CB-101 is an FDA-approved indirect food additive which is regarded as GRAS. It is cleaved by lipases to produce NaB, slowly. While NaB is rapidly excreted through urine and high doses are required to be efficacious, a steady level of NaB in the blood with a lower dose avoids side effects associated with high doses of NaB. This treatment is under development for Huntington’s Disease (HD), Parkinson’s Disease (PD), and Glycine Encephalopathy (GE), also known as Nonketotic Hyperglycinemia (NKH).
HD is a fatal and inherited neurodegenerative disorder. No effective drugs are available to halt the disease progression. Typical symptoms include chorea, rigidity, and writhing motions or abnormal posturing. Psychomotor functions are also severely impaired together with both abnormal facial expression and difficulties in chewing, swallowing, and speaking.
The efficacy of CB-101 in HD and PD has been fully confirmed with relevant animal models. CB-101-fed animals showed improved motor and cognitive functions, suggesting a potential effective treatment for HD. CB-101 also protects dopaminergic neurons and restores striatal dopamine levels in a PD animal model. NaB, a CB-101 metabolite, has also demonstrated efficacy in improving locomotor functions in MPTP-insulted hemiparkinsonian mice.
GE is caused by an inborn error of the glycine cleavage enzyme system (GCS) leading to the accumulation of glycine in the plasma and cerebral spinal fluid (CSF). GCS is composed of 4 proteins (P-, H-, T-, and L-protein). P protein is a pyridoxal phosphate-dependent glycine decarboxylase encoded by the GLDC gene. H-protein is a lipoic acid with hydrogen-carrier protein encoded by the GCSH gene. T-protein is a tetrahydrofolate (THF)-dependent protein encoded by the AMT gene. L-protein is a lipoamide dehydrogenase. Biallelic variants in either GLDC or AMT lead to both the dysfunction of GCS and a significant impairment in glycine metabolism. Eighty-five percent of patients are very severely affected with intellectual disability, serious seizures, and spasticity.
CB-101 produces NaB molecules through lipases, thereby converting glycine to hippurate which is secreted into the urine. Thus, CB-101 attenuates hyperglycinemia with less side effects compared to NaB which requires a large amount to be effective.