West Coast May 16-20!
Finally, don’t forget to renew your membership before March 15! Maintain access to benefits like discounted registration for the Annual Meeting and other events, a subscription to Molecular Therapy, on-demand access to professional development opportunities, and much more.
Sincerely,
Hans-Peter Kiem, MD, PhD
ASGCT President
Breaking Through
Driving adult tissue repair via re-engagement of a pathway required for fetal healing
Ghatak S, Khanna S, Roy S, Thirunavukkarasu M, Pradeep SR, Wulff BC, El Masry MS, Sharma A, Palakurti R, Ghosh N, Xuan Y, Wilgus TA, Maulik N, Yoder MC, Sen CK
DOI: https://doi.org/10.1016/j.ymthe.2022.09.002
Summary by Jessica Schneller, PhD
Skin wound healing occurs via the complex coordination of several processes, including hemostasis and inflammation, proliferation and migration, and matrix deposition and remodeling. A better understanding of these processes is critical for the development of therapies in cases of aberrant healing, for example in patients with diabetes. Skin tissue regeneration occurs faster in fetal versus adult models, suggesting the mechanisms regulating skin healing during early development can beneficially be applied to adult lesions. While there are major differences in the pathways and proteins that are activated during skin healing in fetal development versus adults, evidence suggests that adult dermal fibroblasts can exhibit fetal wound healing-like properties. In this study by Ghatak et al, the authors sought to gain a better understanding of the fetal pathways promoting rapid skin wound closure. They focused on the expression of a single microRNA family, the miR-29 family, which is minimally expressed during fetal development across species. Over-expression of miR-29 has been linked to abnormal adult tissue healing. miR-29 additionally contains potential binding sites for the protein nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase (NPGPx), which functions to maintain redox homeostasis. Decreased NPGPx expression results in a number of health issues in mice, such as oxidative stress, cardiovascular disease, obesity, autoimmunity, and more. NPGPx expression may be wound inducible; however, the biological significance of NPGPx as a key element in tissue injury and repair remains unclear. The authors sought to address the role of NPGPx, how its abundance in skin changes during fetal development, and how its expression is altered in injured adult models via miR-29-regulatory mechanisms.
Initially the kinetics of NPGPx expression in fetal and adult models following wounding were examined. NPGPx was found to be injury inducible and abundant in developing fetal skin. In adult mice, excisional skin abrasion rapidly and transiently induced NPGPx expression at the wound-edge tissue in the epidermis. High expression of NPGPx was also observed in murine fetal epidermis on embryonic day (E) 15.5, however, by E18.5, the expression of NPGPx was reduced, approaching levels similar to those in adult skin. In human fetal skin at mid-second trimester, when cutaneous injury heals without scarring, NPGPx was localized predominantly in epidermis and was more abundant than in adult epidermis. These data suggested that NPGPx is developmentally expressed in fetal keratinocytes and declines in expression in adult skin, but may be re-expressed in the epidermis following injury.
The expression of NPGPx and its effects on fetal skin injury were also examined. To determine if NPGPx is involved in keratinocyte activity after skin laceration, NPGPx expression was suppressed in utero by delivery of short hairpin (sh)-NPGPx lentiviral particles (iLV-NPGPx). After delivery of iLV-NPGPx, fetal skin exhibited slower wound closure, with stalled keratinocyte migration at the wound-edge. NPGPx expression in healing and non-healing adult human skin injury showed that healing cutaneous wounds exhibited higher epidermal expression of NPGPx compared with non-healing subjects or normal skin. Furthermore, the highest level of NPGPx expression in the human epidermis correlated with the highest level of wound closure among the subjects. To examine the effect of epithelial NPGPx expression in a healthy adult murine model, lentiviral particles constructed to suppress NPGPx abundance (iLV-NPGPx) or overexpress NPGPx (pLV-NPGPx) were delivered to the superficial skin before wounding. Suppression of NPGPx abundance impaired, while overexpression of NPGPx significantly improved, wound closure, demonstrating that NPGPx is critical for fetal and adult wound closure in murine and human models.
To validate the role of miR-29 in regulating NPGPx expression in cultured keratinocytes, commercially available mimics and inhibitors were tested for their ability to enhance or reduce NPGPx expression. The mimics showed enhanced miR-29a–c abundance and diminished NPGPx activity, while the inhibitors displayed pan-miR-29 inhibition and elevated NPGPx abundance. These observations established NPGPx as a direct target of miR-29a–c, while also implicating it as potentially having an essential role in miR-29 modulation of cell functions.
