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Therapeutics for Rare and Neglected Diseases

LUM-001 as a Treatment for Creatine Transporter Deficiency

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 United States are affected by creatine transporter deficiency (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 therapies for CTD patients approved by the Food and Drug Administration (FDA). The lead collaborator has identified a creatine analog (LUM-001) that can penetrate the brain and serve the same role as creatine, even when creatine transporters are defective. The goal of this project is to develop LUM-001 into an oral therapeutic to treat CTD.

Scientific Synopsis

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. 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 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 a seizure disorder, requiring dependent care for life. Creatine transporter knockout mice were treated with LUM-001, a repurposed small molecule that was shown to be capable of (1) getting across the blood brain barrier and (2) improving brain metabolism and cognitive function of the mice.

Two parallel groups of patients with brain creatine deficiency syndromes (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 because 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. LUM-001 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.

Lead Collaborator

Lumos Pharma, Inc., Austin, Texas
Robert Davis

Public Health Impact

CTD is a serious lifelong medical condition that affects approximately 42,000 males. Currently, there is no treatment for CTD. 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 patients and caregivers.


After NCATS’ acceptance of the project, Lumos was able to secure additional funding from the Wellcome Trust to speed the team’s collaborative work. TRND scientists performed pharmacokinetic studies in animal models of the disease to better understand brain uptake of LUM-001. Key toxicology, formulation development, and chemistry and manufacturing activities have been completed, which enabled Lumos to successfully file an Investigational New Drug (IND) application with the FDA. To support future clinical trials of LUM-001, TRND is collaborating with Lumos on a prospective natural history study of the disease course in patients, which will occur at multiple sites, including the NIH Clinical Center.

Last updated: 05-11-2017
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