Superoxide dismutase 1 target therapeutics(Thera Neuropharma, Inc.)

As one of the most devastating forms of trauma, spinal cord injury (SCI) remains a challenging clinical problem. The secondary processes associated with the primary injury, such as overproduction of reactive oxygen species (ROS) and inflammation, lead to concomitant compression of the injured spinal cord and neuronal death. Delivery of copper-zinc superoxide dismutase (SOD1), an efficient ROS scavenger, to the site of injury can mitigate SCI-induced oxidative stress and tissue damage. Towards this goal catalytically active nanoformulations of SOD1 ("nanozymes") are developed as a modality for treatment of SCI. Along with the cross-linked polyion complex of SOD1 with polycation poly(ethylene glycol) (PEG)-polylysine (single-coat (SC) nanozyme), we introduce for the first time the chemically cross-linked multilayer polyion complex in which SOD1 is first incorporated into a polyion complex with polycation, then coated by anionic block copolymer, PEG-polyglutamic acid (double-coat (DC) nanozyme). We developed DC nanozymes with high enzymatic activity and ability to retain and protect SOD1 under physiological conditions. Pharmacokinetic study revealed that DC nanozymes significantly prolonged circulation of active SOD1 in the blood stream compared to free SOD1 or SC nanozymes (half-life was 60 vs 6min). Single intravenous injection of DC nanozymes (5kU of SOD1/kg) improved the recovery of locomotor functions in rats with moderate SCI, along with reduction of swelling, concomitant compression of the spinal cord and formation of post-traumatic cysts. Thus, based on the testing in a rodent model the SOD1 DC nanozymes are promising modality for scavenging ROS, decreasing inflammation and edema, and improving recovery after SCI.

Use of antioxidants to mitigate oxidative stress during ocular inflammatory diseases has shown therapeutic potential. This work examines a nanoscale therapeutic modality for the eye on the base of antioxidant enzyme, superoxide dismutase 1 (SOD1), termed “nanozyme.” The nanozyme is produced by electrostatic coupling of the SOD1 with a cationic block copolymer, poly(L‐lysine)‐poly(ethyleneglycol), followed by covalent cross‐linking of the complexes with 3,3′‐dithiobis(sulfosuccinimidylpropionate) sodium salt. The ability of SOD1 nanozyme as well as the native SOD1 to reduce inflammatory processes in the eye was examined in vivo in rabbits with immunogenic uveitis. Results suggested that topical instillations of both enzyme forms demonstrated anti‐inflammatory activity; however, the nanozyme was much more effective compared to the free enzyme in decreasing uveitis manifestations. In particular, we noted statistically significant differences in such inflammatory signs in the eye as the intensities of corneal and iris edema, hyperemia of conjunctiva, lens opacity, fibrin clots, and the protein content in aqueous humor. Clinical findings were confirmed by histological data. Thus, SOD1‐containing nanozyme is potentially useful therapeutic agent for the treatment of ocular inflammatory disorders.