Neurodegenerative disorders, such as Alzheimer’s disease and multiple sclerosis (MS), are notoriously difficult to treat mainly because, despite decades of research, little is known about the underlying molecular mechanisms of disease. Without this knowledge, it is challenging to generate animal models, identify targets, and develop effective therapies.
However, symptoms caused by neurodegeneration can be monitored. So what about looking at neurodegenerative disorders from a different angle—by examining their effect on brain metabolism?
Taking a snapshot of brain metabolomics
Metabolomics studies of body fluids, including serum, plasma, and urine can take snapshots of the metabolic pattern in a patient sample at a given time and are well-established. The resulting data have helped researchers better understand mechanisms of metabolic disorders and characterize biomarkers for a broad range of diseases, such as cancer.
As neurodegenerative disorders often lead to long periods of neuronal inflammation, researchers at the French start-up company MedDay Pharmaceuticals wanted to know how this affects brain metabolism.
The result of their efforts is SPECMET, an innovative, ultra high resolution mass spectrometry-based platform enabling sensitive detection of metabolites in cerebrospinal fluid (CSF), the liquid that surrounds the brain tissue and the spinal cord.
“There is no barrier between the brain and the spinal cord, so CSF is a true witness of what happens inside the brain,” Frédéric Sedel, CEO and co-founder of MedDay Pharmaceuticals, explains.
Introducing the SPECMET platform
Employing cutting-edge bioinformatics by an experienced team of researchers, SPECMET enables identification of up to 2,000 metabolites and lipids at very low concentration. By comparing profiles in samples from patients suffering from neurodegenerative disorders with those from healthy individuals, changes in metabolomics patterns are monitored to find new drug targets or biomarkers.
“For example, we know that myelin degeneration occurs in many disorders, such as MS, Alzheimer’s disease, and some forms of autism. Myelin, in turn, plays an important role in providing energy to the axons. When myelin sheaths degenerate, axons suffer from starvation and energy failure, and eventually die,” Frédéric says.
“So what we are looking for are compounds that boost energy production in the brain by monitoring core metabolic processes such as ATP and NADH production in the Krebs cycle.”
Biotin: A promising candidate for treatment of progressive MS
One particularly promising candidate is currently the focus of Frédéric and his team: Compound MD1003, or high-dose biotin. In mice, the molecule was shown to easily cross the blood-brain barrier, a prerequisite for any kind of CNS treatment. In a clinical trial with patients suffering from progressive MS, biotin significantly slowed down progression of disability compared to placebo, and some patients even improved.
Encouraged by these data, a large multinational study enrolling more than 600 patients across Europe, North America, and Australia has been initiated, with final results expected by late 2019. Biotin may also be helpful in treating other neurodegenerative diseases, and several pilot studies are currently underway or in planning stage.
“The mode of action we propose for biotin is twofold: First, biotin boosts the productivity of the Krebs cycle, increasing energy supply to axons. Second, biotin is a coenzyme for myelin synthesis, and therefore stimulates myelin regeneration,” Frédéric explains.
Sometimes, more is better
But to achieve this effect, a very high dose of biotin is needed: “Our therapy has nothing to do with the food supplements you can buy in drug stores, that typically contain five milligrams biotin per tablet. Instead, we suggest an oral uptake of 300 milligrams biotin per day,” Frédéric emphasizes.
This dosage requires a very high degree of purity, as any additional substance present in the formulation might be toxic at higher concentrations. Production of this high-grade biotin formulation is therefore tightly controlled and meets all the regulatory requirements of a pharmaceutical drug.
Up to now, no major side effects have been detected except that high concentrations of biotin in body fluids can interfere with diagnostic assays based on biotin: streptavidin interaction, a fact that must be communicated to patients and laboratories to avoid false results.
As a result of the brain metabolomics screening on SPECMET, two additional compounds have been identified and are currently in preclinical phase. MD1105 is being developed as a disease-modifying therapy in Alzheimer’s, and MD1103 is intended to have an impact on certain core symptoms of autism, including social withdrawal and apathy.
The SPECMET platform is not at all limited to human samples: MedDay scientists have established successful partnerships with academic groups and start-ups to evaluate the effect of new compounds on the brain metabolome in animal models.
“This is something that we would certainly like to expand,” Frédéric states. “Our vision is to become a true CNS company that develops treatment for neurodegenerative diseases by alleviating or even reversing symptoms related to brain metabolism.”
Interested in learning more about how brain metabolomics can help elucidate the effects of neurodegenerative disorders? Visit MedDay Pharmaceuticals to find out!
Images via Kateryna Kon, Vasily Smirnov, Lerner Vadim, Minerva Studio, Iryna Imago and Shutterstock.com