| Title |
Prolonged Prophylactic Protection from Botulism with a Single Adenovirus Treatment Promoting Serum Expression of a VHH-Based Antitoxin Protein
|
|---|---|
| Published in |
PLOS ONE, August 2014
|
| DOI | 10.1371/journal.pone.0106422 |
| Pubmed ID | |
| Authors |
Jean Mukherjee, Igor Dmitriev, Michelle Debatis, Jacqueline M. Tremblay, Gillian Beamer, Elena A. Kashentseva, David T. Curiel, Charles B. Shoemaker |
| Abstract |
Current therapies for most acute toxin exposures are limited to administration of polyclonal antitoxin serum. We have shown that VHH-based neutralizing agents (VNAs) consisting of two or more linked, toxin-neutralizing heavy-chain-only VH domains (VHHs), each binding distinct epitopes, can potently protect animals from lethality in several intoxication models including Botulinum neurotoxin serotype A1 (BoNT/A1). Appending a 14 amino acid albumin binding peptide (ABP) to an anti-BoNT/A1 heterodimeric VNA (H7/B5) substantially improved serum stability and resulted in an effective VNA serum half-life of 1 to 2 days. A recombinant, replication-incompetent, adenoviral vector (Ad/VNA-BoNTA) was engineered that induces secretion of biologically active VNA, H7/B5/ABP (VNA-BoNTA), from transduced cells. Mice administered a single dose of Ad/VNA-BoNTA, or a different Ad/VNA, via different administration routes led to a wide range of VNA serum levels measured four days later; generally intravenous > intraperitoneal > intramuscular > subcutaneous. Ad/VNA-BoNTA treated mice were 100% protected from 10 LD50 of BoNT/A1 for more than six weeks and protection positively correlated with serum levels of VNA-BoNTA exceeding about 5 ng/ml. Some mice developed antibodies that inhibited VNA binding to target but these mice displayed no evidence of kidney damage due to deposition of immune complexes. Mice were also successfully protected from 10 LD50 BoNT/A1 when Ad/VNA-BoNTA was administered up to 1.5 hours post-intoxication, demonstrating rapid appearance of the protective VNA in serum following treatment. Genetic delivery of VNAs promises to be an effective method of providing prophylactic protection and/or acute treatments for many toxin-mediated diseases. |
X Demographics
The data shown below were collected from the profile of 1 X user who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Science communicators (journalists, bloggers, editors) | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 53 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Germany | 1 | 2% |
| Unknown | 52 | 98% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Bachelor | 26 | 49% |
| Researcher | 6 | 11% |
| Professor | 3 | 6% |
| Student > Ph. D. Student | 3 | 6% |
| Student > Postgraduate | 3 | 6% |
| Other | 8 | 15% |
| Unknown | 4 | 8% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 33 | 62% |
| Biochemistry, Genetics and Molecular Biology | 7 | 13% |
| Agricultural and Biological Sciences | 3 | 6% |
| Immunology and Microbiology | 3 | 6% |
| Veterinary Science and Veterinary Medicine | 1 | 2% |
| Other | 1 | 2% |
| Unknown | 5 | 9% |