# Novel therapeutic approaches to treatment of botulinum neurotoxin poisoning

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $980,692

## Abstract

PROJECT SUMMARY/ABSTRACT:
 Botulinum neurotoxin (BoNT) is a highly potent, neuroparalytic poison that cleaves presynaptic SNARE
proteins required for neurotransmitter release. The primary toxic effect of BoNT poisoning is blockade of
neuromuscular transmission, leading to flaccid paralysis and death by respiratory arrest. There are no specific
countermeasures capable of reversing symptomatic botulism. Current treatment strategies for lethal exposures
are limited to post-exposure prophylaxis via passive immunoglobulin therapy, which cannot prevent respiratory
collapse once botulism symptoms emerge, and supportive care. In the event of a large-scale botulism outbreak
or deliberate attack, there is limited ability to maintain large numbers of symptomatic victims on artificial
ventilation for weeks or longer. Consequently, development of effective therapeutics for respiratory paralysis is
a high priority for public health and national defense. A major limitation in creating an effective therapeutic for
botulinum poisoning has been the inability to identify post-exposure treatments that block or terminate the
molecular toxicity of the BoNT light chain (LC) within the nerve terminal. This project aims to develop a new class
of botulism antidotes that exploit the natural neuronal receptors and trafficking pathways normally employed by
the targeted toxin itself. Unlike available antibody-based therapeutics and small molecule inhibitors of the light
chain metalloprotease, the botulinum neurotoxin (BoNT)‐based therapeutics that we have developed can reach
an intracellular target in a post‐exposure setting. Unlike conventional small molecule therapeutics, which would
equally affect all cells in the body with potentially deleterious side effects, the proposed method will specifically
deliver a therapeutic moiety only to the cytosol of the target cells (neurons). This is a unique approach toward
treating not only botulism, as embodied in this proposal, but also infectious and neurodegenerative diseases in
which the causative agents reside and exert their action intra-neuronally. 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 nanobodies, extensive expertise in expressing
neuron-targeted physiologically active fusion proteins that use metalloprotease-inactivated BoNT/C1 as a
molecular vehicle for delivery of nanobodies, expertise in test systems for development of compounds promoting
accelerated degradation of intracellular targets through the endogenous proteasomal system, and extensive
experience in developing in vitro and in vivo models that can be used to test novel botulism antidotes.

## Key facts

- **NIH application ID:** 10851740
- **Project number:** 5R01AI093504-13
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Konstantin Ichtchenko
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $980,692
- **Award type:** 5
- **Project period:** 2011-04-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851740

## Citation

> US National Institutes of Health, RePORTER application 10851740, Novel therapeutic approaches to treatment of botulinum neurotoxin poisoning (5R01AI093504-13). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10851740. Licensed CC0.

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