Systemic low-molecular weight drug delivery to pre-selected neuronal regions

Autor: Mayu Suzuki, Paul F. Kenna, Peter Humphries, Oliviero L. Gobbo, G. Jane Farrar, Marian M. Humphries, Lawrence C. S. Tam, Anna-Sophia Kiang, Anh T. H. Nguyen, Matthew Campbell, Ema Ozaki, Finnian Hanrahan
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Retinal degeneration
Pathology
medicine.medical_specialty
genetic structures
Blood–retinal barrier
RNAi/claudin-5
Biology
Pharmacology
Blood–brain barrier
blood–brain barrier
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Retinitis pigmentosa
medicine
Animals
Humans
RNA
Small Interfering
age-related macular degeneration
030304 developmental biology
0303 health sciences
Retinal
Biological Transport
Genetic Therapy
Macular degeneration
medicine.disease
eye diseases
3. Good health
medicine.anatomical_structure
Choroidal neovascularization
chemistry
Gene Expression Regulation
Blood-Brain Barrier
Drug delivery
drug delivery
Molecular Medicine
blood–retina barrier
RNA Interference
sense organs
medicine.symptom
030217 neurology & neurosurgery
Research Article
Zdroj: EMBO Molecular Medicine
ISSN: 1757-4684
1757-4676
Popis: We describe a procedure for controlled, periodic, reversible modulation of selected regions of the blood–brain barrier (BBB) or the inner-blood–retina barrier (iBRB) based on incorporation into an AAV-2/9 vector of a doxycycline-inducible gene encoding shRNA targeting claudin-5, one of 30 or so proteins constituting the BBB and iBRB. The vector may be introduced stereotaxically into pre-selected regions of the brain or into the retina, rendering these regions permeable to low-molecular weight compounds up to approximately 1 kDa for the period of time during which the inducing agent, doxycycline, is administered in drinking water, but excluding potentially toxic higher molecular weight materials. We report on the use of barrier modulation in tandem with systemic drug therapy to prevent retinal degeneration and to suppress laser-induced choroidal neovascularization (CNV), the latter being the hallmark pathology associated with the exudative, or wet, form of age-related macular degeneration (AMD). These observations constitute the basis of a minimally invasive systemic therapeutic modality for retinal diseases, including retinitis pigmentosa and AMD, where, in early stage disease, the iBRB is intact and impervious to systemically administered drugs.
Databáze: OpenAIRE
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