CaMKII Gene Therapy Preserves RGC Axons & Somas

Article: Gene Therapy May Preserve Vision in Retinal Disease and Serious Retinal Injury
Source: Icahn School of Medicine at Mount Sinai
Published: July 22, 2021
Article: Scientists discover gene therapy provides neuroprotection to prevent glaucoma vision loss
Source: National Eye Institute
Published: July 22, 2021
Article: Gene Therapy Protects Optic Nerve Cells and Vision in Mice with Retinal Injury and Glaucoma
Source: Genetic Engineering & Biotechnology News
Published: July 23, 2021

Graphical abstract

Some conditions, such as excitotoxicity and retinal ischemia, injure the retinal ganglion cell (RGC) soma, while damage to the retinal ganglion cell axon can result from optic nerve transection, compression, intracranial hypertension, and glaucoma. A neuroprotective therapy that preserves both RGC axons and somas would therefore have wide-ranging benefit. Researchers are investigating the potential of calcium / calmodulin-dependent protein kinase II (CaMKII) as a target for gene therapy to protect RGCs from diverse pathological insults and ultimately preserve vision. Studies in small animal models indicate that damage to RGC somas or optic nerve axons led to inactivation of CaMKII and its downstream signaling target, cAMP response element binding protein (CREB). However, reactivation of CaMKII and CREB provided robust protection for retinal ganglion cells. For example, experiments wherein CaMKII was delivered via adeno-associated viral vector to mice just prior to the toxic insult or just after optic nerve crush led to increased CaMKII activity and robust protection of retinal ganglion cells. In particular, the gene therapy introduced a more active version of CaMKII with a modified amino acid to boost their activity in RGCs. The researchers then tested the modified enzyme in a range of injury and disease animal models, including two models of glaucoma for both high and normal intraocular pressure. The results indicated that among gene therapy-treated mice, 77% of retinal ganglion cells survived 12 months after the toxic insult compared with 8% in control mice, and six months following optic nerve crush, 77% of retinal ganglion cells had survived versus 7% in controls. The mice treated with CaMKII gene therapy also showed preserved function for visually-guided behavior such as finding a submerged platform, depth perception, and avoiding overhead shadows (simulated predators). Further research in larger animal models is warranted to better characterize the precise role of CaMKII, which might vary depending on different conditions, before starting clinical trials. Nonetheless, as one of the researchers highlights, the fact that gene therapy with CaMKII would involve a one-time transfer of a single gene adds to its vast potential to treat many retinal and optic nerve conditions.

My rating of this study: ⭐⭐⭐

Guo X, Zhou J, Starr C, et al. "Preservation of vision after CaMKII-mediated protection of retinal ganglion cells." Cell.  22 July 2021. https://doi.org/10.1016/j.cell.2021.06.031