We recently developed a gene immunotherapy that reverses paralysis in a murine model of MS. However, the efficacy has only been established in the primary progressive disease model. Whereas, proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) in SJL mice is an animal model that resembles human disease with an initial relapsing- remitting (RR) disease phase followed by a secondary progressive stage. Given that ~85% of MS patients are diagnosed with RRMS, demonstrating the therapeutic efficacy in models that better resemble clinical disease an essential step toward a cure.
Demonstrate the therapeutic potential of Adeno-Associated Virus (AAV) gene immunotherapy to prevent and/or reverse disease in multiple models of RRMS. Additionally, to show that this novel immunotherapy is also effective at abrogating epitope spreading in preexisting disease.
A single hepatocyte directed AAV vector expressing mouse PLP was engineered to induce/restore antigen-specific tolerance to multiple antigenic PLP epitopes. EAE was induced in SJL (H-2s) and C57BL (H-2b) mice using PLP139-151 or PLP178‑191 in adjuvant. For prevention of RR-disease, a single dose of therapeutic (or Null control) vector was given >7 days prior to EAE induction. For therapeutic reversal of pre-existing disease, immunotherapy treatment was administered after the first appearance of symptoms (early reversal) or during the first remission (late reversal). To demonstrate control of epitope spreading, PLP178‑191 was used to induced disease in SJL mice.
For prevention of RR disease: therapeutic vector completely blocked clinical disease, cellular infiltration, and demyelination in PLP139-151 immunized SJL and C57BL/6 mice. For reversal RR disease: by day 30 of RR-EAE, AAV.PLP gene immunotherapy abrogated disease, reduced cellular infiltration, and suppressed demyelination, in both early and late treated mice. To evaluate efficacy against epitope spreading, cohorts of SJL mice were immunized with PLP178-191, an de novo epitope known to be revealed after induction with PLP139-151. AAV.PLP completely resolved disease in >90% of treated mice, rapidly after an initial but mild onset. In contrast, 100% of the control mice relapsed after the initial remission phase.
For the first time we provide definitive evidence that AAV directed gene immunotherapy efficiently prevents the development of disease as well as abrogates pre-existing disease and relapses in genetically different murine models of RRMS. The data further supports that treatment dynamically adjusts to protect against epitope spreading. Clinical translation of this novel gene immunotherapy could result in therapy that could effectively prevent or minimize the early inflammatory responses associated with MS, thus stopping the transition into secondary progressive MS and significantly improving the quality of life for MS patients.