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A Modality-Agnostic Potency Assay Enabling Both Ex Vivo and In Vivo Genome Editing Therapeutics for Sickle Cell Disease

Award Number: U01AI176469
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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A Modality-Agnostic Potency Assay Enabling Both Ex Vivo and In Vivo Genome Editing Therapeutics for Sickle Cell Disease - ABSTRACT / PROJECT SUMMARY Sickle-cell disease (SCD) is an autosomal recessive disorder that causes considerable morbidity and mortality, affecting an estimated 100,000 individuals in the US, and millions more worldwide. Multiple editing-based cures for SCD are currently in clinical development, however, there are no clinical-grade laboratory tests available capable of characterizing the biophysical and rheological properties of RBCs derived from genome-edited SCD HSPCs. Assays capable of characterizing RBC quality are urgently needed to assess the potency of emerging editing-based genomic therapies for SCD, regardless of the editing modality. One of the central challenges that has impeded the development of a highly performant potency assay for evaluating the functional efficacy of editing-based genomic therapies for SCD has been the lack of laboratory technologies capable of sensitively, accurately, and precisely capturing the biophysical properties of SCD-RBCs utilizing only a small number of cells. In recent years, several innovations have emerged that now make the development and analytical validation of a potency assay for editing-based SCD genomic therapies feasible. One of these has been the advent of microfluidics-based diagnostic devices capable of functionally characterizing the health of RBCs at unprecedented levels of resolution and sensitivity. This proposal seeks to leverage (1) an existing suite of these aforementioned next-generation RBC biophysical and functional characterization devices, (2) conventional hematologic assays, and (3) a well-established machine learning approach to develop and analytically validate a first-in-kind potency assay for editing-based therapies for SCD. To achieve this, we will first construct a panel of comprehensively profiled, gold-standard reference samples of HSPCs that simulate a representative range of genome editing outcomes in SCD and prepare data for machine learning training. A machine learning model will then be trained to predict the percentage of RBCs that functionally exhibit a non-SCD phenotype. Once trained, we will validate the performance of the new potency assay, a panel of HSPCs affected by SCD will be therapeutically edited using at least three different modalities (e.g. homology-directed repair, base-editing, etc.).


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 = $470,454 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Trans-NIH Research Support	000	3	4/16/2025	NON-COMPETING CONTINUATION	$470,454
														Subtotal = $470,454

Issue Date FY: 2024 ( Subtotal = $471,367 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Trans-NIH Research Support	001	2	4/17/2024	NON-COMPETING CONTINUATION	$47,135
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Trans-NIH Research Support	000	2	3/12/2024	NON-COMPETING CONTINUATION	$424,232
														Subtotal = $471,367

Issue Date FY: 2023 ( Subtotal = $489,542 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Trans-NIH Research Support	000	1	4/28/2023	NEW	$489,542
														Subtotal = $489,542

Grand Total All Awards = $1,431,363

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A Modality-Agnostic Potency Assay Enabling Both Ex Vivo and In Vivo Genome Editing Therapeutics for Sickle Cell Disease

Award Number: U01AI176469

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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