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Personalized prime editing as a platform for hepatic inborn errors of metabolism

Award Number: U01TR005355
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Personalized prime editing as a platform for hepatic inborn errors of metabolism - PROJECT SUMMARY Inborn errors of metabolism (IEMs) are rare, devasting disorders arising from pathogenic variants in genes encoding enzymes of key biochemical pathways. The liver plays an important role in the pathogenesis of over 150 IEMs, often failing to metabolize a toxic metabolite that can injure secondary organs, such as brain. Liver transplantation is employed in some IEMs; however, its utility is limited by scarcity of donors and lifelong risk of post-transplant complications. To address the unmet medical need of IEM patients, we aim to develop a master protocol for the rapid development of personalized prime-editing therapies for severe, rare hepatic IEMs. We envision a platform regulatory framework where IND-enabling studies for a “leader” hepatic IEM prime-editing therapy also support programs for varied “follower” indications. The leader and follower therapies will differ only in patient-variant-specific guide RNA sequences. For our leader indication, we have selected phenylketonuria (PKU). In PKU, an autosomal recessive disorder, impaired phenylalanine (Phe) catabolism in the liver induces neurotoxic Phe accumulation. In our proof-of-concept studies, a single dose of an AAV8-based, R408W prime- editing therapy completely and durably normalized Phe levels in humanized PKU R408W mice. We will leverage our PKU R408W IND-enabling studies to accelerate development for our follower indications: ultra-rare, severe, neonatal urea cycle disorders (UCDs) and organic acidemias (OAs) that affect ≈1:20,000 births. Neonates with UCDs or OAs present with severe toxic accumulation of ammonia and/or organic acids. While liver transplantation can improve metabolic control, patients must grow to an appropriate size to receive a transplant. During this wait, most patients experience irreversible neurologic damage and episodes of life- threatening metabolic decompensation. We seek to develop just-in-time, personalized, liver-directed prime- editing therapies addressing the pathogenic variants identified through newborn screening at our large referral center. A platform regulatory approach is essential to develop therapies in time to meaningfully improve outcomes in this patient cohort who typically suffer significant early morbidity and mortality. Our primary objectives are to (1) establish a therapeutic platform, comprising a single prime editor and AAV delivery system, for numerous hepatic IEMs, and (2) streamline approvals through regulatory innovation, informed by stakeholder input and disseminated to the scientific community.


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 = $4,137,885 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Trans-NIH Research Support	000	1	11/27/2024	SUPPLEMENT FOR EXPANSION	$1,427,560
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Trans-NIH Research Support	001	2	8/6/2025	NON-COMPETING CONTINUATION	$2,710,325
														Subtotal = $4,137,885

Issue Date FY: 2024 ( Subtotal = $2,748,908 )
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Trans-NIH Research Support	000	1	9/20/2024	NEW	$2,748,908
														Subtotal = $2,748,908

Grand Total All Awards = $6,886,793

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Personalized prime editing as a platform for hepatic inborn errors of metabolism

Award Number: U01TR005355

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/20/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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