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  • CRISPR/Cas9 Genome Engineering in Engraftable Human Brain-Derived Neural Stem Cells. iScience Dever, D. P., Scharenberg, S. G., Camarena, J., Kildebeck, E. J., Clark, J. T., Martin, R. M., Bak, R. O., Tang, Y., Dohse, M., Birgmeier, J. A., Jagadeesh, K. A., Bejerano, G., Tsukamoto, A., Gomez-Ospina, N., Uchida, N., Porteus, M. H. 2019; 15: 524–35

    Abstract

    Human neural stem cells (NSCs) offer therapeutic potential for neurodegenerative diseases, such as inherited monogenic nervous system disorders, and neural injuries. Gene editing in NSCs (GE-NSCs) could enhance their therapeutic potential. We show that NSCs are amenable to gene targeting at multiple loci using Cas9 mRNA with synthetic chemically modified guide RNAs along with DNA donor templates. Transplantation of GE-NSC into oligodendrocyte mutant shiverer-immunodeficient mice showed that GE-NSCs migrate and differentiate into astrocytes, neurons, and myelin-producing oligodendrocytes, highlighting the fact that GE-NSCs retain their NSC characteristics of self-renewal and site-specific global migration and differentiation. To show the therapeutic potential of GE-NSCs, we generated GALC lysosomal enzyme overexpressing GE-NSCs that are able to cross-correct GALC enzyme activity through the mannose-6-phosphate receptor pathway. These GE-NSCs have the potential to be an investigational cell and gene therapy for a range of neurodegenerative disorders and injuries of the central nervous system, including lysosomal storage disorders.

    View details for DOI 10.1016/j.isci.2019.04.036

    View details for PubMedID 31132746

  • Genome Edited Human Hematopoietic Stem Cells Correct Lysosomal Storage Disorders: Proof-of-Concept and Safety Studies for Mucopolysaccharidosis Type I and Gaucher Disease Gomez-Ospina, N., Scharenberg, S., Mostrel, N., Raj, N., Attardi, L., Khan, S., Tomatsu, S., Lee, C., Bao, G., Porteus, M. H. CELL PRESS. 2019: 329
  • Human genome-edited hematopoietic stem cells phenotypically correct Mucopolysaccharidosis type I. Nature communications Gomez-Ospina, N., Scharenberg, S. G., Mostrel, N., Bak, R. O., Mantri, S., Quadros, R. M., Gurumurthy, C. B., Lee, C., Bao, G., Suarez, C. J., Khan, S., Sawamoto, K., Tomatsu, S., Raj, N., Attardi, L. D., Aurelian, L., Porteus, M. H. 2019; 10 (1): 4045

    Abstract

    Lysosomal enzyme deficiencies comprise a large group of genetic disorders that generally lack effective treatments. A potential treatment approach is to engineer the patient's own hematopoietic system to express high levels of the deficient enzyme, thereby correcting the biochemical defect and halting disease progression. Here, we present an efficient ex vivo genome editing approach using CRISPR-Cas9 that targets the lysosomal enzyme iduronidase to the CCR5 safe harbor locus in human CD34+ hematopoietic stem and progenitor cells. The modified cells secrete supra-endogenous enzyme levels, maintain long-term repopulation and multi-lineage differentiation potential, and can improve biochemical and phenotypic abnormalities in an immunocompromised mouse model of Mucopolysaccharidosis type I. These studies provide support for the development of genome-edited CD34+ hematopoietic stem and progenitor cells as a potential treatment for Mucopolysaccharidosis type I. The safe harbor approach constitutes a flexible platform for the expression of lysosomal enzymes making it applicable to other lysosomal storage disorders.

    View details for DOI 10.1038/s41467-019-11962-8

    View details for PubMedID 31492863

  • Engineering the Hematopoietic System for Lysosomal Storage Disorders: Correction of Mucopolysaccharidosis Type I Using Genome-Edited, Human Hematopoietic Stem and Progenitor Cells Gomez-Ospina, N., Scharenberg, S., Mostrel, N., Mantri, S., Nicolas, C., Porteus, M. M. CELL PRESS. 2018: 310–11
  • Engineering blood stem cells for autologous transplants for lysosomal diseases: Correction of mucopolysaccharidosis type I using genome-edited hematopoietic stem and progenitor cells Gomez-Ospina, N., Scharenberg, S. G., Mantri, S., Nicolas, C., Bak, R. O., Porteus, M. H. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2018: S54–S55