Personalized prime editing as a platform for hepatic inborn errors of metabolism
Active Cooperative Agreement Awarded Last action
- Award ID
- U01TR005355
- Recipient
-
The Children's Hospital Of Philadelphia UEI G7MQPLSUX1L4
- Awarding agency
-
National Center for Advancing Translational Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $17,843,166
Award facts
- Assistance listing
- 93.310 Trans-NIH Research Support
- Completion date 54% complete
- Funding agency
- Office of the Director National Institutes of Health, Department of Health and Human Services
- Place of performance
- Philadelphia, PA 19104, USA
Award details come from USAspending.gov.
Description
- Abstract
- 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.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $3,924,785 | |
| Amendment | $0 | |
| Amendment | $2,710,325 | |
| Amendment | $1,427,560 | |
| Amendment | $1,427,560 | |
| Amendment | $1,427,560 | |
| Amendment | $2,748,908 | |
| Original award | $2,748,908 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Case Western Reserve University | $341,039 | |
| Franklin Biolabs, LLC | $178,302 | |
| Case Western Reserve University | $30,877 | |
| Case Western Reserve University | $546,641 | |
| Aldevron, L.l.c | $275,238 | |
| The Trustees Of The University Of Pennsylvania | $993,910 | |
| Franklin Biolabs, LLC | $486,110 | |
| Franklin Biolabs, LLC | $385,985 | |
| The Trustees Of The University Of Pennsylvania | $4,217,828 | |
| The Trustees Of The University Of Pennsylvania | $4,217,828 | |
| Amplifybio LLC | $602,000 | |
| Aldevron, L.l.c | $200,000 |
Show all 12
Quick answers
Who received award U01TR005355?
U01TR005355 was awarded to The Children's Hospital Of Philadelphia by National Center for Advancing Translational Sciences (National Institutes of Health) on September 20, 2024.
How much is award U01TR005355 worth?
$17,843,166 has been obligated on U01TR005355.
Which agency awarded U01TR005355?
National Center for Advancing Translational Sciences (National Institutes of Health) awarded U01TR005355, with funding from Office of the Director (National Institutes of Health).
On GovTribe
See this award's full record
- Every transaction and subaward
- The recipient's other awards and teaming partners
- Similar grant awards
- Ask GovTribe AI about this award