Unmet Medical Need
Despite many decades of research, there is still no cure for ALS, Frontotemporal Dementia, Huntington’s Disease, Parkinson’s Disease and similar diseases.
2N Pharma builds on a decade of research and development by co-founder and CSO Dr John Nieland and collaborators. To translate the scientific discoveries into treatment options for patients, 2N Pharma has developed novel small molecule therapeutic candidates which we have named Mitometin.
COMMON PATHOGENIC MECHANISMS AND OUR MEDICAL HYPOTHESIS
The essence of our medical hypothesis is the strong correlation – and we believe, causality – between dysregulated fatty acid oxidation and the development of neurological disorders.
Strongly upregulated lipid metabolism and deficient glucose metabolism are important, shared pathogenic mechanisms that underlie processes such as increased production of radical oxygen species and oxidative stress, inflammation, myelin sheath damage and demyelination, accumulation of misfolded proteins, neuronal loss and loss of muscle strength.
Our drug candidate Mitometin is a small molecule, orally administered, reversible inhibitor of carnitine palmitoyl transferase 1 (CPT1), a key enzyme in beta-oxidation as it facilitates transport of fatty acids across the mitochondrial membrane. Pre-clinical data from animal models of neurodegenerative diseases including ALS, Parkinson’s Disease, Huntington’s Disease, MS and depression show that down-regulating fatty acid oxidation has a profoundly positive effect on survival and quality of life.
Figure 1. Transport of glucose and fatty acids. Glucose enters the cell via GLUT and is phosphorylated to glucose-6-phosphate by HK1 followed by conversion to fructose-6- phosphate. Fructose-6-phosphate is converted to pyruvate by PFK1. PDH transforms pyruvate into acetyl-CoA in the mitochondria. Acetyl-CoA is used in the Krebs cycle. Fatty acids enter the cell via FATP, which possess acyl-CoA synthase activity and converts fatty acids into fatty acyl-CoA. CPT1 facilitates the transport across the outer mitochondrial membrane by converting fatty acyl-CoA to acyl-carnitine. CPT2 reconverts acyl-carnitine into acyl-CoA and carnitine. Acyl-CoA is used in β-oxidation producing acetyl-CoA. Acetyl-CoA from glucose pathway and lipid pathway is used in the Krebs cycle. The energy produced in the Krebs cycle passes to the ETC, where it is converted into ATP. Inhibitory mechanisms include inhibition of PDH by acetyl-CoA and inhibition of CPT1 by malonyl-CoA (red inhibiting arrow). ATP: adenosine triphosphate, CPT1: carnitine palmitoyl transferase 1, CPT2: carnitine palmitoyl transferase 2, ETC: electron transport chain, FATP: fatty acid transporter, GLUT: glucose transporter, HK1: hexokinase 1, PDH: pyruvate dehydrogenase complex, PFK1: phosphofructokinase 1.