CincY as a Treatment for Creatine Transporter Defect
Creatine serves as a crucial energy source in the brain, and it is delivered to brain tissue by a specialized transport protein. Approximately 42,000 males in the U.S. are affected by creatine transporter defect (CTD), in which creatine cannot enter the brain, resulting in profound learning disabilities, autistic behavior, recurring epileptic seizures and lifelong care needs. There are no FDA approved therapies for this group of patients. The lead collaborator has identified a creatine analog (CincY) that is able to penetrate the brain and serve the same role as creatine, even when creatine transporters are defective. The goal of this project is to develop CincY into an oral therapeutic to treat CTD.
The academic colleagues of Lumos Pharma previously reported severe expressive and cognitive delays in a 6-year-old boy, who has a unique creatine deficiency in the brain, which was diagnosed by proton magnetic resonance spectroscopy (MRS). They found that he has a nonsense mutation in the X-linked creatine transporter gene (CT1; SLC6A8), which resulted in the expression of a truncated (non-functional) creatine transporter protein. This condition is now known as creatine transporter deficiency (CTD), and is one of three creatine deficiency syndromes. The creatine deficiency syndromes are considered rare disorders and have autism-like features. The discovery of inborn errors of metabolism involving creatine synthesis (two other disorders are readily reversed with creatine treatment) and transport, as well as the use of creatine transporter knockouts, that model the phenotype of these diseases, provide compelling evidence suggesting that the creatine/PCr/CK system plays a critical role in normal brain function.
It is estimated that CTD causes between 1 and 5 percent of all x-linked mental retardation. The primary clinical manifestations of the affected males are mental retardation, severe expressive language disorder and often with a seizure disorder, requiring dependent care for life. The creatine transporter knockout mice were treated with our compound (CincY), a compound shown to be capable of 1) getting across the blood brain barrier and 2) improving brain metabolism and cognitive function of the mice. Lumos' compound, CincY, a repurposed small molecule, that has an inactive investigational new drug (IND) application filed for another indication, has shown to be effective in treating and reversing CTD in the knockout mouse model.
Two parallel groups of patients with brain creatine deficiency syndrome (GAMT and AGAT), which have similar clinical manifestations as CTD, show significant clinical improvement when supplemented with creatine monohydrate. Creatine monohydrate supplementation is not effective in CTD since the creatine transporter gene is defective, preventing creatine from crossing the blood-brain barrier. As a result, no clinical improvement is seen in CTD patients when supplemented with creatine monohydrate. CincY has been shown to cross the blood-brain barrier, interact with creatine kinase in the brain, become phosphorylated and act in the same way as creatine as an energy buffer. The focus of this TRND collaboration is the manufacture of necessary API, completion of a new CMC section, and the completion of all pre-clinical and IND-enabling studies. Upon completion, Lumos Pharma intends to file a new IND and begin clinical trials to study the use of CincY in the treatment of CTD in human subjects.
Lumos Pharma, Inc., Austin, Texas
Public Health Impact
CTD is a serious lifelong medical condition that affects approximately 42,000 males for which there currently is no treatment. A child with CTD requires dependent care for life due to varying degrees of mental retardation, lack of language development, and autism spectrum disorders. A therapy for boys with CTD would result in increased quality of life and societal productivity of the patient and care givers.
TRND is performing efficacy studies in animal models of the disease and will generate all data needed to file an IND with the Food and Drug Administration, including additional in vivo efficacy and toxicology studies, pharmacokinetic evaluations and development of appropriate formulations for human drug dosing. In addition, TRND is developing and performing a prospective natural history study of the disease course in humans, along with a registry system for identifying and recruiting patients with the disease, both of which will be necessary for a clinical trial.