Delivery Success in Gene Editing

June 29, 2024 by Max Sellman

Focusing on lipid nanoparticles to show effectiveness

Any successful gene editing technique will depend on an effective delivery strategy to bring the gene editing reagent into close proximity with the target nucleic acid. At the 2024 Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT), I found the discussion of the use of lipid nanoparticles (LNP) to be an exciting part of the event, which had the added bonus of being my first-ever business trip to my hometown!

Delivering treatments
A key theme throughout the event was how critical delivery technology is to the success of cell or gene therapy programs. The delivery space has historically been dominated by viral vector technology, and indeed a large proportion of talks and posters focused on new advancements improving the safety and efficacy of gene therapy vectors.

However, researchers have branched out to non-viral delivery techniques in recent years. Spurred by the success of the COVID-19 vaccines, LNP encapsulation and delivery of gene editing reagents in mRNA format has been demonstrated to be an effective, scalable method to dose patient cells ex vivo or directly dose patients in vivo. There were a number of exciting presentations highlighting therapeutic breakthroughs in LNP-mediated delivery of mRNA for gene editing, with the following in particular catching my attention.

Michelle LeBlanc, SalioGen Therapeutics
The first LNP delivery talk I attended was from Michelle LeBlanc at SalioGen, where they have developed a new transposase called Saliogase™ and are studying a variety of disease indications in the eye and lung. Their lead program, SGT-1001, is a one-time treatment for Stargardt Disease (STGD1), the most common inherited macular dystrophy.

After delivery of an LNP containing Saliogase mRNA and the DNA transgene, the transposase is translated and specifically delivers the transgene to a pre-screened location in the genome. A recent NHP study demonstrated 40% expression of introduced DNA in treated cell population, which would confer a therapeutic benefit in humans.

Kartika Venugopal, Tessera
Tessera is developing novel gene editing reagents to directly correct complex genetic mutations. Tessera calls its technology Gene Writing™, which can create a variety of edits including small insertions/deletions or large insertions of entire exons/genes. These tools are delivered as mRNA reagents via proprietary LNP that is targetable to multiple tissue types.

Tessera has been able to achieve ~42% CAR integration in ex vivo, preclinical T cell editing studies. This same technology can create a multiplexed knock-out at the TRAC and B2M loci with 88+% efficiency rates and no detectable translocations. Even more intriguingly, both sets of edits (B2M/TRAC KO + CAR “Writing”) can be performed simultaneously at a 20% editing rate.

Joseph Biedenkapp, Verve Therapeutics
Conference organizers saved one of the more exciting presentations for Saturday. We heard from Joseph Biedenkapp of Verve Therapeutics, who presented safety data around its lead clinical program, VERVE-101, for Atherosclerotic Cardiovascular Disease (ASCVD). ASCVD is the leading cause of death worldwide, caused by prolonged exposure to LDL-C in the bloodstream.

There are some naturally occurring loss-of-function mutations of PCSK9, the gene that up-regulates LDL-C. Patients who naturally have these mutations are protected against cholesterol-related cardiovascular events with no deleterious effects. VERVE-101 is a base editing medicine that seeks to reduce blood LDL-C levels by replicating these natural LOF mutations in PCSK9.

Verve performed extensive population genetic screening and off-target site nomination to build confidence in its targeting strategy and demonstrate a lack of off-target/non-specific adenine base editing. This treatment is delivered as an LNP-encapsulated mRNA.

The Takeaway
As researchers continue to push the boundaries of LNP delivery, Aldevron stands ready to support. We recently launched an mRNA drug product service offering, enabling us to manufacture and fill/finish LNP-encapsulated mRNA drug products for clinical studies. I am excited to see the continued evolution of non-viral delivery technology and for more innovative genetic medicines to reach patients in the clinic over the next year.

And if you want to learn more about editing cells using a CRISPR-based non-viral vector, view our webinar, Going Non-Viral: How Cell Therapy Manufacturing is Moving Away From Viral Vectors.

• Learn more about Aldevron’s mRNA platform and services
• Have questions on this topic? Contact Max Sellman
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