Autoimmune disease like MS present with a loss of tolerance against endogenous proteins. Regulatory T cells (Tregs) maintain homeostasis between immune activation and suppression; however, in MS the mechanisms dependent on thymically produced Treg cells appear insufficient to prevent the initial priming of encephalitogenic T cells. Using an animal model of MS (experimental autoimmune encephalomyelitis (EAE)), we have shown that neuroinflammation and clinical symptoms can be prevented or even completely ameliorated by extrathymically induced antigen specific Tregs following tolerogenic gene immunotherapy. Historically, antigen specific therapies have remained elusive due to the myriad of known and unknown encephalitogenic epitopes present in patients due to differing HLA/MHC backgrounds. Developing a treatment capable of overcoming these hurdles may provide the most effective option for patients suffering from MS.
Demonstrate the efficacy and dynamic ability of a novel Adeno-Associated Virus (AAV) gene immunotherapy to not only prevent disease onset, but to also ameliorate 'reverse' preexisting demyelinating EAE disease: 1) induced with various immunodominant and non-dominant encephalogenic myelin oligodendrocyte glycoprotein (MOG) antigens and, 2) do so in multiple strains of mice that have different HLA/MHC genetic backgrounds. Overall, validating the ability of the vector to be an effective therapy without prior knowledge of antigens or genetic background.
Demyelinating EAE disease was induced in genetically diverse mice (C57BL/6, H2b; DBA/1, H2q; SJL/J, H2s) using combinations of immunogenic epitopes (MOG35-55, MOG79-96, MOG92-106, or MOG1-125) emulsified in adjuvant. For Prevention, mice were given a single dose of a hepatocyte directed AAV vector expressing MOG that induces antigen specific Tregs and restore immune tolerance or control vector, 2-weeks prior to inducing EAE. For Reversal of preexisting disease, the therapeutic vector was given after disease onset as mice reached various predetermined levels of disease severity. Mice were monitored daily for changes in clinical score.
For Prevention: Mice receiving the therapeutic vector showed no signs of disease onset, cellular infiltration or demyelination within the spinal cord. In contrast, controls developed inflammation and severe demyelinating EAE. For Reversal: Treated mice had lower disease peaks and a significant reduction in neurological impairment (clinical score returned to near baseline) with virtually no cellular infiltration or demyelination, compared to controls.
We have developed and demonstrated efficacy of a powerful AAV gene immunotherapy capable of dynamically adjusting to the unique antigen requirements needed to restore tolerance and independent of genetic background. This gene immunotherapy has the potential to be a paradigm shifting treatment options for MS.