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Precision Medicine in Pediatric Rehabilitation - Variability in Gabapentin Exposure

Award Number: R03HD107642
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/03/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Precision Medicine in Pediatric Rehabilitation - Variability in Gabapentin Exposure - PROJECT SUMMARY Although gabapentin is the most commonly prescribed medication for patients with neuropathic pain, the high level of variability in reduction in pain limits effective treatment of pain. Work products from this grant would allow the formation of a model-informed dosing strategy for this disorder. This research will have a lasting impact on the way in which drugs are prescribed to pediatric patients with disabilities. Medications which require transport across the blood-brain barrier (BBB) frequently require transport to reach the cerebrospinal fluid (CSF). The gene SLC7A5 encodes for a light-chain protein (LAT1) that forms a heterodimer with the a heavy chain protein CD98hc (encoded by SLC3A2) to create a membrane transport protein referred to as the L-type amino acid transporter-1 (LAT1). 21 Previous in vitro studies have shown that this transporter is one of the primary mechanisms of gabapentin transport across the BBB. This transporter is also the confirmed or theorized transporter of several other commonly prescribed medications frequently prescribed by rehabilitation providers. Determining the variability in the amount of gabapentin a patient has in their plasma (systemic exposure) and the amount that crosses the blood-brain-barrier (BBB) (central exposure) is significant to optimally determine the most appropriate dose for each individual child (AIM1). The overall goal of my research strategy is to identify factors influencing variability in central exposure (cerebrospinal fluid) in pediatric patients with CP. AIM 1 investigates the amount of central exposure by determining the amount of gabapentin that crosses the BBB. A secondary portion of AIM 1 addresses the impact of the SCL7A5 gene (LAT1 transporter) by performing whole- exome sequencing to evaluate the SLC7A5 gene and genotyping of selected single-nucleotide polymorphisms in the intronic region of the LAT1 transporter. AIM 2 is divided into two sub-aims using similar methodology. The first sub-aim evaluates the impact of concurrently administered medications that also utilize the LAT1 transporter using a cell line model that is transfected with the SLC7A5 gene to evaluate potential drug-drug interactions with commonly prescribed medications in rehabilitation medicine, specifically levodopa, baclofen, and pregabalin. The second sub-aim of AIM 2 involved transfection of genetic variants of the LAT1 transporter to determine the impact of coding region changes to the function of this transporter. These variants may be informed by the whole-exome sequencing variants found in AIM 1. Both of these independent but complementary AIMs allows for data that will be incorporated within future decision support tools to more appropriate anticipate what dose of gabapentin is needed to reach a desired level of exposure and, subsequently, a desired level of clinical response (neuropathic pain reduction).


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: 2026 ( Subtotal = $0 )
2026	2023	CHILDRENS MERCY HOSPITAL	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Child Health and Human Development Extramural Research	000	2	2/9/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $167,503 )
2023	2023	CHILDRENS MERCY HOSPITAL	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Child Health and Human Development Extramural Research	000	2	7/18/2023	NON-COMPETING CONTINUATION	$167,503
														Subtotal = $167,503

Issue Date FY: 2022 ( Subtotal = $151,169 )
2022	2022	CHILDREN'S MERCY HOSPITAL, THE	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Child Health and Human Development Extramural Research	000	1	8/3/2022	NEW	$151,169
														Subtotal = $151,169

Grand Total All Awards = $318,672

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Precision Medicine in Pediatric Rehabilitation - Variability in Gabapentin Exposure

Award Number: R03HD107642

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/03/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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