A Q&A with Rick Layer, Vice President, Myrtelle’s Head of Pharmacology and Translational Science

New research is changing the way we think about oligodendrocytes. Below we breakdown some common questions:

How are oligodendrocytes involved in brain functions like learning and memory?

We’ve known for a long time that cells called “neurons” pass information along processes (like wires) called “axons” and that oligodendrocytes wrap nearby axons with a material called myelin. Myelin is an insulating fatty substance.  Imagine the axon as a very long hot dog with oligodendrocytes providing the buns. Many buns would be needed to cover a long axon. The little gap between successive buns (the myelin sheaths) is called the node of Ranvier. Electrical signals transmitted along axons “jump” from one node to the next, greatly enhancing the speed of transmission (known as conduction velocity). It was long thought that the structure of myelin sheaths was stable, with the sole function of maximizing the velocity of signal propagation. However, new research shows that the structure and function of myelin is far more dynamic than we once thought.

For example, we now know that oligodendrocytes can supply energetic fuel to neurons via their myelin sheaths. Much like it takes many logs in a fireplace to keep a cabin warm, it takes a lot of energy to transmit electrical signals along axons. However, axons don’t store energy very well (in the form of “ATP,” the energy molecule). Just like a good neighbor can offer his extra logs to help warm up a cold cabin, oligodendrocytes can transfer a chemical fuel called “lactate” through myelin to neurons. Neurons then turn the lactate into ATP. Neurons can also return the favor. When oligodendrocytes are building myelin and need extra fuel, neurons can send them the chemical “N-acetylaspartate (NAA),” which oligodendrocytes can then turn into ATP. The ability of neurons and oligodendrocytes to be good neighbors enables the brain to perform energetically costly functions like learning and memory.

We are also learning that myelin structure is not fixed, but adaptive, and can change depending on the need. Oligodendrocytes can adjust conduction velocity by altering myelin structure. Conduction velocities can be sped up by increasing the length or thickness of existing myelin sheaths (longer, thicker buns) as well as by adding new myelin sheaths. These subtle changes in myelin structure can fine-tune conduction velocities and enhance communication between neurons. This remodeling of myelin structure by oligodendrocytes appears to be critical for learning and memory. On the other hand, disruptions in the ability to remodel myelin may be important in certain disease states.

What is driving the resurgence of interest in oligodendrocytes? 

We’re learning a lot about the role of oligodendrocytes in normal brain function and in disease states thanks to the development of new tools and technologies. For example, we can develop new animal models of genetic diseases like leukodystrophies (diseases affecting the white matter of the central nervous system) using gene-editing technology. Many leukodystrophies result from a change in a single nucleotide in a gene, like a spelling error that changes the meaning of a word and sentence (‘He wore a hAt’ vs ‘He wore a hUt’). We now have new tools, like CRISPR-Cas9, that can create specific mutations in model systems that mimic human genetic diseases and can be used to test the effectiveness of our therapies.

We can also use a technique called ‘single-cell RNA sequencing’ to map gene expression in individual cells from a brain region. It helps to think of brains as cities and brain cells as people in a city. Imagine comparing Boston and Philadelphia (where most of the Myrtelle team live). Previously, we could only look at averages. The average Bostonian makes slightly more lobster rolls than the average Philadelphian (not very interesting). Now, we can look at every individual in each city (like single cells in a brain). We can learn that cooks (not plumbers, teachers, or dentists) are making all the lobster rolls in Boston. Cooks in Philadelphia are making cheese steaks! In other words, we learn so much more at this level of detail. Instead of cooks in cities, we can compare individual cells from normal animals to cells from animals with a specific disorder and identify the cell types (like cooks) and specific genes (like lobster rolls) that are associated with disease states. This technique has been used to identify oligodendrocytes as important in the pathology of various neurological and psychiatric diseases.

