Targets for Neuroprotection, Remyelination & Repair
Currently available therapies, as well as those in later stage clinical trials, each modulate the immune system in an attempt to prevent ongoing inflammation in the CNS. The overall goal (and the primary outcome measure used in most of the above clinical trials) is to decrease the number of relapses, which presumably limits the accumulation of damage to the nervous system and therefore disability over time. However, none of these therapies address how injury can be limited or reversed when immunomodulation only partially controls the disease and new lesions continue to develop.
The complex interactions that exist in the cellular environment in and around lesions are currently the subject of intense research. Opportunities that have been identified in this arena include strategies to limit demyelination through oligodendrocyte protection as well as those to promote repair through remyelination.
Remyelination can be robust early on, but fails in many patients as the disease progresses. Remyelination is accomplished not by the existing mature oligodendrocytes involved in the demyelinating event but rather by new oligodendrocytes that differentiate from oligodendrocyte precursor cells (Figure 2). One obstacle to myelin repair seems to be depletion of the pool of oligodendrocyte precursors over time, however, these progenitors have been demonstrated in the vicinity of active and chronic MS lesions. It appears that at times, particularly in later stages of the disease process, the local milieu inhibits differentiation of these cells into mature oligodendrocytes, thus inhibiting the process of remyelination.
(Enlarge Image)
Figure 2.
Remyelination involves a sequence of orchestrated steps, the dysregulation of which will result in remyelination impairment.
In response to a demyelinating insult, the myelinated axons undergo demyelination (1), a process that generates myelin debris. Demyelination causes the activation of resident astrocytes and microglia (2). The activated astrocytes and microglia produce factors that contribute to the recruitment of monocytes from blood vessels (3). Microglia (4a) and recruited monocytes (4b) differentiate into macrophages. Activated astrocytes and macrophages produce factors that activate each other (5a). As a result of this activation, both produce growth factors that act on oligodendrocyte progenitors (5b). Macrophages remove myelin debris (6), a function that may be beneficial to remyelination. Under the influence of factors that are produced by astrocytes and macrophages, recruited oligodendrocyte progenitors engage demyelinated axons (7) and differentiate into remyelinating oligodendrocytes (8).
Reproduced from [72] with permission from Macmillan Publishers Ltd.
There are many targets under investigation to protect existing oligodendrocytes as well as to encourage oligodendrocyte precursor migration and differentiation to promote remyelination; here we discuss a select few.