Adeno-associated virus vector gene delivery elevates Factor I levels and down-regulates the complement alternative pathway in vivo.

2021 ◽  
Author(s):  
Amina Ahmad ◽  
Mawj Mandwie ◽  
Anna K Dreismann ◽  
Christine Smyth ◽  
Helen Doyle ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Alternative Pathway ◽  
Virus Vector ◽  
Complement Alternative Pathway ◽  
Adeno Associated Virus ◽  
Factor I

scholarly journals In vivo gene delivery to articular chondrocytes mediated by an adeno-associated virus vector

2004 ◽  
Vol 22 (4) ◽  
pp. 726-734 ◽  
Author(s):  
M. Ulrich-Vinther ◽  
M. R. Duch ◽  
K. Søballe ◽  
R. J. O'Keefe ◽  
E. M. Schwarz ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Articular Chondrocytes ◽  
Virus Vector ◽  
Adeno Associated Virus ◽  
In Vivo Gene Delivery

scholarly journals New functional and structural insights from updated mutational databases for complement factor H, Factor I, membrane cofactor protein and C3

2014 ◽  
Vol 34 (5) ◽  
Author(s):  
Elizabeth Rodriguez ◽  
Pavithra M. Rallapalli ◽  
Amy J. Osborne ◽  
Stephen J. Perkins
Keyword(s):  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor H ◽  
Complement C3 ◽  
Complement Factor ◽  
Membrane Cofactor Protein ◽  
Complement Alternative Pathway ◽  
Factor I ◽  
Mutational Hotspots ◽  
Structural Insights

A new compilation of 324 mutations in four major proteins from the complement alternative pathway reveals mutational hotspots in factor H and complement C3, and less so in factor I and membrane cofactor protein. Their associations with function are discussed.

scholarly journals Identification and Validation of Small Molecules That Enhance Recombinant Adeno-associated Virus Transduction following High-Throughput Screens

2016 ◽  
Vol 90 (16) ◽  
pp. 7019-7031 ◽  
Author(s):  
Sarah C. Nicolson ◽  
Chengwen Li ◽  
Matthew L. Hirsch ◽  
Vincent Setola ◽  
R. Jude Samulski
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
High Throughput ◽  
Adeno Associated Virus ◽  
Virus Gene ◽  
Diploid Cells ◽  
High Throughput Screens ◽  
Group 1

ABSTRACTWhile the recent success of adeno-associated virus (AAV)-mediated gene therapy in clinical trials is promising, challenges still face the widespread applicability of recombinant AAV(rAAV). A major goal is to enhance the transduction efficiency of vectors in order to achieve therapeutic levels of gene expression at a vector dose that is below the immunological response threshold. In an attempt to identify novel compounds that enhance rAAV transduction, we performed two high-throughput screens comprising 2,396 compounds. We identified 13 compounds that were capable of enhancing transduction, of which 12 demonstrated vector-specific effects and 1 could also enhance vector-independent transgene expression. Many of these compounds had similar properties and could be categorized into five groups: epipodophyllotoxins (group 1), inducers of DNA damage (group 2), effectors of epigenetic modification (group 3), anthracyclines (group 4), and proteasome inhibitors (group 5). We optimized dosing for the identified compounds in several immortalized human cell lines as well as normal diploid cells. We found that the group 1 epipodophyllotoxins (teniposide and etoposide) consistently produced the greatest transduction enhancement. We also explored transduction enhancement among single-stranded, self-complementary, and fragment vectors and found that the compounds could impact fragmented rAAV2 transduction to an even greater extent than single-stranded vectors.In vivoanalysis of rAAV2 and all of the clinically relevant compounds revealed that, consistent with ourin vitroresults, teniposide exhibited the greatest level of transduction enhancement. Finally, we explored the capability of teniposide to enhance transduction of fragment vectorsin vivousing an AAV8 capsid that is known to exhibit robust liver tropism. Consistent with ourin vitroresults, teniposide coadministration greatly enhanced fragmented rAAV8 transduction at 48 h and 8 days. This study provides a foundation based on the rAAV small-molecule screen methodology, which is ideally used for more-diverse libraries of compounds that can be tested for potentiating rAAV transduction.IMPORTANCEThis study seeks to enhance the capability of adeno-associated viral vectors for therapeutic gene delivery applicable to the treatment of diverse diseases. To do this, a comprehensive panel of FDA-approved drugs were tested in human cells and in animal models to determine if they increased adeno-associated virus gene delivery. The results demonstrate that particular groups of drugs enhance adeno-associated virus gene delivery by unknown mechanisms. In particular, the enhancement of gene delivery was approximately 50 to 100 times better with than without teniposide, a compound that is also used as chemotherapy for cancer. Collectively, these results highlight the potential for FDA-approved drug enhancement of adeno-associated virus gene therapy, which could result in safe and effective treatments for diverse acquired or genetic diseases.

scholarly journals Complement alternative pathway activation by chronic lymphocytic leukemia cells: its role in their hepatosplenic localization

Blood ◽  
1984 ◽  
Vol 63 (2) ◽  
pp. 463-467 ◽  
Author(s):  
F Praz ◽  
G Karsenty ◽  
JL Binet ◽  
P Lesavre
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Alternative Pathway ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Complement Alternative Pathway ◽  
Acetylneuraminic Acid ◽  
Pathway Activation ◽  
Do So

Abstract Using affinity-purified 125I-F(ab')2 anti-human C3, we have investigated the ability of various leukemic cells to activate complement. Lymphocytes from patients with chronic lymphocytic leukemia (CLL) activated the alternative pathway, but cells from patients with other forms of leukemia or normal lymphocytes did not do so. The amount of C3 deposited on the CLL cells was significantly higher in patients with organomegaly (i.e., splenomegaly and/or hepatomegaly). Activation of complement by CLL cells as assessed by C3 deposition on the membrane occurred both in vivo and in vitro and was not related to the N- acetylneuraminic acid content of the membrane.

scholarly journals Targeted Gene Delivery to Vascular Tissue In Vivo by Tropism-Modified Adeno-Associated Virus Vectors

Circulation ◽  
2004 ◽  
Vol 109 (4) ◽  
pp. 513-519 ◽  
Author(s):  
Stephen J. White ◽  
Stuart A. Nicklin ◽  
Hildegard Büning ◽  
M. Julia Brosnan ◽  
Kristen Leike ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Vascular Tissue ◽  
Adeno Associated Virus ◽  
Virus Vectors ◽  
Targeted Gene Delivery

Adeno-associated Virus (AAV) for In Vivo a– and b– Cell Gene Delivery

2012 ◽  
Vol 36 (5) ◽  
pp. S62-S63
Author(s):  
Eva Tuduri ◽  
Maria M. Glavas ◽  
Robert K. Baker ◽  
Frank K. Huynh ◽  
Michael J. Riedel ◽  
...  
Keyword(s):  
Gene Delivery ◽  
B Cell ◽  
Adeno Associated Virus ◽  
Cell Gene
Sign in / Sign up

Export Citation Format

Share Document