New microscopy techniques and MRI methods are available to image oligodendrocytes and white matter (where oligodendrocytes are concentrated) in the living brain, enabling the ability to measure white matter structure and volume. For example, Dr. Chris Janson recently showed some very exciting MRI data that show increases in myelin and white matter content in the brains of Canavan disease patients treated with MYR-101. Finally, we now have next-generation viral vectors, like the recombinant AAV Olig001, that allow targeted delivery of genetic cargo to oligodendrocytes. Altogether, these techniques are rapidly advancing our knowledge of oligodendrocyte function and our ability to both target and affect these cells, which we believe will spur the development of gene therapies for a host of myelin disorders.

How are these new technologies and the expanding knowledge of oligodendrocyte physiology benefiting our understanding of myelin disorders?

The ability to deliver therapeutic genetic cargoes (such as a healthy copy of a gene) to oligodendrocytes (that have a nonfunctional copy of that gene) has already had an impact on treatment of myelin disorders like the leukodystrophies. Myrtelle recently reported positive 6-month post-treatment data in its first-in-human clinical study of a gene therapy for Canavan disease that uses the oligodendrocyte-selective AAV delivery vector Olig001 to deliver a replacement gene (for the enzyme ASPA) in Canavan disease. Specifically, improvements in clinical measurements of motor, language, and cognitive function, improvements in MRI-based measures of myelin, white matter, grey matter and CSF volumes, and reductions in levels of NAA (the substrate for the ASPA enzyme) were observed in Canavan patients within 3 to 6 months after treatment. Myrtelle is also evaluating oligodendrocyte-targeted gene therapies in animal models of other leukodystrophies like Pelizaeus-Merzbacher disease.

Leukodystrophies like Canavan and Pelizaeus-Merzbacher disease are classified as hypomyelinating diseases in which the formation of white matter is disrupted. Other myelin disorders result from degeneration of established myelin. For example, the most common myelin disorder is multiple sclerosis, which affects an estimated one million patients in the United States alone. The main problem in multiple sclerosis is that a person’s immune system begins to attack one or more of the components of myelin, resulting in demyelination and neurological symptoms. Certain immunomodulatory therapies may reduce the attacks by immune cells that characterize the initial course of the disease, but these treatments are less effective at halting the later, progressive course, and they are not oriented to restoring myelin once it has been lost. One potential strategy to address progressive multiple sclerosis is to encourage oligodendrocytes to make new myelin (this is called ‘promoting endogenous remyelination’).

Recent studies using single-cell RNA sequencing have shown that oligodendrocytes from brains from multiple sclerosis patients displayed distinct gene expression signatures compared with oligodendrocytes from non-multiple sclerosis brains, and that mature oligodendrocytes can contribute to remyelination in the disease state. These results raise the possibility that delivering the right gene to oligodendrocytes with the right vector could promote remyelination.

Since oligodendrocytes have a more dynamic role in brain function than previously thought, are we learning more about their role in other brain disorders?

We’ve seen that oligodendrocytes and myelin structure are involved in learning and memory. For example, we have known for twenty years that learning new tasks, like juggling or playing the piano, can change white matter structure. As a reminder, “grey matter” contains the neuronal cell bodies and dendrites, and “white matter” contains bundles of myelinated axons (oligodendrocytes are enriched in white matter but are also found in grey matter). With the new tools available to scientists now, such as the ability to measure changes in myelin genes and subtle alterations in myelin structure, we are finding out that oligodendrocytes, myelin, and white matter structure changes are involved in a wide range of neurological and psychiatric disorders. In hindsight, it shouldn’t be surprising, since white matter takes up about half the human brain.

For example, neuroimaging studies show that white matter abnormalities and demyelination are important in Alzheimer’s disease, and single-cell RNA sequencing studies show that Alzheimer’s disease risk is associated with altered cholesterol deposition in oligodendrocytes and reduced myelination. Similarly, there is an association between Parkinson’s disease risk and oligodendrocyte-specific gene expression. Atypical myelination patterns and changes in gene expression implicate disrupted oligodendrocyte function in patients with autism spectrum disorder, schizophrenia, and major depressive disorder. New tools and technologies have led to a new appreciation for the role of altered oligodendrocyte gene expression in a host of different diseases. The ability to use AAV vectors like Olig001 to deliver therapeutic genes to oligodendrocytes opens many new possibilities for developing new treatments for these different diseases.

Share via: