Postnatal and prenatal therapeutic base editing for metabolic diseases

Active Cooperative Agreement Awarded Last action

Award ID
U19NS132301
Recipient
Awarding agency
Obligated
$54,175,368

Award facts

Assistance listing
93.310 Trans-NIH Research Support
Completion date 65% complete
Funding agency
Office of the Director National Institutes of Health, Department of Health and Human Services
Place of performance
Philadelphia, PA 19146, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
The potential for the development of novel therapeutic modalities has energized the genome editing field since IT first emerged in the 1990S and especially since the demonstration of programmable genome editing with crispr-CAS9 by multiple groups in 2012. There has been substantial progress with EX vivo therapeutic applications of genome editing in patients in the past few years, most notably with car-t immunotherapies for cancer and with durable treatment of hemoglobinopathies. Progress with in vivo therapeutic applications, i.e., somatic cell genome editing, has been slower due to the technical challenges inherent in the delivery of genome- editing tools into the body. As of the time of this writing, there are few published examples of successful genome editing performed in vivo in primates (including humans), with almost all examples involving somatic genome editing in the liver: TTR with CAS9 nuclease delivered by lipid nanoparticles (lnps), PCSK9 and ANGPTL3 with adenine base editors delivered by lnps, and PCSK9 with meganucleases delivered by adeno-associated virus (AAV) vectors. The prospects for genome-editing therapies extend to before birth, with in utero genome editing having the potential to treat genetic diseases that result in significant morbidity and mortality before or shortly after birth. Although restricted to small animal models so far, in utero genome editing has proven effective in the liver, lungs, heart, and other organs. Our overall program seeks to build on these early successes, pursuing goals that that would be of major impact in advancing the field of therapeutic genome editing. Our three research projects seek to develop base-editing therapies targeting the liver in order to treat three rare metabolic genetic diseases: phenylketonuria (PKU), hereditary tyrosinemia type 1 (HT1), and mucopolysaccharidosis type 1 (mpsi). Lead project 1 will focus on LNP-based postnatal treatment of PKU, with the aim to file an IND application by the end of the five-year funding period and begin a phase 1/2 clinical trial soon afterwards. Project 2 will focus on LNP-based postnatal treatment of HT1, with the aim to file an IND application and begin a clinical trial, and prenatal treatment of HT1, with the aim of performing preclinical studies during the five-year funding period to enable an eventual IND application if the postnatal clinical trial proves successful. Project 3 will focus on AAV-based postnatal and prenatal treatment of mpsi, with similar aims as project 2. Unique, specialized resource cores focused on off-target editing and in utero treatment of small and large animals will be indispensable in achieving these aims.

Transactions

Action Obligated Date
Amendment $0
Amendment $5,455,342
Amendment $9,996,957
Amendment $0
Amendment $0
Amendment $0
Amendment $0
Amendment $0
Amendment $1,000,000
Amendment $1,000,000
Amendment $5,059,052
Amendment Guide RNA manufacturing capabilities for platform in vivo base editing therapies for metabolic liver diseases $5,059,052
Amendment Replication study of in vivo postnatal gene editing for metabolic liver disease in the nonhuman primate model $29,667
Amendment $29,667
Amendment Guide RNA manufacturing capabilities for platform in vivo base editing therapies for metabolic liver diseases $29,667
Amendment $5,051,652
Amendment $5,051,652
Original award $6,415,703
Show all 18

Subawards

Subrecipient Amount Awarded
KK Women's And Children's Hospital Pte. LTD. KKH will coordinate and perform in utero NHP studies including, but not limited to, scheduling surgeries, performing the injections, pre- and post-operative… $155,000
The Trustees Of The University Of Pennsylvania We contribute to the invitro screen for efficacy and safety of select gRNAs and assist in the conduction of and analyses of the in vivo studies in the mouse… $848,975
The Trustees Of The University Of Pennsylvania We will coordinate with NIH SCGE program staff to ensure timely submission of required progress reports, appropriate collection and sharing of data, and all… $73,270
The Trustees Of The University Of Pennsylvania We will perform in vitro dose response studies in HuH7 cells and primary human hepatocytes for all projects. This will also include making new cell lines for… $844,772
The Trustees Of The University Of Pennsylvania We contribute to the invitro screen for efficacy and safety of select RNAs and assist in the conduction of and analyses of the invivo studies in the mouse… $1,207,492
The Trustees Of The University Of Pennsylvania $996,242
The Trustees Of The University Of Pennsylvania We contribute to the invitro screen for efficacy and safety of select gRNAs and assist in the conduction of and analyses of the in vivo studies in the mouse… $848,975
The Trustees Of The University Of Pennsylvania We will coordinate with NIH SCGE program staff to ensure timely submission of required progress reports, appropriate collection and sharing of data, and all… $73,268
The Trustees Of The University Of Pennsylvania We will perform in vitro dose response studies in HuH7 cells and primary human hepatocytes for all projects. This will also include making new cell lines for… $844,772
KK Women's And Children's Hospital Pte. LTD. My laboratory will support the in utero gene editing work performed in the NHP model as well as juvenile in vivo gene editing work performed in the NHP model.… $50,000
The Trustees Of The University Of Pennsylvania WewillcreateLNPsandmRNArequiredfortheinvitroandinvivostudiesproposed.mRNAwillbe… $2,161
Show all 11

Quick answers

Who received award U19NS132301?

U19NS132301 was awarded to The Children's Hospital Of Philadelphia by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on August 1, 2023.

How much is award U19NS132301 worth?

$54,175,368 has been obligated on U19NS132301.

Which agency awarded U19NS132301?

National Institute of Neurological Disorders and Stroke (National Institutes of Health) awarded U19NS132301, with funding from Office of the Director (National Institutes of Health).

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