Censa Pharmaceuticals is developing CNSA-001 as a therapy for orphan metabolic diseases associated with abnormal function of tetrahydrobiopterin dependent enzymes. The company is also exploring the potential role of CNSA-001 as a therapy for chronic central nervous system conditions.
Phenylketonuria (PKU) is an inborn error of metabolism caused predominantly by mutations in the phenylalanine hydroxylase (PAH) gene. Gene mutations of PAH result in decreased catalytic activity leading to hyperphenylalaninemia. There are many different mutations in the PAH gene (>400), resulting in phenotypic variation in the amount of enzyme produced and/or enzyme activity. High levels of phenylalanine are toxic to the brain. PKU is typically diagnosed at birth with the near universal adoption of newborn screening for high plasma phenylalanine. PKU has been described in all ethnic groups, and its incidence worldwide varies widely, but is estimated to occur in approximately 1 in every 10,000 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.
Gastroparesis is characterized by delayed gastric emptying in the absence of mechanical obstruction. Idiopathic gastroparesis accounts for most cases, but gastroparesis is also frequently associated with diabetes. Nitric oxide synthase which depends on tetrahydrobiopterin as a cofactor and is present in the enteric nervous system is considered an important factor in gastrointestinal motility. Nitric oxide synthase was found to be deficient in diabetic rats and such deficiency was associated with impaired smooth muscle relaxation and slower gastric emptying. The core signs and symptoms of gastroparesis are nausea, postprandial fullness, early satiety and upper abdominal pain. Administration of pterins in diabetic animal models and to diabetic human patients showed enhanced nitric oxide synthase expression and improved gastric motility. CNSA-001 could potentially become an important therapy for patients with diabetic gastroparesis.
PRIMARY BH4 DEFICIENCY
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. Primary BH4 Deficiency is typically diagnosed at birth with the near universal adoption of newborn screening for high plasma phenylalanine. Signs and symptoms of this condition can include intellectual disability, progressive problems with development, movement disorders, difficulty swallowing, seizures, behavioral problems, and an inability to control body temperature. CNSA-001 treatment may normalize phenylalanine plasma concentrations and could potentially eliminate or reduce the need for neurotransmitter supplementation in these patients.
Segawa disease is a rare disorder caused by an autosomal dominant mutation in the GTPCH gene which is associated with the de novo synthesis of tetrahydrobiopterin. The prevalence of Segawa Disease is thought to be 0.5–1.0 per million but may well be higher as cases are still consistently misdiagnosed. Low tetrahydrobiopterin concentration is responsible for the deficient production of key neurotransmitters such as dopamine and serotonin. Clinical symptoms include dystonia which is fully or partially responsive to dopamine treatment and non-motor symptoms such as sleep problems, depression, anxiety or obsessive-compulsive disorder. CNSA-001 could potentially eliminate or reduce the need for dopamine administrations in these patients while also addressing non-motor symptoms which are frequently attributed to serotonin deficiency.
CENTRAL NERVOUS SYSTEM DISEASES
A correlation between biopterin levels and CNS disorders has been reported in the literature. This may suggest an etiological role of a tetrahydrobiopterin deficiency in these disorders causing dysregulation of neurotransmitters production and release. Autism, for example, is associated with low tetrahydrobiopterin levels and recent studies have demonstrated positive effects of tetrahydrobiopterin administration in these patients. Major depression and obsessive-compulsive disorder have been found in subjects with a biopterin deficiency disorder. Decreased plasma concentrations of biopterin is common in bipolar disease, schizophrenic and schizoaffective patients. In Parkinson’s disease, motor and non-motor symptoms like depression are attributed to the deficiency in the production of neurotransmitters. CNSA-001 could potentially increase or normalize the production of neurotransmitters and improve symptoms associated with CNS diseases associated with neurotransmitter imbalances.