Science
Our therapeutic
approach
GliaPharm’s pioneering approach is to stimulate energy utilization in the brain by targeting a type of glial cells called astrocytes. While the importance of glial cells has been largely overlooked in neuro drug development, it is now clear that these cells play a key role in sustaining brain functions and neuroprotection.
Targeting glial cells represents an innovative approach for the treatment of neurological and psychiatric disorders.
A healthy
brain needs
energy
The brain requires high amounts of energy to function and to ensure neurotransmission and neuroprotection. The brain weighs 2% of the body mass but requires 20-25% of the energy consumed.
The main source of energy for the brain is glucose. A decrease in glucose use by the brain, which is called brain hypometabolism, is at the core of various neurological conditions.
Astrocytes, the brain's metabolic regulators
In addition to neurons that transmit electrical information, the brain is composed of other types of cells called glial cells. Glial cells represent about 50% of all brain cells, and are critical to control cerebral functions. An important type of glial cells called astrocytes play a major role in the regulation of brain metabolism. Astrocytes are localized in between between capillaries – the source of energy for the brain – and neurons – the consumer of energy in the brain. Astrocytes promote the transfer of energy from the circulation to neurons through the process known as the ANLS (see below).
Schematic representation of the Astrocyte Neuron Lactate Shuttle (ANLS), showing how glucose enters the brain through astrocytes, is metabolized into lactate and finally used by neurons.
The Astrocyte-
Neuron Lactate
Shuttle (ANLS)
The role of astrocytes in the regulation of brain energy metabolism was first discovered by the group of Prof. Magistretti in the 1990s. The so-called astrocyte-neuron lactate shuttle (ANLS), which explains how energy is transferred from the blood circulation to neurons through astrocytes, was discovered.
Astrocytes exhibit a specific metabolism called ‘aerobic glycolysis’, meaning that they can metabolize glucose and produce lactate in the presence of oxygen. Once secreted by astrocytes, lactate can be used by neurons to produce energy. Importantly, aerobic glycolysis in astrocytes is stimulated by neuronal activity, thereby providing a direct relationship between energy need upon brain activity and energy supply.
Our therapeutic approach is to target astrocytes in the brain to promote the ANLS, thereby stimulating the supply of energy to neurons that is defective in neurological conditions.
Indications
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) Scan showing reduced glucose uptake in Alzheimer’s patients compared to healthy subject. Modified from Kuehn, JAMA, 2020.
A number of neurological diseases exhibit hypometabolic features. These include neurodevelopmental, neurodegenerative and psychiatric disorders.
First, the orphan neurometabolic disease GLUT1 deficiency syndrome (GLUT1-DS, also known as De Vivo disease) is caused by a mutation in the transporter of glucose GLUT1, which is expressed in the endothelial cells of brain capillaries and astrocytes. Decreased functionality of glucose uptake into the brain in GLUT1-DS leads to decreased levels of glucose and lactate in the brain. Symptoms range from epilepsy in young children to motor dysfunction and cognitive impairments.
Neurodegenerative diseases are also severely affected by hypometabolism. Alzheimer’s disease is well known for its hypometabolic status that appears early in the pathology. Amyotrophic lateral sclerosis (ALS) is also a key target indication with hypometabolic features and defects in lactate transport in the central nervous system.
Finally, psychiatric disorders such as major depression are also prevalent indications with important hypometabolic features and glial cells dysfunction.
