1. A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice.

    Nature Biotechnology 34(3):334 (2016) PMID 26829317 PMCID PMC4786489

    Many genetic liver diseases in newborns cause repeated, often lethal, metabolic crises. Gene therapy using nonintegrating viruses such as adeno-associated virus (AAV) is not optimal in this setting because the nonintegrating genome is lost as developing hepatocytes proliferate. We reasoned that ...
  2. Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII.

    Molecular Therapy 24(2):206 (2016) PMID 26447927 PMCID PMC4817811

    Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease arising from mutations in β-d-glucuronidase (GUSB), which results in glycosaminoglycan (GAG) accumulation and a variety of clinical manifestations including neurological disease. Herein, MPS VII dogs were injected intravenously (...
  3. Comparative Study of Liver Gene Transfer With AAV Vectors Based on Natural and Engineered AAV Capsids.

    Molecular Therapy 23(12):1877 (2015) PMID 26412589 PMCID PMC4700115

    Vectors based on the clade E family member adeno-associated virus (AAV) serotype 8 have shown promise in patients with hemophilia B and have emerged as best in class for human liver gene therapies. We conducted a thorough evaluation of liver-directed gene therapy using vectors based on several n...
  4. Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS I Dogs and Nonhuman Primates.

    Molecular Therapy 23(8):1298 (2015) PMID 26022732 PMCID PMC4817868

    The potential host immune response to a nonself protein poses a fundamental challenge for gene therapies targeting recessive diseases. We demonstrate in both dogs and nonhuman primates that liver-directed gene transfer using an adeno-associated virus (AAV) vector in neonates induces a persistent...
  5. Motor neuron transduction after intracisternal delivery of AAV9 in a cynomolgus macaque.

    HUMAN GENE THERAPY, Part B: Methods 26(2):43 (2015) PMID 25885277

    The image shows a section of the lumbar spinal cord from a cynomolgus macaque that had received AAV9.CB.EGFP via the cisterna magna. Expression of GFP in multiple motor neurons is visible. Injection into the cerebrospinal fluid has been shown to be an effective route of vector administration for...
  6. Intrathecal injection of lentiviral vector results in high expression in the brain of mucopolysaccharidosis VII dogs but the pattern of expression is different than for AAV9 or AAV-rh10

    Molecular Genetics and Metabolism 114(2):S95 (2015)

  7. Adeno-associated virus vector-mediated gene therapy can effectively treat CNS and cardiac lesions and induce immune tolerance to the therapeutic enzyme in large animal models of mucopolysaccharidosis type I

    Molecular Genetics and Metabolism 114(2):S126 (2015)

  8. Evaluating the impact of systemic AAV9.cIDUA administration on brain pathology in MPS I dogs

    Molecular Genetics and Metabolism 114(2):S20 (2015)

  9. Development and rescue of human familial hypercholesterolaemia in a xenograft mouse model.

    Nature Communications 6:7339 (2015) PMID 26081744 PMCID PMC4557302

    Diseases of lipid metabolism are a major cause of human morbidity, but no animal model entirely recapitulates human lipoprotein metabolism. Here we develop a xenograft mouse model using hepatocytes from a patient with familial hypercholesterolaemia caused by loss-of-function mutations in the low...
  10. Intrathecal gene therapy corrects CNS pathology in a feline model of mucopolysaccharidosis I.

    Molecular Therapy 22(12):2018 (2014) PMID 25027660 PMCID PMC4429692

    Enzyme replacement therapy has revolutionized the treatment of the somatic manifestations of lysosomal storage diseases (LSD), although it has been ineffective in treating central nervous system (CNS) manifestations of these disorders. The development of neurotrophic vectors based on novel serot...
  11. Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I.

