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Principal Investigator: Kiran Musunuru
Organization: CHILDREN'S HOSP OF PHILADELPHIA
Fiscal Year: 2024
Award: $5,051,652
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
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.
Terms: <1H-Purin-6-amine><AAV vector><AAV-based vector><ANGPT5><ANGPTL3><ANGPTL3 gene><Address><Adenine><Adeno-Associated Viruses><Anaphylactic Reaction><Anaphylactic Shock><Anaphylaxis><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Area><Bacteria><Biodistribution><Birth><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><CRISPR><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><DNA><Deoxyribonucleic Acid><Dependoparvovirus><Dependovirus><Development><Disease><Disorder><Dose><Drug Kinetics><Drugs><Enzyme Gene><Enzymes><Funding><Gene Alteration><Gene Mutation><Genes><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic defect><Goals><Guide RNA><HSC transplantation><Health><Heart><Hematopoietic Stem Cell Transplant><Hematopoietic Stem Cell Transplantation><Hemoglobinopathies><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hereditary Disease><Hereditary Tyrosinemias><Human><Inborn Genetic Diseases><Inherited disorder><Injectable><Intravenous><Joints><Lead><Life><Liver><Liver Cells><Lung><Lung Respiratory System><Medical><Medication><Metabolic><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Modality><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Mucopolysaccharidoses><Mucopolysaccharidosis><Murine><Mus><Mutation><Neurologic><Neurological><Nucleotides><Organ><Outcome><Ovine><Ovis><Parturition><Pathogenicity><Patients><Pb element><Pharmaceutical Preparations><Pharmacokinetics><Pharmacology and Toxicology><Phase 1/2 Clinical Trial><Phase I/II Clinical Trial><Phenotype><Phenylalanine hydroxylase deficiency><Phenylketonurias><Pre IND FDA meeting><Pre-IND mtg><Primates><Primates Mammals><Process><Protein Replacement Therapy><Publishing><R-Series Research Projects><R01 Mechanism><R01 Program><Research Activity><Research Grants><Research Project Grants><Research Projects><Research Resources><Resources><Sheep><T cells for CAR><Therapeutic><Therapeutic Gene Editing><Thesaurismosis><Time><Tissue Sample><Treatment Efficacy><Tyrosinemias><Variant><Variation><Vitamin B4><Writing><adeno associated virus group><adeno-associated viral vector><adeno-associated virus vector><angiopoietin 5><angiopoietin-like 3><animal resource><anti-cancer immunotherapy><anticancer immunotherapy><base editing><base editor><cancer immunotherapy><chimeric antigen T cell receptor><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><death risk><developmental><disease causing variant><disease-causing mutation><drug/agent><efficacy testing><enzyme replacement therapy><fetal><gRNA><gene corrected><gene correction><gene editing platform><gene editing system><gene editing technology><gene editing tools><gene-editing therapy><gene-editing toolkit><genetic condition><genetic disorder><genome editing><genome editing based therapy><genome editing therapy><genome editing treatment><genome editing-based therapeutics><genome mutation><genomic correction><genomic editing><heavy metal Pb><heavy metal lead><hematopoietic cell transplantation><hematopoietic cellular transplantation><hematopoietic progenitor cell transplantation><hepatic body system><hepatic organ system><hereditary disorder><heritable disorder><human model><humanized mice><humanized mouse><immune-based cancer therapies><immunotherapy for cancer><immunotherapy of cancer><improved><in utero><in vivo><inborn error><inherited diseases><inherited genetic disease><inherited genetic disorder><intervention efficacy><lead optimization><lipid based nanoparticle><lipid nanoparticle><meeting><meetings><metabolism disorder><model of animal><model of human><mortality><mortality risk><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non-compliance><non-compliant><non-human primate><noncompliance><noncompliant><nonhuman primate><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nuclease><pathogenic variant><pharmacologic><phenylalaninemia><postnatal><pre-IND consultation><pre-IND discussion><pre-IND meeting><pre-Investigational New Drug meeting><pre-clinical study><preclinical study><prenatal><prime editing><programs><pulmonary><response><somatic cell gene editing><somatic cell genome editing><somatic gene editing><somatic genome editing><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic editing><therapeutic efficacy><therapeutic genome editing><therapy efficacy><timeline><tool><treatment strategy><unborn>