IMPROVED AMINOPYRIDINE ANALOGS FOR SYMPTOMATIC TREATMENT OF BOTULISM - PROJECT SUMMARY/ABSTRACT BOTULINUM N…

Assistance award details

Assistance award identifier

ASST_NON_R61AI197853_075

FAIN

R61AI197853

Recipient

WAKE FOREST UNIVERSITY HEALTH SCIENCES

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.855

Total obligated

$480,448

Period

Jun 1, 2026 – May 31, 2028

Fiscal year

2026

Place of performance state

NC

Source file

FY2026_All_Assistance_Full_20261006.zip

Description

IMPROVED AMINOPYRIDINE ANALOGS FOR SYMPTOMATIC TREATMENT OF BOTULISM - PROJECT SUMMARY/ABSTRACT BOTULINUM NEUROTOXINS (BONTS) ARE THE MOST POTENT BIOLOGICAL THREATS KNOWN, WITH ESTIMATED HUMAN LETHAL DOSES AS LOW AS 0.1–10 NG/ML DEPENDING ON SEROTYPE AND EXPOSURE ROUTE. BONTS ACT BY ENTERING MOTOR NEURONS AND CLEAVING SNARE PROTEINS ESSENTIAL FOR NEUROTRANSMITTER RELEASE, RESULTING IN FLACCID PARALYSIS AND, IN SEVERE CASES, LETHAL RESPIRATORY FAILURE. ALTHOUGH NATURALLY OCCURRING CASES OF BOTULISM ARE RARE, THE POTENTIAL FOR DELIBERATE OR ACCIDENTAL EXPOSURE PRESENTS A SERIOUS PUBLIC HEALTH RISK. BONTS ARE CLASSIFIED AS TIER 1 SELECT AGENTS DUE TO THEIR EXTREME POTENCY, EASE OF DISSEMINATION, AND CAPACITY TO OVERWHELM HEALTH CARE INFRASTRUCTURE. CURRENTLY, THE ONLY FDA-APPROVED TREATMENT IS AN EQUINE-DERIVED IMMUNOGLOBULIN ANTITOXIN ADMINISTERED POST-EXPOSURE TO NEUTRALIZE CIRCULATING TOXIN. HOWEVER, ANTITOXIN HAS A NARROW THERAPEUTIC WINDOW AND CANNOT REVERSE PARALYSIS ONCE TOXIN IS INTERNALIZED INTO NEURONS—CONSEQUENTLY, MOST PATIENTS STILL REQUIRE PROLONGED MECHANICAL VENTILATION TO SURVIVE. WE RECENTLY DEMONSTRATED THAT THE FDA-APPROVED VOLTAGE-GATED POTASSIUM CHANNEL (VGKC) BLOCKER, 3,4-DIAMINOPYRIDINE (3,4-DAP), REVERSES SYMPTOMS OF BOTULISM BY INCREASING ACETYLCHOLINE RELEASE AT INTOXICATED NEUROMUSCULAR JUNCTIONS. IN RODENT AND NON-HUMAN PRIMATE MODELS OF LETHAL BONT EXPOSURE, 3,4-DAP IMPROVES RESPIRATORY FUNCTION, RESTORES NEUROMUSCULAR TRANSMISSION, AND PROLONGS SURVIVAL. BASED ON THESE FINDINGS, WE ARE CURRENTLY FUNDED BY THE DEPARTMENT OF DEFENSE TO PURSUE REGULATORY APPROVAL FOR 3,4-DAP UNDER THE FDA ANIMAL RULE. HOWEVER, TWO KEY LIMITATIONS RESTRICT ITS BROADER CLINICAL USE: (1) SEIZURE LIABILITY DUE TO CNS PENETRATION, AND (2) HIGHLY VARIABLE BLOOD LEVELS DUE TO POLYMORPHISMS IN N-ACETYLTRANSFERASE-2 (NAT2), ITS PRIMARY METABOLIC ENZYME. THESE LIMITATIONS ARE PRIMARY BOTTLENECKS TO ITS USE AS A MEDICAL COUNTERMEASURE FOR BOTULISM EXPOSURE UNDER EM