Neural Stem Cell Gene Therapy Ameliorates Pathology and Function in a Mouse Model of Globoid Cell Leukodystrophy

Abstract

Murine neural stem cells (mNSCs), either naive or genetically modified to express supranormal levels of β-galactocerebrosidase (GALC), were transplanted into the brain of Twitcher mice, a murine model of globoid cell leukodystrophy, a severe sphingolipidosis. Cells engrafted long-term into the host cytoarchitecture, producing functional GALC. Levels of enzyme activity in brain and spinal cord tissues were enhanced when GALC-overexpressing NSC were used. Enzymatic correction correlated with reduced tissue storage, decreased activation of astroglia and microglia, delayed onset of symptoms, and longer lifespan. Mechanisms underlying the therapeutic effect of mNSC included widespread enzyme distribution, cross-correction of host cells, anti-inflammatory activity, and neuroprotection. Similar cell engraftment and metabolic correction were reproduced using human NSC. Thus, NSC gene therapy rapidly reconstitutes sustained and long-lasting enzyme activity in central nervous system tissues. Combining this approach with treatments targeting the systemic disease associated with leukodystrophies may provide significant therapeutic benefit. Stem Cells 2011;29:1559–1571

Wnt3a Reestablishes Osteogenic Capacity to Bone Grafts from Aged Animals

“…We then used established protocols 51 to further enrich for bone-marrow stem and/or stromal cells from the attached population. Using immunostaining for CD45(-), CD73(1), CD105(1), and Stro1(1), we confirmed that this population was enriched for marrow-derived stem cells 55,56 ( Fig. 4-G).…”

Extended Normal Life After AAVrh10-mediated Gene Therapy in the Mouse Model of Krabbe Disease

“…They become hunchbacked by 30 days and die usually around 40 days of age. 7 Treatment trials in twi mice include bone marrow transplantation (BMT), 9,10 stem cell transplantation, [11][12][13][14] in vivo and ex vivo gene therapies, [15][16][17][18][19][20][21] substrate reduction therapy, 22 enzyme replacement therapy, 23 and small molecule therapy. [24][25][26] BMT has been so far the most effective therapeutic strategy in the treatment of twi mice.…”

Part I: Minicircle vector technology limits DNA size restrictions on ex vivo gene delivery using nanoparticle vectors: Overcoming a translational barrier in neural stem cell therapy

“…Several preclinical models of CNS pathology have demonstrated the utility of genetically engineered NSCs for improving functional neurological outcomes [12][13][14][15][16]. Recent data prove that transplantation of NSCs engineered to release insulin-like growth factor (IGF-1) reduced plaque pathology and enhanced learning, cognitive and memory processes in a mouse model…”