Alida Chen and Fred de Winter

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS, clinically characterized by intermittent attacks (relapses) and a subsequent progressive increase in neurological disability. Although current MS treatments can prevent relapses and delay disability in some patients, regenerative therapies remain a major unmet medical need in MS.

The project ‘Development of a regenerative gene therapy for Multiple Sclerosis’’ aimed to identify targets that promote remyelination in tissue of the well characterized MS autopsy cohort of the Netherlands Brain Bank, and to test these targets functionally using viral vector technology.

We generated a transcriptomics data of remyelinating lesions of MS brain donors that were efficient in remyelination. In this data set potential pro-remyelinating targets were identified by bioinformatic analyses and in situ validation. In parallel, viral vector capsids that efficiently cross the blood brain barrier were characterized in healthy animals and in a model for MS, experimental allergic encephalomyelitis (EAE). Also, promotors targeting transgene expression to specific CNS cell types were developed. These viral vectors were used to evaluate identified potential remyelinating targets functionally in vitro in brain slice cultures and in vivo in the EAE model. Here we present initial results of minimally-invasive TGFbeta2-gene therapy in EAE. When TGFbeta2 is expressed in neurons, we observed a transient improvement in neurological scores which is likely attributable to reduced demyelination and attenuated microglia activation. Targeting TGFbeta2 expression to astrocytes instead leads to vascular leakage, as indicated by enhanced fibrinogen deposition, and activation of microglia. These findings suggest that the therapeutic efficacy of TGFbeta2-gene therapy in EAE is dependent on the specific cell population engineered to express this cytokine.

The project is financed by the Start 2 Cure foundation and is a collaboration between the Neuroimmunology group of Huitinga and Neuroregeneration group of Verhaagen that combine their expertise in MS pathology and viral vector technology.