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Deciphering the mechanism of action of carnitine, a novel treatment for chronic Chagas disease

Award Number: R01AI170605
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: 07/12/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Deciphering the mechanism of action of carnitine, a novel treatment for chronic Chagas disease - Project summary/abstract Chagas disease is a leading but poorly-understood infectious cause of heart failure, resulting from infection with Trypanosoma cruzi parasites. T. cruzi has a worldwide prevalence of 7 million, with over 300,000 infected individuals in the United States. Chagas disease causes a significant burden on health care and the economy of over $7 billion annually in total costs. No vaccines are available, and current treatment options are limited by significant adverse effects, long treatment duration, and poor efficacy in late-stage disease. New treatment options for Chagas disease have therefore been identified as a research priority by the World Health Organization, the World Heart Federation, and the Inter-American Society of Cardiology. Our work has identified L-carnitine as a novel treatment regimen for acute and chronic T. cruzi infection, able to improve readouts of cardiac damage and disease severity, and with a good safety profile alone and in combination with the antiparasitic standard-of-care benznidazole. L-carnitine has high potential for clinical translatability, being affordable, readily available, and already FDA-approved to treat inborn metabolic disorders. However, the mechanism of action of L-carnitine in chronic T. cruzi infection is currently unknown. The overall objective of this proposal is to elucidate this mechanism of action, enabling in the long-term continued development of L- carnitine into clinical implementation, and the identification of new alternative treatment regimens for Chagas disease. L-carnitine differs from classic antiparasitic agents in that it improves T. cruzi infection outcomes without reducing parasite load. Thus, results will also expand our understanding of Chagas disease pathogenesis. The central hypothesis of this proposal is that L-carnitine’s mechanism of action is mediated by lessening cardiac fatty acid oxidation, increasing cardiac glucose metabolism, and lowering infection-induced cardiac contractile impairment. This central hypothesis will be tested in experimental models of chronic T. cruzi infection, using three complementary yet independent aims. We will combine metabolomic and pharmacological analyses of the impact of L-carnitine on fatty acid oxidation (aim 1) and on glucose oxidation (aim 2) with echocardiographic analyses of the impact of L-carnitine treatment on cardiac contractility (aim 3). The proposed research is innovative because it centers around a new candidate treatment regimen for Chagas disease with novel mechanism of action, and it will lead to the identification of additional avenues for Chagas disease treatment. The proposed research is significant because it will lead to a rigorous understanding of L- carnitine’s mechanism of action, facilitating its progression to the clinic, and will identify novel candidates for further Chagas disease drug development. Overall, this work will provide valuable new translational avenues for Chagas disease treatment, as well as significant fundamental insight into cardiac Chagas disease pathogenesis.


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: 2025 ( Subtotal = $528,585 )
2025	2025	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	5	7/10/2025	NON-COMPETING CONTINUATION	$528,585
2025	2023	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	2	1/21/2025	NON-COMPETING CONTINUATION	-$35,438
2025	2023	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	3	1/21/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$35,438
														Subtotal = $528,585

Issue Date FY: 2024 ( Subtotal = $466,493 )
2024	2024	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	4	6/19/2024	NON-COMPETING CONTINUATION	$466,493
2024	2023	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	2	4/22/2024	NON-COMPETING CONTINUATION	-$291,099
2024	2023	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	3	4/22/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$291,099
														Subtotal = $466,493

Issue Date FY: 2023 ( Subtotal = $421,656 )
2023	2023	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	2	6/21/2023	NON-COMPETING CONTINUATION	$421,656
														Subtotal = $421,656

Issue Date FY: 2022 ( Subtotal = $402,774 )
2022	2022	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	1	7/12/2022	NEW	$402,774
														Subtotal = $402,774

Grand Total All Awards = $1,819,508

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Deciphering the mechanism of action of carnitine, a novel treatment for chronic Chagas disease

Award Number: R01AI170605

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: 07/12/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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