Packgene’s π-Icosa Platform Delivers Next-Generation AAV Capsid PG007 for Muscle-Specific Gene Therapy

Packgene, a leader in AAV vector services, has announced significant advancements in AAV capsid engineering through its π-Icosa system. These developments are further detailed in their recent preprint publication on BioRxiv, titled “Engineering novel AAV capsids by global de-targeting and subsequent muscle-specific tropism in mice and NHPs“. The π-Icosa platform enables the creation and screening of AAV capsid variants with enhanced organ targeting, reduced off-target effects, and improved overall gene delivery efficiency for specific cell types or tissues. Recent publications detail the successful development and characterization of PG007, a novel AAV capsid variant engineered for highly efficient and specific muscle transduction while minimizing liver targeting.

Engineering AAV Capsids for Precision Delivery

The π-Icosa system employs a three-phase process involving AAV capsid library construction and in vivo screening. Initial screening of an AAV capsid library identified variants (AAV.1R1-R4) with enhanced muscle transduction, though some liver tropism remained. Building on the AAV.Zero3 backbone, Packgene incorporated myotropic RGD-containing peptides, leading to the development of PG007 (AAV.eM). This strategic modification successfully enhanced muscle transduction efficiency, with PG007 showing luciferase expression in skeletal muscle comparable to, or even superior to, known myotropic AAV variants like MyoAAV 4A, all while maintaining its non-hepatotropic profile.

PG007’s Superior Muscle Targeting and Safety Profile

Further comprehensive in vivo studies characterized PG007’s performance across various animal models:

• High Efficiency and Specificity in Mice: In Balb/c mice, systemic administration of PG007 resulted in significantly higher luciferase expression in limb muscles compared to AAV2, AAV9, and MyoAAV 4A. Crucially, it maintained markedly reduced luciferase levels in the liver and low expression in other non-muscular tissues (brain, lung, kidney), confirming its enhanced muscle specificity and liver detargeting.
• Translational Potential in Nonhuman Primates (NHPs): A pivotal finding for clinical translation, PG007 demonstrated superior hepatic safety in Macaca fascicularis (NHPs). Unlike MyoAAV 4A, which induced significant liver enzyme elevation, PG007-treated animals showed no significant increase in AST or ALT levels. It also maintained comparable muscle-targeting efficiency to MyoAAV 4A in various muscle groups.
• Functional Micro-Dystrophin Delivery in DMD Model: To evaluate its therapeutic potential, PG007 was used to deliver a microdystrophin (μDys) transgene in a Duchenne Muscular Dystrophy (DMD) mouse model. PG007-μDys-treated mice exhibited significantly greater muscle strength recovery and lower serum creatine kinase (CK) levels (indicating reduced muscle damage) compared to AAV9-μDys and controls. Immunofluorescence confirmed enhanced dystrophin expression in targeted muscles with minimal expression in non-target tissues.

Conclusion: A Leap Forward for Gene Therapy

The successful development of PG007 through the π-Icosa platform underscores its ability to balance efficacy and safety, minimizing hepatic toxicity while maximizing muscle-specific gene delivery. The π-Icosa platform integrates rational design, directed evolution, and high-throughput screening, leveraging computational approaches to create AAV capsid variants for potent and safe gene delivery to any target tissue or cell type.

Packgene’s π-Icosa platform represents a cutting-edge tool for AAV capsid optimization, promising to accelerate the development of next-generation gene therapies by identifying tissue-specific vectors with improved safety and efficacy profiles.

Reference:

https://www.biorxiv.org/content/10.1101/2025.05.19.654800v1