ARW's CGT+RNA Manufacturing Must-Reads (Sports Cliché Edition!)

By Anna Rose Welch, Director, Cell & Gene Collaborative
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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.

Lucky for us, this newsletter was sent on July 13, which is smack dab in the middle of Sports Cliché Week (July 11-17). As such, I stepped up to the plate and carefully selected a sports cliché to accompany your manufacturing must-reads. Here’s hoping you think at least one of these selections hits it out of the park. Play ball!

You gotta want it!
[PDA ATMPs RECAP]

• As someone who regularly seeks out opportunities to improve my knowledge, skill set, and general “self,” I felt particularly inspired by a (not clichéd) quote from the FDA’s Tiffany Lucas at June’s PDA ATMP conference about the role of “self-improvement” in CMC. In my takeaway, I share three areas in which we can close the gap between where we currently are and where we know our CGT manufacturing processes (and brains) can be in the future.

The ball’s in your court.
[REGULATORY]

• ^^What we say to the FDA and what the FDA inevitably says back to us.
• Your nonclinical teammates will have a chance to punt their most pressing questions to the FDA at the forthcoming OTP Town Hall on the Nonclinical Assessment of Cell & Gene Therapy Products on August 30, 11:30 AM-1 PM ET.
• Props to the mRNA quality experts who took the ball and ran with it when USP asked for comments on the first version of its quality guidelines for mRNA vaccine drug substance development. Be sure to check out USP’s recently released Analytical Procedures for mRNA Vaccine Quality guidelines, version 2.0.
• In a previous must-reads newsletter, I shared an FDA discussion paper on the role of AI in drug manufacturing. My colleague Louis Garguilo of Outsourced Pharma does a nice job of dribbling between the main takeaways of the FDA’s document and some of his concerns about how the implementation of AI may challenge biotechs and their outsourcing partners.
• Following Sarepta’s accelerated approval a few weeks ago, I thought this article summarizing the discussion from a DIA panel was a worthwhile read — particularly the section elaborating on why there is “no ‘cookie cutter’ approach” to determining which rare disease therapies are worthy of an accelerated approval.

They’re in a league of their own —
[MANUFACTURING FLEXIBILITY]

• And so is every person’s definition of “flexibility” when it comes to manufacturing technology.
• Hence why I took the chance to pick the brains of two executives — one from a cell therapy biotech and one from a tech provider — about how they are defining flexibility in cell therapy manufacturing platform technology and what this may mean for technology partnerships in the broader CGT space.
  • BTW, innovations in scalable, automated manufacturing is just one of many topics in this call for articles/case studies/reviews etc. for a special CAR-T cell therapy issue of Frontiers in Immunology. The deadline for manuscripts is July 31.

We must play within ourselves.
[mRNA ADVANCEMENTS]

• Is it just me, or can we turn this cliché into an mRNA joke?
• As I am no doubt the only one that finds this “joke” clever, allow me to offer you something infinitely smarter — a recent paper from Advanced Drug Delivery Reviews walking us through the current understanding of mRNA’s structure, the IVT reaction, RNA polymerases, capping agents/strategies, and future RNA technologies (i.e., saRNA and circRNA).
• This week, partners Merck & Moderna just announced their plans for an 1,100-person pivotal trial for their cancer vaccine in combination with Keytruda. As such, it seemed like a great opportunity to share this publication from Stanford scientists on some of the latest developments in the mRNA cancer immunotherapy space.
• In addition to Merck and Moderna’s big news, I’d be remiss if I didn’t share the news out of Cartesian Therapeutics published last month in The Lancet: The biotech’s autologous RNA CAR-T therapy showed its skills playing offense against Myasthenia Gravis in a Ph.1/2 trial, making it the first (so far successful!) study of an rCAR-T in an autoimmune disease indication.

He brought his A-game today.
[SHAMELESS COWORKER PROMOTION]

• The first official interview and first published piece of editorial is a big rite of passage here at Life Science Connect.
• Today, I’m celebrating my newest editorial colleague Tyler Menichiello, not only because he recently published his first Cell & Gene article on some of the challenges of licensing ATMP platforms from universities, but also because he didn’t pull any punches and carried out that interview in-person while visiting a Pittsburgh biotech.

On paper, they’re the team to beat.
[AAV MARKET RESEARCH]

• In the ATMP world, it’s not just about looking good on paper — it’s also about how a product is formulated and how long it can last on a shelf at room temp.
• Special thanks go out to one of my favorite Cell & Gene Collaborative “geneiuses” for tipping me off to this trusty “AAV Formulation Cheat Sheet,” outlining the stability, concentration, and excipient profiles of currently approved viral vector therapies.

They have all the right pieces.
[AAV QUALITY]

• I guess that’s one way of saying your vector is high quality.
• If you’re trying to figure out if you have all the right “pieces” of technology to determine that your vector has all the right “pieces,” this BioProcess Online article shares the pros and cons of 10 methods for characterizing and quantifying AAV empty-full ratios.
• Though the previous article does discuss AEX and SEC-MALS chromatography methods, if you’d like to continue your foray even deeper into chromatography methods for AAV development, check out this publication homing in on how IEX, RPLC, and HILIC methods are currently being used (successfully or less successfully) to measure AAV quality attributes.

It’s a slam dunk!
[DELIVERY]

• Someday, hopefully, we’ll be able to say this about the delivery of our ATMPs — particularly using nonviral delivery mechanisms.
• This article in Nature is a nice review of how several different gene therapy biotechs are playing with nonviral delivery methods, whether they be LNPs, DNA or protein-based nanoparticles, exosomes, or an array of physiochemical tools (for ex vivo products).
• Speaking of exosomes and peptide-guided delivery — catch!
  • Journal of Nanobiotechnology [June 2023]: Current & Prospective Strategies for Advancing the Targeted Delivery of CRISPR/Cas System via Extracellular Vesicles
  • Science Advances [Jan. 2023]: Peptide-guided LNPs Deliver mRNA to the Neural Retina of Rodents & Nonhuman Primates