Systemic low‐molecular weight drug delivery to pre‐selected neuronal regions
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Injection of AAV-shRNA-cldn5 enhances passive diffusion of Gd-DTPA from the blood into the brain.
“injection of AAV-shRNA-cldn5 enhances passive diffusion of Gd-DTPA from the blood into the brain33”
From Social stress induces neurovascular pathology promoting depression (2017) · cites this paper as [33]
The Results section (“Systemic and stereotaxic injection of CLDN5 AAV-2/9”) reports enhanced passive diffusion of Gd-DTPA from blood to brain after injection in mice. However, the effect was induced with doxycycline; the paper says no barrier permeability was observed after doxycycline was removed, a necessary condition omitted from the claim. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
Foust, K. D., Wang, X., McGovern, V. L., Braun, L., Bevan, A. K., Haidet, A. M., Le, T. T., Morales, P. R., Rich, M. M., Burghes, A. H. M., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1610 · Cited by 688 · see citing works
RetractedSafety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis
Maguire, A. M., Simonelli, F., Pierce, E. A., Pugh, E. N., Mingozzi, F., Bennicelli, J., Banfi, S., Marshall, K. A., Testa, F., Surace, E. M., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0802315 · Cited by 2,145 · see citing works
Effect of gene therapy on visual function in Leber’s congenital amaurosis
Bainbridge, J. W. B., Smith, A. J., Barker, S. S., Robbie, S., Henderson, R., Balaggan, K., Viswanathan, A., Holder, G. E., Stockman, A., Tyler, N., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0802268 · Cited by 1,924 · see citing works
Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes
Foust, K. D., Nurre, E., Montgomery, C. L., Hernandez, A., Chan, C. M., & Kaspar, B. K. (2009) · Nature Biotechnology · doi:10.1038/nbt.1515 · Cited by 1,456 · see citing works
Age-related macular degeneration
de Jong, P. T. V. M. (2006) · New England Journal of Medicine · doi:10.1056/nejmra062326 · Cited by 787 · see citing works
Stieger, K., Le Meur, G., Lasne, F., Weber, M., Deschamps, J.-Y., Nivard, D., Mendes-Madeira, A., Provost, N., Martin, L., Moullier, P., et al. (2006) · Molecular Therapy · doi:10.1016/j.ymthe.2005.12.001 · Cited by 110 · see citing works
Flagged first, then by citations
Research works printed but not linked: 25
- Abdollahi M Shafiee A Bathaiee FS Sharifzadeh M Nikfar S Drug-induced toxic reactions in the eye: an overview J Infus Nurs 2004 27 386 398 15586102
- Campbell M Kiang AS Kenna PF Kerskens C Blau C O'Dwyer L Tivnan A Kelly JA Brankin B Farrar GJ RNAi-mediated reversible opening of the blood–brain barrier J Gene Med 2008 10 930 947 18509865
- Campbell M Nguyen AT Kiang AS Tam LC Gobbo OL Kerskens C Ni Dhubhghaill S Humphries MM Farrar GJ Kenna PF An experimental platform for systemic drug delivery to the retina Proc Natl Acad Sci USA 2009 106 17817 17822 19822744 PMC2760489
- Chadderton N Millington-Ward S Palfi A O'Reilly M Tuohy G Humphries MM Li T Humphries P Kenna PF Farrar GJ Improved retinal function in a mouse model of dominant retinitis pigmentosa following AAV-delivered gene therapy Mol Ther 2009 17 593 599 19174761 PMC2835099
- Giannini C Sarkaria JN Saito A Uhm JH Galanis E Carlson BL Schroeder MA James CD Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme Neuro Oncol 2005 7 164 176 15831234 PMC1871885
- Hauswirth WW Aleman TS Kaushal S Cideciyan AV Schwartz SB Wang L Conlon TJ Boye SL Flotte TR Byrne BJ Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial Hum Gene Ther 2008 19 979 990 18774912 PMC2940541
- Helmy A Vizcaychipi M Gupta AK Traumatic brain injury: intensive care management Br J Anaesth 2007 99 32 42 17556349
- Kane J Honigfeld G Singer J Meltzer H Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine Arch Gen Psychiatry 1988 45 789 796 3046553
- Motzer RJ Hutson TE Tomczak P Michaelson MD Bukowski RM Rixe O Oudard S Negrier S Szczylik C Kim ST Sunitinib versus interferon alfa in metastatic renal-cell carcinoma N Engl J Med 2007 356 115 124 17215529
- Muldoon LL Nilaver G Kroll RA Pagel MA Breakefield XO Chiocca EA Davidson BL Weissleder R Neuwelt EA Comparison of intracerebral inoculation and osmotic blood–brain barrier disruption for delivery of adenovirus, herpesvirus, and iron oxide particles to normal rat brain Am J Pathol 1995 147 1840 1851 7495307 PMC1869962
- Neuwelt EA Howieson J Frenkel EP Specht HD Weigel R Buchan CG Hill SA Therapeutic efficacy of multiagent chemotherapy with drug delivery enhancement by blood–brain barrier modification in glioblastoma Neurosurgery 1986 19 573 582 3097567
