We propose studies that will allow for new pioneering gene editing approaches for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. As orphan disease ALSP is in desperate need for treatment options. This disease strikes individuals in the prime of their life and families live with uncertainty as to the fate of their children who also carry the genetic burden. Beyond allogeneic bone marrow transplantation there are currently no treatment modalities available, and the procedure carries high mortality and complication rate. A simple gene addition approach, like viral mediated gene therapy, is also not possible due to the oncogenic potential of overexpression of CSF1R. In addition to new gene editing approaches, we also introduce a new humanized mouse model that allows us to assess engraftment of bone marrow cells. This carries wider relevance for the field of leukodystrophies.