Phenylketonuria (PKU) is an inborn error of metabolism caused predominantly by mutations in the phenylalanine hydroxylase (PAH) gene and resulting in toxic buildup of the amino acid phenylalanine (Phe) in the brain. Gene mutations of PAH result in inefficient Phe metabolism leading to hyperphenylalaninemia. There are at least 1,000 unique mutations in the PAH gene, resulting in phenotypic variation in the amount of enzyme produced and/or enzyme activity. With the near universal adoption of newborn screening for high plasma phenylalanine PKU is typically diagnosed at birth. PKU has been described in all ethnic groups, and its incidence worldwide varies widely, but is estimated to occur in approximately 1 in every 15,000 births. If left untreated, severe and irreversible disability can occur to include permanent intellectual disability, seizures, delayed development, behavioral problems, and possibly psychiatric disorders. It has been shown that administration of tetrahydrobiopterin improves the function of PAH resulting in reduction in phenylalanine plasma concentration. If compared to current available therapies, CNSA-001 could potentially address more effectively the metabolic and neurological signs and symptoms of PKU patients.


Primary BH4 deficiency (PBD) is a rare disorder caused by a deficiency in one of the pathways responsible for the production of tetrahydrobiopterin (BH4). There are approximately 100-200 PBD patients in the US and close to 1,000 in the developed world. This condition is sometimes associated with hyperphenylalaninemia as well as deficiency in the production of neurotransmitters, dopamine and serotonin. Due to the near universal adoption of newborn screening for high plasma phenylalanine primary BH4 Deficiency is typically diagnosed at birth.  Signs and symptoms of this condition can include intellectual disability, seizures, and disorders of movement, swallowing, thermoregulation, and behavioral regulation. CNSA-001 treatment may normalize phenylalanine plasma concentrations and could potentially eliminate or reduce the need for neurotransmitter supplementation in these patients.