Remyelination Induced by a DNA Aptamer in a Mouse Model of Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a debilitating inflammatory disease of the central nervous system (CNS) characterized by local destruction of the insulating myelin surrounding neuronal axons. With more than 200 million MS patients worldwide, the absence of treatments that prevent progression or induce repair poses a major challenge. Anti-inflammatory therapies have met with limited success only in preventing relapses. Previous screening of human serum samples revealed natural IgM antibodies that bind oligodendrocytes and promote both cell signaling and remyelination of CNS lesions in an MS model involving chronic infection of susceptible mice by Theiler’s encephalomyelitis virus and in the lysolecithin model of focal demyelination. This intriguing result raises the possibility that molecules with binding specificity for oligodendrocytes or myelin components may promote therapeutic remyelination in MS. Because of the size and complexity of IgM antibodies, it is of interest to identify smaller myelin-specific molecules with the ability to promote remyelination in vivo. Here we show that a 40-nucleotide single-stranded DNA aptamer selected for affinity to murine myelin shows this property. This aptamer binds multiple myelin components in vitro. Peritoneal injection of this aptamer results in distribution to CNS tissues and promotes remyelination of CNS lesions in mice infected by Theiler’s virus. Interestingly, the selected DNA aptamer contains guanosine-rich sequences predicted to induce folding involving guanosine quartet structures. Relative to monoclonal antibodies, DNA aptamers are small, stable, and non-immunogenic, suggesting new possibilities for MS treatment.

Aptamer Oligonucleotides: Novel Potential Therapeutic Agents in Autoimmune Disease

“…Remyelination of CNS lesions was observed in the TMEVinfected JL/J mice after intraperitoneal (i.p.) injection of LJM-3064b (3¢ biotin-conjugated aptamer combined with streptavidin) [33]. Interestingly, this result is consistent with the report that immunoglobulins targeting MBP isoforms can stimulate remyelination [34].…”

Aptamers as Promising Molecular Recognition Elements for Diagnostics and Therapeutics in the Central Nervous System

“…Multiple sclerosis (MS) is an inflammatory neurological demyelinating disease characterized by loss of neuronal axon-insulating myelin [57]. This deficit leads to gait, cognitive, and vision impairments as well as fatigue.…”

“…The first aptamer investigated as a treatment modality for MS was selected to bind interleukin (IL)-23, a protein shown to be elevated in patients with MS [58]. More recently, Nastasijevic et al were successful in selecting a DNA aptamer that binds to myelin and promotes remyelination in a mouse model of MS [57]. Briefly, Theiler's encephalomyelitis virus (TMEV)-infected SJL/J mice were given 3¢-biotinaptamer conjugate injections biweekly for 5 weeks.…”

“…TMEVinfected mice exhibit MS-like lesions. Spinal cords from TMEV-infected mice treated with aptamer showed significantly more remyelination than controls (35% vs. 4%-9% respectively) [57]. Current methods to diagnosis MS require multiple tests and are time consuming.…”

Depletion of Olig2 in oligodendrocyte progenitor cells infected by Theiler’s murine encephalomyelitis virus

“…However, other mechanisms have been postulated. Remyelination can be improved by myelin-binding antibodies and a DNA aptamer through undefined mechanisms (Nastasijevic et al 2012;Pirko et al 2004;Warrington et al 2007). Additionally, remyelination improves following depletion of CD8+ T cells, suggesting that the adaptive immune response contributes to TMEV-IDD during the chronic phases of infection (Denic et al 2014;Rodriguez and Lindsley 1992).…”