ARW's Cell & Gene + RNA Manufacturing Must-Reads (Class Reunion Edition!)

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

Day-in and day-out, I write, read, listen to, and watch as much content as I can about CGT and RNA therapy manufacturing, in particular, and/or other ATMP industry-related topics that you should at least be aware of in the manufacturing facility. Every two weeks, I compile the articles and industry updates I think are most worthy of your time into an unconventional newsletter format (below) and send them out via email.

A few weeks ago, I attended my partner John’s 25th high school reunion so he — a formerly angsty, thrill-seeking daredevil — could prove that all the things he and his friends did in high school that should have killed them were in no way tall tales. This got me thinking about the personas we’re most likely to run into at high school reunions — and, as I looked over the list of CGT/RNA articles I wanted to share, I thought that they all in some way fit within one of these persona groups. So, please enjoy this class reunion you may not have even wanted to attend — but which ended up happening right in front of you regardless.

"The Changed One:" They go to prove just how much they’ve grown up (resumés/CVs available upon request).

• Take that, “Class Clown” yearbook ranking!
• To be fair, I suppose we all do this. But as a manufacturing expert, you’re also in the unique position to demonstrate not only how much you’ve grown, but how much your manufacturing paradigm has grown up and changed for the better, too.
• Look no farther than industry leader bluebird bio. Their FDA AdCom may have been deep in the clinical weeds — but how their CMC changed and could continue to change in the years ahead were naturally an important part of the discussion. Check out my third & final installment highlighting some of the development/manufacturing changes that arose during the June AdCom here: For Cell & Gene Manufacturing, FDA Approval Is Just One Of Many Milestones.

"The Unabashed Nerd:" They show up with their real name AND their Dungeon’s & Dragon’s character name on their name tag.

• Say hi to Kregud the Wretched, Zonud Gnome Gasher, Elawraek Spiritbirth, and…apparently Bob has been quite popular lately, as well.
• We all have some nerdy skeletons in the closet. But if our old classmate Mike (a.k.a. Ermmek Rustbelch) can teach us anything, it’s that our hobbies can/will influence our “grown-up” life and work.
• For example, I (and in turn, you) have poetry camp to thank for my introduction to The Game of Risk, which, two decades later, became fodder for a brand-new, creative project I will be debuting in the mRNA space. More details are forthcoming soon — but in the meantime, a teaser: What Playing Risk Can Teach Us About mRNA Manufacturing.

"The Jack of All Trades:" The star basketball player, accomplished cellist, debate team captain, and one who learned Latin on the weekends — just for fun.

• Of course they grew up and became a biotech CEO and a volunteer firefighter who is rescuing a kitten in their LinkedIn photo.
• In the ATMP space, no single person or company will have every solution to the industry’s challenges. But we can certainly get behind the efforts/initiatives that put all that talent and brainpower into one easily referenced document.
• So, let’s give it up for The Alliance for Regenerative Medicine & NIIMBL for delivering us this highly anticipated collaboration, Project A-Cell: A case study-based approach to integrating QbD principles in cell therapy CMC programs. (Open access!)
• This jack-of-all-trades manufacturing case study of a CAR-T product literally has something for everyone to crush on, whether it be regulatory sciences, starting material collection, the LVV mfrg process, analytical technologies & characterization, ancillary materials… the list goes on.
• A-Cell comes a year after the publication of its gene-therapy sister publication, Project A-Gene, which unpacked many of these same topics on the AAV gene therapy side.

"The Square:" They never partied, got all their homework done a week early, and then got more assigned for the entire class.

• Some people are just born to be regulators, aren’t they?
• We may not love every new assignment we get from the regulators, but we can’t do our jobs without them. Hence, why both the industry & FDA are anxiously awaiting the reauthorization of the FDA’s user fee programs by the end of September.
• Unfortunately, you just sat down at the table with the class “Debbie Downer.” The industry is not exactly optimistic Congress will make the Sept. 30th deadline as there are a few controversial “riders” (centered around cosmetics, diagnostics, and dietary supplements) included in the reauthorization legislation that are holding things up.
• Naturally, a delay in reauthorization would impact FDA hiring and our product’s review timelines. But I’d also point out that such reauthorization is critical for the FDA to implement some of its “wildest dreams” to get the ATMP industry up-and-running more efficiently.
  • For example, the FDA’s Peter Marks recently outlined his hopes to launch an “Operation Warp-Speed”- style gene therapy approval process to provide “real-time feedback.”
  • Obviously, the resources for such a program don’t exist today — but data from a pilot program could help encourage Congress that such an interaction framework (and the user fee structure to support it) would be a great idea to formally implement.

"The Life of the Party" — they delivered personality, adventure, style, and good looks, and they never showed up to a party empty-handed.

• If our therapies — more specifically their delivery vehicles — were people, these are the type of people we’d hope they’d grow up to be… albeit we’d like them to be mature and responsible partiers that come bearing the right kind and amount of high quality “goods” and who know how to shut down the party before the cops get called.
• We can’t get more responsible than with lipid nanoparticles these days. I was psyched to find this excellent “character study” unpacking what each specific lipid individually brings to the LNP party (e.g., stability, structure, encapsulation efficiency, etc.).
• Perhaps it’s also worth catching up not just on what’s new but revisiting the good old times in this (somewhat older) article from 2020 that reviews the scientific advances in LNP development and their use in different mRNA therapeutic modalities (i.e., vaccines; CAR-T; mRNA encoding for mABs).
• But LNPs aren’t the only ones who had/know how to have some fun; AAVs have undergone some noteworthy personal growth, starting first with the industry’s slow but sure progression toward dual-plasmid transfection to progress beyond the limitations of triple transfection.
• I also appreciated my colleague Louis Garguilo’s discussion — Executive Director, AAV: Title As Leading Indicator — on how the increasing reliance on AAV is introducing a new age of professional and scientific development for manufacturing execs and the outsourcing realms — both individually and collectively.

"From ‘Who?’ To ‘Whoa!’:" They were there all four years, but now the music stops when they walk in.

• These stunners may not have been anywhere near the prom court back in the day, but after the past few years of their “hot” mRNA sibling showing off its brains and brawn during the pandemic, these RNA brothers/sisters are starting to turn heads.
• Circular RNA may be the youngest of the three, but it’s therapeutic potential has not gone unnoticed. These Stanford Professors ever-so-modestly outline the development of a modular circRNA platform and it’s increased therapeutic protein production potential.
• This first article in a three part series is a great primer on the eldest (in terms of market approval) and perhaps most overlooked child, siRNA, who has a lot to teach us, but also still has a lot to learn despite its age/experience.