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Resubmission: Systems for Exploring Pathogenicity in Clinical Variants of a Presynaptic Protein Involved in Epilepsy

Award Number: R43NS108847
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2020

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Resubmission: Systems for Exploring Pathogenicity in Clinical Variants of a Presynaptic Protein Involved in Epilepsy - Technical Summary Epilepsy is a large health problem affecting 1% of the human population. Genetic alterations in STXBP1 represents one of the most common causes of severe Early Infantile Epileptic Encephalopathy and many patients with pathogenic variations in STXBP1 are resistant to standard antiepileptic treatment. Genome wide DNA sequencing is now being adopted in clinical practice and an increasing number of variants are identified in epilepsyassociated genes, yet the clinical interpretation of the new variants is challenging. Some of the variants are known to be either pathological or benign, yet a majority of the gene variations remain unknown for their functional consequence. A large number of Variant of Uncertain Significance (VUS) are becoming commonplace in genes for human diseases, providing a significant barrier in making diagnoses and implementing therapies. Bioinformatic approaches can provide some insight into pathogenic probability of VUS alleles, but functional studies in animal model systems are often needed to make definitive of pathogenicity assignments. The expense and long timelines of mouse models production make the use of alternative small animal models attractive. In this proposal, the C. elegans nematode is used as an alternative model capable of fast highthroughput production and screening. Human genes are installed as geneswap replacements of the native diseasegene homologs. In preliminary work, geneswap humanization of STXBP1 in the unc18 locus rescued severe locomotion and behavior defects present in the gene KO animals. Further, installation of two pathogenic variants into the geneswap locus lead to significant disruption of activity. In this proposal, a larger set of clinicallyobserved variants are installed as a geneswap humanized STXBP1 locus, then function deviations are measured with various behavioral and physiological assays. In Aim 1 of proposal, a set of pathogenic variants are installed and measured capacity to exhibit detectable defects of function. In Aim 2, a set of known benign variants are installed and measured for presence of functional defects. In Aim 3, a set of VUS alleles are installed and activity is compared to the known pathogenic and benign variants. Achieving all aims provides a body of data for assessing the predictive capacity of humanized STXBP1 strains to support or refute the remaining variants for capacity to be pathogenic. In additional future phase II work, once pathogenic behavior of a variant is detected as deviant activity in the functional assays, the system can then be used to screen for compounds that lead to reversal of activity back towards wild type. As a result, success of the phase I work, create a platform for probing variant biology and drug discovery. Applied to other targets, similar discovery systems can be developed for many of the 6000+ disease associated genes of the human genome.


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 = $0 )
2021	2019	NEMAMETRIX, INC	1505 WESTEC DR	EUGENE	OR	97402	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/12/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $224,703 )
2019	2019	NEMAMETRIX, INC	44 W 7TH AVE	EUGENE	OR	97401	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/1/2019	NEW	$224,703
														Subtotal = $224,703

Grand Total All Awards = $224,703

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Resubmission: Systems for Exploring Pathogenicity in Clinical Variants of a Presynaptic Protein Involved in Epilepsy

Award Number: R43NS108847

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2020

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