    PNAS 111(41):14894 (2014) PMID 25267637 PMCID PMC4205647

    Patients with mucopolysaccharidosis type I (MPS I), a genetic deficiency of the lysosomal enzyme α-l-iduronidase (IDUA), exhibit accumulation of glycosaminoglycans in tissues, with resulting diverse clinical manifestations including neurological, ocular, skeletal, and cardiac disease. MPS I is c...
  12. Professional regulation: a potentially valuable tool in responding to "stem cell tourism".

    Stem cell reports 3(3):379 (2014) PMID 25241736 PMCID PMC4266009

    The growing international market for unproven stem cell-based interventions advertised on a direct-to-consumer basis over the internet ("stem cell tourism") is a source of concern because of the risks it presents to patients as well as their supporters, domestic health care systems, and the stem...
  13. Formation of newly synthesized adeno-associated virus capsids in the cell nucleus.

    HUMAN GENE THERAPY, Part B: Methods 25(3):179 (2014) PMID 24933465

    Adeno-associated virus (AAV) particles inside the nucleus of a HEK 293 cell are shown by electron microscopy. Cells have been triple-transfected for vector production and were analyzed for capsid formation three days later. Newly assembled particle are visible as seemingly unstructured conglomer...
  14. The Effects of Symptoms and Medication on Working Memory in Parkinsonism

    Neurobiology of Aging 35(3):716 (2014)

  15. Gene therapy for mucopolysaccharidosis VII: evaluation of intrathecal rAAV vectors in the canine model

    Molecular Genetics and Metabolism 111(2):S51 (2014)

  16. Widespread gene transfer in the central nervous system of cynomolgus macaques following delivery of AAV9 into the cisterna magna.

    Molecular therapy. Methods & clinical development 1:14051 (2014) PMID 26052519 PMCID PMC4448732

    Adeno-associated virus serotype 9 (AAV9) vectors have recently been shown to transduce cells throughout the central nervous system of nonhuman primates when injected into the cerebrospinal fluid (CSF), a finding which could lead to a minimally invasive approach to treat genetic and acquired dise...
  17. AAV8 induces tolerance in murine muscle as a result of poor APC transduction, T cell exhaustion, and minimal MHCI upregulation on target cells.

    Molecular Therapy 22(1):28 (2014) PMID 23778424 PMCID PMC3978810

    Following gene transfer of adeno-associated virus 2/8 (AAV2/8) to the muscle, C57BL/6 mice show long-term expression of a nuclear-targeted LacZ (nLacZ) transgene with minimal immune activation. Here, we show that pre-exposure to AAV2/8 can also induce tolerance to the more immunogenic AAV2/rh32....
  18. Intramuscular injection of AAV8 in mice and macaques is associated with substantial hepatic targeting and transgene expression.

    PLoS ONE 9(11):e112268 (2014) PMID 25393537 PMCID PMC4230988

    Intramuscular (IM) administration of adeno-associated viral (AAV) vectors has entered the early stages of clinical development with some success, including the first approved gene therapy product in the West called Glybera. In preparation for broader clinical development of IM AAV vector gene th...
  19. Biodistribution of AAV8 vectors expressing human low-density lipoprotein receptor in a mouse model of homozygous familial hypercholesterolemia.

    Human Gene Therapy Clinical Development 24(4):154 (2013) PMID 24070336 PMCID PMC4003465

    Recombinant adeno-associated viral vectors based on serotype 8 (AAV8) transduce liver with superior tropism following intravenous (IV) administration. Previous studies conducted by our lab demonstrated that AAV8-mediated transfer of the human low-density lipoprotein receptor (LDLR) gene driven b...
  20. The role of apoptosis in immune hyporesponsiveness following AAV8 liver gene transfer.

    Molecular Therapy 21(12):2227 (2013) PMID 24126962 PMCID PMC3863804

    Gene therapy provides a significant opportunity to treat a variety of inherited and acquired diseases. However, adverse immune responses toward the adeno-associated virus (AAV) antigens may limit its success. The mechanisms responsible for immunity or tolerance toward AAV-encoded transgene produ...