Some experimental therapies have been reported recently for treatment of autoimmune ON, including corticosteroid therapy, which suppresses ON and prevents RGC loss if treatment is initiated before onset of optic nerve inflammation, but is less effective after inflammation has begun.
26 The Bowman-Birk inhibitor (BBI), a soybean-derived serine protease inhibitor, significantly reduces the incidence of ON and prevents loss of RGCs.
27 Intraocular delivery of antioxidant genes such as superoxide dismutase or catalase cloned into recombinant AAV provides a long-lasting suppression and showed a decreased RGC loss by 29%, optic nerve demyelination by 36%, axonal loss by 44%, and cellular infiltration by 34%, compared with the control eye with ON at 6 months PI.
28 Lipoic acid, also an antioxidant, reduces inflammation and protected axonal injury when delivered on day 8 or 13 PI in the C57BL/6 EAE model.
29 RTL molecules are new biologics that consist of the membrane distal α1 and β1 domains of class II MHC molecules and contain covalently linked antigenic peptides,
15,18,30 including the MOG
35-55 peptide. By inhibiting autoreactive T-cell responses, RTLs have been shown to suppress clinical and histologic signs in various experimental autoimmune disease models, including uveitis,
31,32 encephalomyelitis (EAE), arthritis,
33 and stroke.
16 The application of RTL342M is a new therapy for ON in humanized mice. Our studies demonstrated that RTL342M had a therapeutic effect on both ON and EAE, and its treatment led to the suppression of inflammatory responses, myelin recovery, and some axonal protection. A recent study of human ON suggested that all optic nerve inflammatory lesions tend to remyelinate regardless of the size of the initially demyelinated zone.
34 This study showed that smaller lesions get more complete remyelination than larger lesions, and the extent of the initial inflammatory demyelinating assault was probably the single most important factor determining success of remyelination. Moreover, the first 5 to 6 months after the demyelinating event may be crucial for the remyelinating process to succeed.
34 Therefore, by suppressing acute inflammation in the optic nerve, RTL therapy could be regarded as a remyelination-enhancing therapy that could accelerate myelin recovery in the CNS if applied almost immediately after onset. Recent animal studies using SJL/J mice with established EAE could support this notion. A successful treatment with a different myelin-specific RTL401 (I-A
s/PLP
139-151 peptide) after the peak of EAE markedly reduces inflammation in the CNS associated with an increase in remyelinating axons and the presence of small, presumably regenerative axonal sprouts.
35 These findings indicate that RTL therapy targeting pathogenic T cells may promote CNS neuroregenerative processes, and these findings may also have implications for clinical trials.