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Treatment of Primary Amoebic Meningoencephalitis via Modulation of Antibody Effector Functions

Award Number: R01NS121067
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Treatment of Primary Amoebic Meningoencephalitis via Modulation of Antibody Effector Functions - Abstract: Opportunistic CNS invasion by eukaryotic pathogens requires a highly coordinated, yet restrained, multi- pronged immune response. CNS Infection by extracellular parasites such as Naegleria fowleri, Acanthamoeba, and Balamuthia have proven nearly impossible to treat, yet immune directed therapies against N. fowleri have the potential alter the course of almost universally fatal disease. The “brain eating amoeba” N. fowleri is responsible for a devastating form of meningoencephalitis known as primary amoebic meningoencephalitis (PAM) that is almost universally fatal (>97%) despite intensive clinical intervention, and new therapeutic approaches are desperately needed. The protective relevance of Naegleria-reactive antibodies (Abs) in humans is unclear, but animal models of PAM suggest that vaccinations and passive Ab administration variably delay death and foster survival. Extracellular parasites cannot simply be neutralized by antibody, but rather immunity relies on targeting antibody isotype specific effector mechanisms from immune cells. After parasites are bound by antibody, isotype specific binding to fragment crystallizable receptors (FcRs) can direct cell type specific effector functions against parasites. Prior studies of N. fowleri specific antibody responses have not rigorously linked antibody specificity with the functional outcomes of individual antibody isotypes, creating a critical gap in understanding how antibody can optimally eliminate parasites from the within the central nervous system (CNS) while not exacerbating immunopathology. We’ve generated a monoclonal Ab specific for N. fowleri cell surface antigens that has shown strong anti-proliferative effects on parasites in vitro and facilitates survival of infected hosts in vivo. This proposal seeks to define how combining anti-proliferative effects of antibody and isotype specific binding can facilitate effective immune response against extracellular CNS parasites while maintaining neuroprotection. Completion of this project will define new therapeutic approaches to CNS infections that currently have few effective options and very poor outcomes.


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 = $362,250 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/27/2025	NON-COMPETING CONTINUATION	$362,250
														Subtotal = $362,250

Issue Date FY: 2024 ( Subtotal = $390,425 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/10/2024	NON-COMPETING CONTINUATION	$28,175
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/26/2024	NON-COMPETING CONTINUATION	$362,250
														Subtotal = $390,425

Issue Date FY: 2023 ( Subtotal = $402,500 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/13/2023	NON-COMPETING CONTINUATION	$402,500
														Subtotal = $402,500

Issue Date FY: 2022 ( Subtotal = $402,500 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/13/2022	NON-COMPETING CONTINUATION	$362,250
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/23/2022	NON-COMPETING CONTINUATION	$40,250
														Subtotal = $402,500

Issue Date FY: 2021 ( Subtotal = $402,500 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/18/2021	NEW	$402,500
														Subtotal = $402,500

Grand Total All Awards = $1,960,175

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Treatment of Primary Amoebic Meningoencephalitis via Modulation of Antibody Effector Functions

Award Number: R01NS121067

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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