Gene Therapy in the Central Nervous System

Suhr, Steven T.; Gage, Fred H.

doi:10.1001/archneur.56.3.287

Cited by 20 publications

(1 citation statement)

References 10 publications

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“…Delivery of these proteins is hampered by the tight regulation of the BBB. Current protocols for delivery of viral vector-mediated gene delivery involve the stereotaxic injection of the vector to the CNS, resulting only in localized gene expression (2). The small size of the mouse may allow more widespread expression with as few as five injections across the whole brain; however, the larger size of the human brain would require far too many injections to be clinically feasible.…”

mentioning

confidence: 99%

Targeted delivery of proteins across the blood–brain barrier

Spencer

Verma

2007

Proc. Natl. Acad. Sci. U.S.A.

213

162

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Treatment of many neuronal degenerative disorders will require delivery of a therapeutic protein to neurons or glial cells across the whole CNS. The presence of the blood-brain barrier hampers the delivery of these proteins from the blood, thus necessitating a new method for delivery. Receptors on the blood-brain barrier bind ligands to facilitate their transport to the CNS; therefore, we hypothesized that by targeting these receptors, we may be able to deliver proteins to the CNS for therapy. Here, we report the use of the lentivirus vector system to deliver the lysosomal enzyme glucocerebrosidase and a secreted form of GFP to the neurons and astrocytes in the CNS. We fused the low-density lipoprotein receptor-binding domain of the apolipoprotein B to the targeted protein. This approach proved to be feasible for delivery of the protein and could possibly be used as a general method for delivery of therapeutic proteins to the CNS. fusion protein ͉ lentiviral vectors ͉ low-density lipoprotein receptor

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mentioning

confidence: 99%

Targeted delivery of proteins across the blood–brain barrier

Spencer

Verma

2007

Proc. Natl. Acad. Sci. U.S.A.

213

162

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New Molecular Strategies to Cure Brain Tumors

Fathallah‐Shaykh

1999

Arch Neurol

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Overall, malignant primary and metastatic brain tumors remain as lethal in the 1990s as they were in the 1970s. Just as the introduction of radiation therapy 2 decades ago added several months to survival time, numerous chemotherapeutic trials have demonstrated only limited efficacy. Fortunately, recent discoveries in molecular medicine have not only revolutionized our understanding of the events that lead to tumorigenesis, but they have created novel tools for targeting malignant cells. Novel treatment modalities are now being tested in pre-phase I animal models, while others are in different stages of clinical trials. The purpose of this review is to briefly summarize the emerging strategies of gene therapy, antiangiogenesis, immunotherapy, and targeting tumor cells.

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Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease

et al. 2000

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With the ultimate goal of developing safe and effective in vivo gene therapy for the treatment of Canavan disease and other neurological disorders, we developed a non–viral lipid‐entrapped, polycation‐condensed delivery system (LPD) for central nervous system gene transfer, in conjunction with adeno‐associated virus (AAV)–based plasmids containing recombinant aspartoacylase (ASPA). The gene delivery system was tested in healthy rodents and primates, before proceeding to preliminary studies in 2 children with Canavan disease. Toxicity and expression testing was first carried out in human 293 cells, which demonstrated effective transduction of cells and high levels of functional ASPA activity. We performed in vivo toxicity and expression testing of LPD/pAAVaspa and LPD/pAAVlac in rodents, which demonstrated widespread gene expression for more than 10 months after intraventricular delivery, and local expression in deep brain nuclei and white matter tracts for more than 6 months after intraparenchymal injections, with no significant adverse effects. We also performed intraventricular delivery of LPD/pAAVaspa to 2 cynomologous monkeys, with 2 additional monkeys receiving LPD and saline controls. None of the monkeys demonstrated significant adverse effects, and at 1 month the 2 LPD/pAAVaspa monkeys were positive for human ASPA transcript by reverse transcriptase polymerase chain reaction of brain tissue punches. Finally, we performed the first in vivo gene transfer study for a human neurodegenerative disease in 2 children with Canavan disease to assess the in vivo toxicity and efficacy of ASPA gene delivery. Our results suggest that LPD/pAAVaspa is well tolerated in human subjects and is associated with biochemical, radiological, and clinical changes. Ann Neurol 2000;48:27–38

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Gene Therapy in the Central Nervous System

Cited by 20 publications

References 10 publications

Targeted delivery of proteins across the blood–brain barrier

Targeted delivery of proteins across the blood–brain barrier

New Molecular Strategies to Cure Brain Tumors

Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease

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