Aptamer drug for detoxification of Staphylococcus aureus alpha-toxin
Inventors
Vivekananda, Jeevalatha • Millenbaugh, Nancy J.
Assignees
Publication Number
US-9217134-B1
Publication Date
2015-12-22
Expiration Date
2034-08-27
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Abstract
Aptamers and methods of use thereof are presented for the treatment or diagnosis of Staphylococcus aureus infection. The aptamers binds to and capable of neutralization of Staphylococcus aureus alpha-toxin.
Core Innovation
The invention provides aptamers for targeting Staphylococcus aureus alpha-toxin and methods using these aptamers to detoxify the bacterial toxin. These aptamers specifically bind to and neutralize the cytolytic and cytotoxic effects of S. aureus alpha-toxin, which is a major factor in the bacteria’s pathogenicity and causes cellular membrane damage leading to cell death.
The problem addressed is the challenge posed by infections from multidrug-resistant bacterial pathogens such as S. aureus, which secrete toxins enhancing virulence and tissue damage. Existing treatments with antibiotics reduce bacterial burden but do not neutralize secreted toxins like alpha-toxin, leaving pathogenic effects due to toxemia untreated. There were no available inhibitors to neutralize the alpha-toxin’s cytotoxic effects prior to this invention.
Aptamers have been identified by a SELEX in vitro selection process to specifically bind S. aureus alpha-toxin with high affinity. These DNA aptamers inhibit alpha-toxin induced toxicity in human Jurkat T cells, protecting them from cell death. The inventors showed that the aptamers neutralize the toxin’s pore-forming activity, reduce transcriptional activation of proinflammatory cytokine genes (such as TNF-α and IL-17), and increase cell viability in vitro, providing a novel therapeutic approach for treating S. aureus infections.
Claims Coverage
The patent contains four independent claims covering aptamers binding S. aureus alpha-toxin, their therapeutic use, diagnostic application, and methods of inhibiting cytotoxic effects.
Aptamers binding and neutralizing Staphylococcus aureus alpha-toxin
An aptamer comprising a nucleotide sequence selected from SEQ ID NO: 9, 10, 11, or 12 that binds to S. aureus alpha-toxin and reduces its cytolytic and cytotoxic effects.
Therapeutic compositions comprising alpha-toxin binding aptamers
A pharmaceutical composition containing one or more of the aptamers that bind and neutralize alpha-toxin in a pharmaceutically acceptable form.
Diagnostic method using aptamer-reporter complexes
A method to diagnose S. aureus infection by contacting a sample with an aptamer (from SEQ ID NO: 9, 10, 11, 12) complexed with a reporter moiety, wherein binding to alpha-toxin generates a detectable signal.
Method for inhibiting alpha-toxin cytotoxic effects in subjects
Administering a therapeutically effective amount of an aptamer (selected from SEQ ID NO: 9, 10, 11, 12) to inhibit cytolytic and cytotoxic activity of S. aureus alpha-toxin in a subject.
The independent claims cover the identification of specific aptamers that bind and neutralize S. aureus alpha-toxin, pharmaceutical compositions comprising these aptamers, diagnostic methods utilizing aptamer binding, and therapeutic methods for treating alpha-toxin mediated cytotoxicity.
Stated Advantages
The aptamers have high specificity and affinity for alpha-toxin, enabling effective neutralization.
They increase cell viability by inhibiting cytolytic and cytotoxic effects of alpha-toxin.
The aptamers reduce transcriptional activation of inflammatory cytokine genes TNF-α and IL-17, potentially decreasing toxin-induced inflammation.
Aptamers have low toxicity and immunogenicity, making them safer therapeutic agents compared to antibodies.
The aptamers can be rapidly generated and modified through in vitro selection techniques, allowing for controlled specificity and affinity.
Documented Applications
Treatment of Staphylococcus aureus infections by neutralizing the alpha-toxin using aptamer-based therapeutics.
Diagnosis of Staphylococcus aureus infection by detecting alpha-toxin in samples using reporter-tagged aptamers.
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