Given the changes in skin NPGPx mRNA and protein expression following acute wounding, it was plausible that the relative expression of miR-29 and its physiology might be altered in wound-edge cells. miR-29a-c abundance was shown to be significantly diminished following wounding, with evidence of an inverse correlation between miR-29a–c and Npgpx abundance. Interestingly, expression of the miR-29 family was found to be low in human fetal skin and in healing wound-edge keratinocytes compared with non-healing wounds. Similarly, miR-29a–c expression levels were also low in murine fetal skin from E15.5 until E17.5, after which they gradually increased. There was also generally an inverse pattern of NPGPx expression in the epidermis. The results in aggregate supported a physiologically inverse pattern of miR-29 abundance and NPGPx expression in skin during development and wound healing.
Members of the miR-29 family have been reported to modulate cell proliferation and migration in vitro. Delivery of pan-miR-29 inhibitors to keratinocytes lowered miR-29 abundance, enhanced cell migration, and led to increased NPGPx expression. Concomitant delivery of NPGPx shRNA with a pan-miR-29 inhibitor resulted in diminished miR-29 abundance and NPGPx expression and blunted the enhanced migratory response in the treated keratinocytes. Inhibition of NPGPx alone inhibited keratinocyte migration. These results further confirmed NPGPx as a necessary downstream target that mediates the enhanced migratory effects displayed by keratinocytes induced by pan-miR-29 inhibition.
To experimentally test whether lowering of miR-29 expression would result in upregulation of NPGPx expression, lentiviral particles delivering pan-miR-29 inhibitors were applied in wound-edge tissue of diabetic mice. Wounds were closed to a significantly greater extent compared with control-treated diabetic mice, and a significant induction of NPGPx expression in the skin followed pan-miR-29 suppression. To prove a direct relationship between miR-29 family abundance and NPGPx expression in injured diabetic skin, wounded diabetic mice were treated with experimental reagents delivered by keratinocyte-targeted LNPs (TLNPs), restricting uptake to the epidermis. Diabetic animals treated with a pan-miR-29 inhibitor and a sh-control construct by TLNP topical treatment displayed a significant improvement in wound closure. In contrast, animals administered TLNPs containing a pan-miR-29 inhibitor and sh-NPGPx demonstrated a significant loss of wound closure capacity, indicating that NPGPx expression is required to mediate the effects of pan-miR-29 inhibition. These results validate and identify an apparent physiologic injury response that occurs in normal cutaneous wound healing that is blunted in diabetes. The wound healing response may be rescued by augmenting NPGPx expression via transient pan-miR29 suppression post-wounding in diabetic mice. Delivery of a second-generation locked nucleic acid (LNA)-anti-pan-miR-29 (TNT2.0) to wounded diabetic mice led to a significant acceleration in wound closure compared with control-treated diabetic animals. Topical delivery of antipan-miR-29 oligonucleotides via TNT2.0 may therefore provide an approach to inducing NPGPx expression in keratinocytes of human subjects, whose non-healing wounds lack NPGPx.
From Molecular Therapy
Submit a nomination for the inaugural Best of Molecular Therapy Award
Nominate yourself or a colleague for this award by Feb. 28, 2023! The Best of Molecular Therapy Award, supported by Phil and Nancy Reilly, highlights the contributions of leading early-career authors to the Molecular Therapy family of journals.To learn more about the nomination criteria, please visit this section of our website.
Special issue call for papers: Biomanufacturing in gene and cell therapy
Submit to a special issue of Molecular Therapy—Methods and Clinical Development by May 31! The issue will be dedicated to all aspects of preclinical and clinical manufacturing of gene and cell therapy products. Learn more and submit today!
Latest MT issues: Check out the most recent issues of these Molecular Therapy family journals:
Society News
Join Us at the Gene Therapy Patient Engagement Summit
Our Patient Education team will be on site in Boston at this third annual summit, where Senior Outreach Manager Alison Kujawski, MPH, will speak about gene therapy education. Kicking off the summit's first day on June 14, Ali will talk about the process of collaborating with experts and patient groups to create accessible educational materials. Learn more about the summit and register here.
Feb. 28 is the Final Day to Receive Early-Bird Rates for the Annual Meeting
Want to save on your registration for the 26th Annual Meeting? Register by Feb. 28 to receive the lowest rates! We've expanded the meeting to four full days this year, so register now to secure your spot at the largest gathering of gene and cell therapy professionals.
Nominate a Colleague for an Award
We're now accepting nominations for six prestigious Annual Meeting Awards, including two inaugural awards! Submit your nominations by Feb. 28, 2023, for the Outstanding Achievement Award, the Outstanding New Investigator Award, the Sonia Skarlatos Public Service Award, the Jerry Mendell Award for Translational Science, the Best of Molecular Therapy Award, and the Catalyst Award.
