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A Multidisciplinary Approach for the Treatment of Botulinum Intoxication

Award Number: R01AI119564
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/11/2016
PERIOD OF PERFORMANCE END DATE: 06/30/2020

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A Multidisciplinary Approach for the Treatment of Botulinum Intoxication - Project Summary/Abstract. The clinical signature of botulinum neurotoxin (BoNT) is peripheral neuromuscular blockade and flaccid paralysis, which depending on the serotype (A-G) can last for months. BoNTs are the most toxic proteins known to man and have been classified by the Centers for Disease Control and Prevention as one of the six highest-risk biothreat agents. Despite high potential as a bioterrorist weapon, BoNTs are widely used in medical and cosmetic procedures (i.e., Botox). However, even under a controlled environment unwanted side effects have been reported and in some cases severe life-threatening disorders. Clinical intervention of BoNT poisoning is complicated by not only its extreme toxicity but also its long half-life (months for BoNT/A). Currently a botulinum heptavalent antitoxin (BAT) is the only approved medical intervention, yet, has limited value since antibodies can only neutralize circulating toxin, which is negated once cellular poisoning takes place. There are no pharmacologic antagonists available that act once cellular intoxication takes place and none that even advanced to Phase I Clinical Trials. Prohibitive as developing a therapeutic might seem we have shown that BoNT/A intoxication can be attenuated using a synergistic combination of an antibody and a pharmacological antagonist. As significant as this finding has been to the BoNT field, a further mastery would be the use of singular pharmacological agents fashioned to attenuate BoNT/A's toxicity. We currently possess several classes of small molecule inhibitors that can intercede at three junctions critical to BoNT's pathology: SNARE protein cleavage, neurotoxin endocytosis, and blockade of acetylcholine release. From this arsenal we have discovered molecules engendered to block multiple processes associated with BoNT/A neurotoxicity. Impressively, this dual inhibitor-mechanism strategy provides the first small molecule that can extend time to death from a BoNT/A post exposure occurrence. We have established how potassium channel blockade can provide full sustenance in the reversal of paralysis for post- intoxication of BoNT/A. For this research we offer the molecules 3,4-diaminopyridine (3,4-DAP) and 3,4,5- triaminopyridine (3,4,5-TAP); both are highly effective for BoNT/A rescue. However, aminopyridine's effectiveness is severely compromised by their short half-life. We will address this limitation within our proposed studies. Finally, as a means to augment our small molecule pharmacological antagonist research initiative we will use medicinal chemistry, X-ray crystallography and pharmacokinetics to develop both greater selectivity and more potent inhibitors against the botulinum neurotoxins. The successful integration of our research goals will bring the complex and challenging problem of treating botulinum toxicity toward a clinically viable treatment.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = -$2 )
2021	2019	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	1/27/2021	NON-COMPETING CONTINUATION	-$2
														Subtotal = -$2

Issue Date FY: 2019 ( Subtotal = $559,989 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	7/1/2019	NON-COMPETING CONTINUATION	$559,989
														Subtotal = $559,989

Issue Date FY: 2018 ( Subtotal = $561,234 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	6/11/2018	NON-COMPETING CONTINUATION	$561,234
														Subtotal = $561,234

Issue Date FY: 2017 ( Subtotal = $566,245 )
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	6/28/2017	NON-COMPETING CONTINUATION	$566,245
														Subtotal = $566,245

Issue Date FY: 2016 ( Subtotal = $628,233 )
2016	2016	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	7/11/2016	NEW	$628,233
														Subtotal = $628,233

Grand Total All Awards = $2,315,699

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A Multidisciplinary Approach for the Treatment of Botulinum Intoxication

Award Number: R01AI119564

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/11/2016

PERIOD OF PERFORMANCE END DATE: 06/30/2020

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