RAP as a novel therapeutic to promote remyelination after MS demyelinating event

DESCRIPTION provided by applicant Multiple sclerosis MS is a chronic and largely unpredictable disease of the central nervous system CNS characterized by autoimmune activity against the myelin sheath encapsulating CNS neurons which results in death of the myelinating cells known as oligodendrocytes within the lesion site Resultant demyelination or degradation of the myelin sheath is the major contributor to the disability and death caused by this disease Currently approved therapies for MS are aimed at inhibition of the immune response but do not address the need to promote remyelination which is the fundamental step needed to restore functional deficits after MS lesion formation Development of therapeutics that promote remyelination and prevent irreversible consequences leading to neuronal cell death is paramount to improving the quality of life and survival of MS patients The CNS contains oligodendrocyte precursor cells OPCs that have the potential to differentiate into mature oligodendrocytes which would then be capable of remyelination of denuded axons after an MS attack However myelin debris lingering at MS lesion sites inhibits the differentiation of OPCs into mature oligodendrocytes through a process that requires that activation of the small GTPase Rho The lack of functional mature oligodendrocytes and subsequent remyelination exacerbates and perpetuates functional deficits that are the hallmark of MS We have previously demonstrated that the low density lipoprotein receptor related protein LRP is a novel receptor for myelin debris in the CNS We have also shown in multiple cell types and in vivo models that RAP significantly attenuates activation of RhoA More recent studies have demonstrated that genetic deletion of LRP in OPCs promotes remyelination in vivo in rodent models of MS indicating that LRP is a novel facilitator of myelin mediated OPC suppression of differentiation The ability of LRP deletion to enhance OPC differentiation of myelin production combined with the documented capacity of the LRP antagonist RAP to attenuate activation of RhoA indicate that RAP is a novel and exciting therapeutic candidate for enhancement of remyelination after MS lesion As such RAP is an important candidate to bring through pre clinical proof of concept testing as a high value potential therapeutic for restoring myelination and neuronal function after MS attack PUBLIC HEALTH RELEVANCE Disability and death in multiple sclerosis result from neuronal damage that arises from demyelination Oligodendrocyte progenitor cells OPCs have the ability to infiltrate areas of demylination and remyelinate denuded axons thereby preventing neuronal damage and reversing disability but their differentiation into mature myelinating oligodendrocytes is inhibited by debris within the lesion site The goal of this project is to testthe ability of RAP to overcome the suppression of differentiation and restore myelination thereby overcoming the functional deficits that result from neuronal damage and loss