# Novel therapeutic approaches to treatment of botulinum neurotoxin poisoning.

> **NIH NIH U01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $1,127,378

## Abstract

PROJECT SUMMARY/ABSTRACT:
 Human botulism can result from the ingestion of food contaminated with botulinum neurotoxin (BoNT),
from the infection of wounds or intestine, or from direct inhalation of the toxin, which can be transcytosed
across epithelial barriers as a physiologically active molecule. Intoxication, if untreated, may lead to death due
to respiratory muscle failure, while recovery from botulism is a prolonged process (up to several months) and
BoNTs are classified as one of the six highest‐risk threat agents for bioterrorism by the CDC. Developing
may require intensive and expensive hospital care. Due to their extreme toxicity and ease of production,
antidotes to botulinum neurotoxins is a priority goal of the Biodefense Research Agenda. During the previous
funding period, we developed a molecular engineering platform that takes advantage of structural features and
trafficking of BoNTs to enable the delivery within the presynaptic compartment of intoxicated neurons of single
domain camelid antibodies (sdAbs) that bind and inactivate the wt light chain (LC) of BoNT metalloproteases.
We developed a post-exposure anti-botulinum therapeutic (PEABT) targeting wt BoNT/A1, which is the first
compound ever to show reversal of respiratory symptoms in mice at times post-intoxication when standard
antibodies are ineffective. Preliminary data also demonstrated the effectiveness of a second lead candidate
against wt BoNT/B, and attest to the generalizability of the platform. We succeeded in developing a novel
principle for delivering single domain antibodies to the presynaptic compartment of neurons without a viral
vector. In addition, we developed a murine model of botulism that is specifically appropriate to test botulism
antidotes with an intra-neuronal mode of action. The murine model is currently being translated to a guinea pig,
in response to an FDA suggestion that the guinea pig was the species to use for an Animal Rule pivotal study.
Our objective is to expand the therapeutic range of this platform to two other known human pathogenic
serotypes – wt BoNT/B and wt BoNT/E, and to further increase the potency and therapeutic window of the wt
BoNT/A1 countermeasure. We will identify sdAbs that bind and broadly neutralize BoNT/A, /B, and /E LC
subtypes, and we will pursue strategies to increase the potency of PEABTs by increasing the affinity of sdAbs
for the wt LC target and by improving therapeutic efficacy. The team of scientists assembled for this project
includes researchers with unique expertise, who are well-qualified for the task at hand, including a long and
successful history in generating BoNT-neutralizing sdAbs, extensive expertise in expressing neuron-targeted
physiologically active fusion proteins that use metalloprotease-inactivated BoNT/C1 as a molecular vehicle for
delivery of sdAbs, expertise in test systems for development of compounds promoting accelerated degradation
of intracellular targets through the endogenous proteaso...

## Key facts

- **NIH application ID:** 9976431
- **Project number:** 5U01AI093504-09
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Konstantin Ichtchenko
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,127,378
- **Award type:** 5
- **Project period:** 2011-04-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976431

## Citation

> US National Institutes of Health, RePORTER application 9976431, Novel therapeutic approaches to treatment of botulinum neurotoxin poisoning. (5U01AI093504-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9976431. Licensed CC0.

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