Career Center
Are you looking for a job in the field of gene and cell therapy? Check out the new ASGCT Career Center for great opportunities with industry, government, and academic organizations. Sign up to receive alerts for open jobs in your area.
If you're from a recruiting institution, advertise in the Featured Jobs section to target the 5,000+ audience of The Vector.
Featured Jobs
Public Policy
Congressional Policy Fellowship Deadline Extended
Applications for the Congressional Policy Fellowship have been extended through March 15!
Who? ASGCT members with a post-doctoral degree and US citizenship.
Where? Washington, D.C. ASGCT will provide a moving stipend to assist with relocation costs if fellows need to relocate from more than 50 miles away.
When? Beginning this fall, the Fellowship will run for one year. Submit applications by March 15.
Why? You'll make an impact on federal policy while gaining access to leading support and networking resources. At the end of the fellowship, you'll be equipped to forge a new career in policymaking circles or return to your institution with a unique and valuable skillset.
How? Submit applications to fellowship@asgct.org. A summary of application materials and FAQ are available, so take a look and apply today!
Now On Demand: ASGCT + FDA Immunogenicity Workshop
As part of FDA's efforts to improve communications with sponsors, ASGCT partnered with FDA's Office of Tissues and Advanced Therapies (OTAT) for a two-day workshop on Immune Responses to AAV Vectors. ASGCT appreciates the opportunity to collaborate on such an important topic, and to serve as the convener for experts in this space.
Immunogenicity remains an important topic for the field as AAV vectors grow in popularity for their efficiency as an in vivo delivery tool. The first day of the workshop focused on technology and approaches for measuring immunogenicity and immune modulation. Presenters discussed perspectives on measuring safety, efficacy, durability, and predictability, as well as how those elements may be impacted by factors influencing immunogenicity like dose and empty capsid levels. Companion diagnostics and the associated regulatory pathways were also emphasized as important tools for calculating immune response.
The second day shifted the discussion to the therapeutic clinical and pre-clinical considerations for AAV immune response. With immune toxicity, there have been significant new learnings on how and when to best administer and measure response to AAV therapies. Speakers touched on capsids, antibodies, cytotoxic T-cell responses, and anti-transgene immunity. In the clinical setting, presenters discussed various regimens for immune suppression and how these might change between trials. Combined with the technical focus of day one, the hope is for insights gleaned to inform new solutions.
Recordings from both days are now available to watch on demand!
House Cancer Caucus and ASGCT-Hosted Briefing Focuses on CAR T and Immunotherapies
As a follow up to ASGCT's Innovation in Cancer Care: CAR T Therapies and Patient Access Congressional briefing this past fall, the Society presented CAR T and Immunotherapies for Cancer Indications on January 24. In collaboration with the bipartisan House Cancer Caucus, ASGCT members and leaders presented on the following topics for members of Congress and their staff:
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Basics of the science behind gene and cell therapy
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Pipeline of CAR T treatments and approved products
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Delivery of care and patient experience
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Manufacturing challenges with advanced cell and gene therapy products
Much of the Q&A portion of the briefing focused on policy levers to help alleviate manufacturing bottlenecks for advanced therapies. ASGCT is encouraged by the productive dialogue with representatives and their staff on these important issues and will follow up with individual offices later this year.
The Society would like to thank the Caucus co-chairs, Congressmen Higgins (D-NY), Kilmer (D-WA), Fitzpatrick (R-PA), and Kelly (R-PA), and their staff, for collaborating on this briefing. We look forward to engaging on these issues in the future!
Response to OSTP Request Highlights Support for Platform Technology, ARPA-H, Advanced Manufacturing Pathways
In December, the White House Office of Science and Technology Policy (OSTP) announced the release of a Request for Information (RFI) related to the National Biotechnology and Biomanufacturing Initiative. This Initiative was launched through President Biden's Executive Order 14081 and aims to advance biotechnology and biomanufacturing for innovative solutions in health, climate change, energy, food security, agriculture, and supply chain resilience.
ASGCT submitted a response that focused on the needs of the gene and cell therapy field and voiced support for platform technologies, the Advanced Research Projects Agency for Health, advanced manufacturing review pathways, and the use of real-world evidence. Comments emphasized the exponential pipeline of therapies in development and the promise of these therapies to transform patients' lives meaningfully. ASGCT is aligned with the goals of the NBBI to support medical breakthroughs and improve health outcomes, and recommended several actionable steps to help meet these goals for cell and gene therapies.
Responses to this RFI will be followed by virtual listening sessions with OSTP. ASGCT appreciates the opportunity to participate in this process, and thanks the Administration for their commitment to efficient biomanufacturing and a strong bioeconomy.