Functional correction of established central nervous system deficits in an animal model of lysosomal storage disease with feline immunodeficiency virus-based vectors

Abstract

Gene transfer vectors based on lentiviruses can transduce terminally differentiated cells in the brain; however, their ability to reverse established behavioral deficits in animal models of neurodegeneration has not previously been tested. When recombinant feline immunodeficiency virus (FIV)-based vectors expressing ␤-glucuronidase were unilaterally injected into the striatum of adult ␤-glucuronidase deficient [mucopolysaccharidosis type VII (MPS VII)] mice, an animal model of lysosomal storage disease, there was bihemispheric correction of the characteristic cellular pathology. Moreover, after the injection of FIV-based vectors expressing ␤-glucuronidase into brains of ␤-glucuronidase-deficient mice with established impairments in spatial learning and memory, there was dramatic recovery of behavioral function. Cognitive improvement resulting from expression of ␤-glucuronidase was associated with alteration in expression of genes associated with neuronal plasticity. These data suggest that enzyme replacement to the MPS VII central nervous system goes beyond restoration of ␤-glucuronidase activity in the lysosome, and imparts improvements in plasticity and spatial learning.

Adeno-associated virus vector-mediated transduction in the cat brain

“…Although this can be achieved under certain circumstances in the mouse brain, it is a much more difficult problem in a large brain. [3][4][5][6][7][8][9] The brain of a child in the first year of life, when disease diagnosis is most likely and treatment is expected to be most effective, is 1000-2000 times larger than the mouse brain. To provide a foundation for initiating human gene therapy trials, gene transfer to large regions of the brain will need to be demonstrated in a large animal model.…”

FIV: from lentivirus to lentivector

“…Exceptional results in the central nervous system have been obtained [47]. Although controlled infectivity and efficacy comparisons on a per particle basis have been lacking, in several systems, FIV vectors have produced excellent levels of gene transfer and expression in cultured human organs [45,55,56].…”

“…FIV vectors have been used to target cells in the brain, eye, airway, hematopoietic system, liver, muscle and pancreas [8,15,16,19,[45][46][47][48][49][50][51][52][53][54][55][56][57]. Exceptional results in the central nervous system have been obtained [47].…”

Low-Affinity Neurotrophin Receptor p75 Promotes the Transduction of Targeted Lentiviral Vectors to Cholinergic Neurons of Rat Basal Forebrain

“…Low inflammatory and immunogenic characteristics along with minimal toxicity and superior infectivity for terminally differentiated cells render lentiviral vectors especially suitable for delivery of genes into neurons, while their intrinsic capability of integrating transgenes into the genome of host cells with minimal risks for the activation of protooncogenes ensures long-term expression of the genes of interest-a critical condition for treatment of chronic conditions such as AD [3,58]. Despite the fact that lentiviruses belong to the superfamily of enveloped virions (which include a variety of retroviruses, alphavirus, and herpes simplex virus, with superb intra-axonal mobility) characterized by a long transduction range, the VSV-G pseudotyped vectors used in the present study were shown to exhibit limited intra-axonal mobility [59,60]. The latter is in agreement with scant labeling of ependymal cells and few scattered GFP-positive cells of the lateral septum and caudate nucleus after intraventricular injection of GFP-encoding lentiviral vectors.…”