Next-Gen Delivery Dreamers Are Alive & Well, But Patience Is A Virtue

This article is the second in a five-part series unpacking the Top 5 Cell & Gene Therapy Manufacturing Evolutions in 2021. In the previous installment, we started counting down from #5 (here), and we continue on here with #4.

But heaven forbid anything be straightforward. As I was working on this series, it struck me just how nicely the lyrics to some of Taylor Swift’s biggest hits complement the larger themes I’ve noted in the CGT manufacturing space. So, in addition to providing the big CGT picture, each article will offer an accompanying song recommendation (and lyrics!), if only to add a touch of levity to the important discussions at hand.

Music & Lyrics: “Invisible String”
And isn’t it just so pretty to think/
all along there was some invisible string/ 
tying you to me?/ A string that pulled me/ 
out of all the wrong arms right into that dive bar/…
one single thread of gold tied me to you…

One of the easiest takeaways I had after watching ARM’s Meeting of the Mesa conference in October is that this space is full of next-generation dreamers. Of course, the industry is still striving to make its current, predominantly viral-vector-based approaches more efficient. This means creating enough high quality (and well-characterized!) vector; improving vector packaging efficiency; increasing ex-vivo and in-vivo transduction efficiency; ensuring delivery specificity to the right organs/cells following systemic delivery (IV); and achieving meaningful clinical responses using a lower dose containing less vector — or repeatable doses.

But considering that the panel discussing next-gen delivery approaches was all but spilling off the Meeting on the Mesa event stage, it’s clear that the work being done today leaves a lot of gaps in treating genetic diseases that hopefully can be filled. Our gal pal Taylor (cited above) may have found love thanks to a magical “invisible string,” but in the CGT space, there is rarely — or absolutely no — “golden string” guiding our therapies directly to their targets. That’s why there’s been an explosion of interest in exploring next-gen delivery options, including nonviral vectors (e.g., LPNs or … PLVs?!), novel (i.e., more-specifically targeted) capsids, and whittled-down payloads (e.g., smaller gene editing constructs).

While exciting, we can’t be naïve to the fact that some of these novel approaches will also require increased maturity in the service provider community — a market dynamic that we will no doubt continue to see intensifying in the year(s) to come. Though we currently bemoan the availability of CDMO expertise, capacity, and CGT-appropriate raw materials/equipment today, in a lot of cases, we’re only just getting started creating the demand for the additional expertise, raw materials, and equipment on the service provider side that will be a boon for some of these novel delivery methods. The highly scientific, discovery-level work being done on innovative delivery approaches will also require greater collaboration — whether with platform companies or greater in-house R&D and manufacturing teamwork  — to ensure that each new “diamond in the rough” is capable of being manufactured at scale.

2021 offered us a glimpse of what is possible in the nonviral realm. Aside from the mRNA COVID-19 LNP-based vaccines, we celebrated the successful delivery of CRISPR in vivo using LNPs — albeit in the commonly-targeted and easily transduced liver — and saw increased business interest in in vivo gene editing. Big Pharma bought into approaches that halt immune responses to viral vectors and could permit gene therapy redosing. A panel my colleague carried out on exosomes was one of Life Science Connect’s best attended events in 2021.

But, opposite that fireworks show, the end of the year also brought with it yet another high profile (preclinical) disappointment on the non-viral vector front, adding to the list of previous disappointments in the nonviral space.

In this world in which risk vs. benefit remains an increasingly familiar reality, it’s important to remember just how much momentum it took to get us to where the industry currently is with its current generation of viral vectors. For the delivery dreamers, 2021 certainly got the ball rolling and drummed up excitement, thanks to some long-awaited meaningful clinical proof of concepts. But I think it’s safe to say the momentum that will bring with it all the necessary supportive infrastructure is still only just beginning.

Want to keep going? CGT manufacturing evolution #3 is just one click away...