LEAD PROJECT 1: PHENYLKETONURIA (PKU)

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Principal Investigator: Kiran  Musunuru
Organization: CHILDREN'S HOSP OF PHILADELPHIA
Fiscal Year: 2024
Award: $1,419,953
Funding agency: National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY
Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the gene encoding
phenylalanine hydroxylase (PAH), resulting in the accumulation of phenylalanine (Phe) to neurotoxic levels.
Among the five most frequently occurring pathogenic PAH variants worldwide is the c.842C>T (P281L) mutation,
which is amenable to adenine base editing. The current treatment options have significant limitations—a strict
low-Phe diet to which many patients find it difficult to adhere, and a daily injectable enzyme therapy with a
substantial risk of anaphylaxis. Lead Project 1 will focus on a lipid nanoparticle (LNP)-based adenine base
editing treatment for PKU in patients with the P281L variant, 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.

Terms: <1H-Purin-6-amine><Address><Adenine><Anaphylactic Reaction><Anaphylactic Shock><Anaphylaxis><Animal Model><Animal Models and Related Studies><Biodistribution><Blood><Blood Reticuloendothelial System><Cats><Cats Mammals><Classical phenylketonuria><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Defect><Diet><Dietary Intervention><Disease><Disorder><Disturbance in cognition><Domestic Cats><Dose><Drug Kinetics><Drug Packaging><Drugs><Enzyme Gene><Enzymes><Europe><Feline Species><Felis catus><Felis domestica><Felis domesticus><Felis sylvestris catus><Folling's Disease><Food and Drug Administration><Funding><GaAs><Genes><Genetic Alteration><Genetic Change><Genetic defect><Goals><Guide RNA><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hereditary><High Prevalence><Human><Hyperphenylalaninaemias><Impaired cognition><Impairment><Inherited><Injectable><Investigational Drugs><Investigational New Drug Application><Investigational New Drugs><Lead><Link><Liver><Liver Cells><Mediating><Medical><Medication><Metabolic><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Middle East><Modeling><Modern Man><Murine><Mus><Mutation><Nutrition Interventions><Nutritional Interventions><Oral><Outcome><Pathogenicity><Patients><Pb element><Pharmaceutical Preparations><Pharmacokinetics><Pharmacology and Toxicology><Phase 1/2 Clinical Trial><Phase I/II Clinical Trial><Phenotype><Phenylalanine><Phenylalanine 4-Hydroxylase><Phenylalanine 4-Monooxygenase><Phenylalanine Hydroxylase><Phenylalanine Hydroxylase Deficiency Disease><Phenylalanine hydroxylase deficiency><Phenylketonurias><Population><Pre IND FDA meeting><Pre-IND mtg><Risk><Russia><Severe Phenylalanine Hydroxylase Deficiency Disease><Therapeutic><Therapeutic Gene Editing><Thesaurismosis><Toxic effect><Toxicities><USFDA><United States Food and Drug Administration><Variant><Variation><Vitamin B4><Work><amino acid metabolism><autosome><base editing><base editor><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><cofactor><cognitive development><cognitive dysfunction><cognitive loss><curative intervention><curative therapeutic><curative therapy><curative treatments><diet intervention><diets><drug/agent><enzyme therapy><gRNA><gallium arsenide><gene-editing therapy><genome editing><genome editing based therapy><genome editing therapy><genome editing treatment><genome editing-based therapeutics><genome mutation><genomic editing><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><humanized mice><humanized mouse><lead optimization><lipid based nanoparticle><lipid nanoparticle><metabolism disorder><model of animal><mutation correction><neuron toxicity><neuronal toxicity><neuropsychiatric><neuropsychiatry><neurotoxic><neurotoxicity><non-human primate><nonhuman primate><pharmacologic><phenylalaninase><phenylalaninemia><phenylpyruvic oligophrenia><postnatal><pre-IND consultation><pre-IND discussion><pre-IND meeting><pre-Investigational New Drug meeting><prenatal><prime editing><prime editor><response><therapeutic editing><therapeutic genome editing><transition mutation><unborn>