Novartis Halts Development of Gyroscope Therapeutics' Lead Gene Therapy GT005 for Geographic Atrophy

On September 11, Syncona Investment Management Limited, an investor in Gyroscope Therapeutics (Gyroscope), announced that Novartis had halted the development of GT005, an ophthalmic AAV gene therapy. GT005 is known to be Gyroscope’s key investigational product, a gene therapy based on the AAV2 vector.

The decision to halt the development of GT005 was based on the recommendation of its Data Monitoring Committee, which is responsible for overseeing and reviewing the data from the project's clinical trials. After reviewing the existing data, including that from the Phase 2 clinical trial study, the committee concluded that the project should not move forward.

It may be due to AAV toxicity issues that the project development was halted. Here is a reference solution:

The main challenge of using recombinant adeno-associated virus (rAAV) vectors for gene therapy is the host immune barrier. The production of rAAV vectors typically requires large amounts of plasmid DNA, such as the use of a triple-plasmid system to transfect the 293 cell line for rAAV production. Plasmid DNA is usually isolated from DH5α bacterial strains contaminated with lipopolysaccharide (LPS, also known as endotoxin). Commercial LPS removal kits or silica-based ion exchange resins are commonly used to purify plasmid DNA. However, since LPS is a chemically stable molecule that strongly resists high pressure, extreme temperatures, and pH levels, endotoxins often remain during the preparation and purification of plasmid DNA and are subsequently introduced into rAAV vector products. Residual endotoxins in rAAV products may cause significant host immune reactions, as even low levels of endotoxins, down to 10 endotoxin units (EU) in infused products, can trigger severe allergic reactions, septic shock, and even host death. The U.S. Food and Drug Administration (FDA) requires that the endotoxin content in infused gene therapy drugs does not exceed 2.0 EU/dose/eye or 0.5 EU/mL.

In mammalian cells, Toll-like receptor 4 (TLR4) recognizes bacterial endotoxins and then activates NF-κB (nuclear factor-kappa B) via MyD88 (myeloid differentiation primary response gene 88). Additionally, LPS can also induce NF-κB by activating the Toll/IL-1 receptor (Toll/interleukin (IL)-1 receptor). NF-κB is a factor that controls the expression of a series of inflammatory cytokine genes and serves as the first line of defense against invading antigens.

Removing LPS from products is time-consuming, labor-intensive, and costly, and leads to poor recovery of the purified carrier. Therefore, it is crucial to eliminate endotoxins at the source. To achieve this, researchers genetically modified LPS-related genes in the strain by knocking out seven genes (ΔgutQ, ΔkdsD, ΔlpxL, ΔlpxM, ΔPAGP, ΔlpxP, and ΔEPTA), deleting the polysaccharide chain of LPS and two secondary acyl chains. The modified strain is called the ClearColi K-12 strain, whose synthesized Lipid IVA cannot be recognized by TLR4, thus failing to activate the NF-κB pathway or induce the production of pro-inflammatory cytokines in the body.