- O'Reilly M Palfi A Chadderton N Millington-Ward S Ader M Cronin T Tuohy T Auricchio A Hildinger M Tivnan A RNA interference-mediated suppression and replacement of human rhodopsin in vivo Am J Hum Genet 2007 81 127 135 17564969 PMC1950918
- Owen CG Fletcher AE Donoghue M Rudnicka AR How big is the burden of visual loss caused by age related macular degeneration in the United Kingdom Br J Ophthalmol 2003 87 312 317 12598445 PMC1771556
- Rizzolo LJ Chen X Weitzman M Sun R Zhang H Analysis of the RPE transcriptome reveals dynamic changes during the development of the outer blood–retinal barrier Mol Vis 2007 23 1259 1273 17679949
- Sakurai E Anand A Ambati BK van Rooijen N Ambati J Macrophage depletion inhibits experimental choroidal neovascularization Invest Ophthalmol Vis Sci 2003 44 3578 3585 12882810
- Samtani S Amaral J Campos MM Fariss RN Becerra SP Doxycycline-mediated inhibition of choroidal neovascularization Invest Ophthalmol Vis Sci 2009 50 5098 5106 19516001 PMC2836119
- Sanges D Comitato A Tammaro R Marigo V Apoptosis in retinal degeneration involves cross-talk between apoptosis-inducing factor (AIF) and caspase-12 and is blocked by calpain inhibitors Proc Natl Acad Sci USA 2006 103 17366 17371 17088543 PMC1859935
- Sausville EA Tomaszewski JE Ivy P Clinical development of 17-allylamino, 17-demethoxygeldanamycin Curr Cancer Drug Targets 2003 3 377 383 14529389
- Seddon JM George S Rosner B Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of age-related macular degeneration Arch Ophthalmol 2006 124 995 1001 16832023
- Stieger K Colle MA Dubreil L Mendes-Madeira A Weber M Le Meur G Deschamps JY Provost N Nivard D Cherel Y Subretinal delivery of recombinant AAV serotype 8 vector in dogs results in gene transfer to neurons in the brain Mol Ther 2008 16 916 923 18388922
- Tam LC Kiang AS Kennan A Kenna PF Chadderton N Ader M Palfi A Aherne A Ayuso C Campbell M Therapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10) Hum Mol Genet 2008 17 2084 2100 18385099
- Tam LC Kiang AS Campbell M Keaney J Farrar GJ Humphries MM Kenna PF Humphries P Prevention of autosomal dominant retinitis pigmentosa by systemic drug therapy targeting heat shock protein 90 (Hsp90) Hum Mol Genet 2010 19 4421 4436 20817636 PMC2957325
- Tan JS Wang JJ Flood V Rochtchina E Smith W Mitchell P Dietary antioxidants and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study Ophthalmology 2008 115 334 341 17664009
- The Eye Disease Prevalence Group Prevalence of age-related macular degeneration in United States Arch Ophthalmol 2004 122 564 572 15078675
- Yang FY Lin YS Kang KH Chao TK Reversible blood–brain barrier disruption by repeated transcranial focused ultrasound allows enhanced extravasation J Control Release 2010 [Epub a head of print] 21070825
Cited by
Sorted by citations
Social stress induces neurovascular pathology promoting depression
Menard, C., Pfau, M. L., Hodes, G. E., Kana, V., Wang, V. X., Bouchard, S., Takahashi, A., Flanigan, M. E., Aleyasin, H., LeClair, K. B., et al. (2017) · Nature Neuroscience · doi:10.1038/s41593-017-0010-3 · Cited by 1,028 · see citing works
Self-citationThe Blood-Retina Barrier: Tight Junctions and Barrier Modulation
Campbell, M., & Humphries, P. (2013) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4614-4711-5_3 · Cited by 270 · see citing works
Self-citationDose-dependent expression of claudin-5 is a modifying factor in schizophrenia
Greene, C., Kealy, J., Humphries, M. M., Gong, Y., Hou, J., Hudson, N., Cassidy, L. M., Martiniano, R., Shashi, V, Hooper, S. R., et al. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.156 · Cited by 235 · see citing works
Self-citation
- Authors
- Campbell, M., Humphries, M. M., Kiang, A., Nguyen, A. T. H., Gobbo, O. L., Tam, L. C. S., Suzuki, M., Hanrahan, F., Ozaki, E., Farrar, G. ‐., Kenna, P. F., & Humphries, P.
- Affiliations
- Trinity College Dublin (IE)
- Corresponding author
- Campbell, Matthew
- ORCID
- Venue
- EMBO Molecular Medicine
- Published
- 2011-03-04
- Volume
- 3
- Issue
- 4
- Pages
- 235-245
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC3377070
- OpenAlex
- W2135981129
- Cited by
- 42
- References
- 6
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 1 · 2017: 6 · 2016: 4 · 2015: 2 · 2013: 5 · 2012: 6
- FWCI
- 2.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- claudin-5, choroidal neovascularization, age-related macular degeneration, retinal degeneration, retinitis pigmentosa
- MeSH terms
- Dependovirus, Animals, Blood-Retinal Barrier, Cell Line, Disease Models, Animal, Genetic Vectors, Humans, Macular Degeneration, Membrane Proteins, Mice, Inbred BALB C, Mice, Inbred C57BL, Molecular Weight, Genetic Therapy, Drug Delivery Systems, RNA, Small Interfering, Mice, Claudin-5
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
