Disclosed are methods of treating lysosomal storage diseases, including Globoid Cell Leukodystrophy (GSD). GSD is refractory to standard treatments, where even more invasive treatments only provide minor benefits. However, combinations of three treatments can interact synergistically to provide marked extension of life-span and increases in neuronal function. A combination of a primary treatment such as a gene therapy or an enzyme replacement therapy and at least two secondary therapies such as a substrate reduction therapy and an immunomodulation treatment can lead to increased average life expectancy compared to any individual treatment or pair of treatments.
