Brain Regeneration

Highlights

• Remyelination is the regeneration of myelin—a substance that makes up about a third of the brain.
• Scientists are honing in on drugs that promote remyelination that could be used to treat conditions like multiple sclerosis, spinal cord injury, traumatic brain injury, and stroke.

A standard 96-well plate is 128 millimeters long and 85 millimeters wide—small enough to just about fit in the palm of your hand. Each well spans maybe three-quarters of the width of your pinky and is about as deep as the thimble in Monopoly. Hundreds of thousands of cells can fit into each well.

Researchers often use 96-well plates to test the effects of different conditions on specific cell types. If X is added to cell type Y, what happens? X could be a growth factor, a toxin, a cocktail of secreted factors from a different cell type, or it could be a range of experimental drugs.

In 2014, researchers at the University of California San Francisco (UCSF) used modified 96-well plates to screen 1,000 bioactive molecules. Each well of their plates was outfitted with micropillars—microscopic mountain peaks uniformly spaced along the bottom of the well, giving it the appearance of one side of a Velcro strip. The disease they were interested in finding a treatment for was multiple sclerosis (a demyelinating disorder of the brain and spinal cord). The cells were oligodendrocyte precursor cells. Otherwise known as OPCs, which differentiate into oligodendrocytes and generate myelin, the target of misguided immune attacks in multiple sclerosis.

The UCSF group was looking for molecules that pushed oligodendrocytes to wrap the micropillars with myelin as though they were damaged nerves. Myelin rings formed at the bottom of the well meant success. Molecules that created rings in the 96-well plates could potentially be used to stimulate the regeneration of attacked myelin, or remyelination.

Myelin is a fatty substance that wraps around nerve fibers (axons). Myelin increases the speed signals can travel along the long wires of the brain and provide a means of nutritional support. Myelin can become damaged in diseases like multiple sclerosis; after strokes; after spinal cord injuries and traumatic brain injuries; and may even be malformed from birth in congenital leukodystrophies (specific gene abnormalities that lead to improper myelin formation).

Remyelination is the regeneration of myelin after it had been degraded in some way.

“We know from multiple sclerosis, and associated experimental models, that when myelin becomes degraded there are significant neurological deficits,” says Dr. Andrew Caprariello, a Ph.D. scientist with 14 years of experience in the field now working for a biotech company focused on remyelination. “In cases where the primary defect is one that targets myelin causing its degeneration, simply by restoring the myelin sheath, we’re able to both preserve the health of the axon and restore its function. We’re able to take a clinical deficit and make it recovered.”

When myelin is stripped away from nerve fibers, the nerve fiber loses a source of nutritional support. It also becomes more energetically expensive for the fiber to continue to transmit signals. Both of these factors leave the nerve fiber more susceptible to eventual degeneration. And once the fiber degenerates, signals no longer have a path to travel along, and clinical deficits, such as losing the ability to walk or make a fist, become apparent. Remyelination can prevent that degeneration.

The micropillar screen identified a cluster of molecules that promoted myelin formation. One was a drug called clemastine. Clemastine is an over the counter antihistamine. It’s an allergy medication that has been licensed for use since 1992. Clemastine is thought to work by antagonizing the M1 muscarinic acetylcholine receptor expressed by OPCs. Inhibiting that receptor stimulates the maturation of the OPC into an oligodendrocyte. Clemastine may also work by promoting the accumulation of a certain type of lipid in OPCs, priming them for myelin formation.

But remyelination isn’t as simple as getting an OPC to become a myelinating oligodendrocyte. There’s a whole host of barriers to remyelination, some are within the OPC themselves and others are outside of the cell. “[Inside the cell] there’s signaling cascades that inhibit differentiation and, therefore, the remyelinating capacity of the cell,” says Caprariello. “They exist for a good reason. The fine-tuning of myelin during development requires a go signal, but a stop signal as well. You must have the yang to its yin to get the fine-tuning of conduction velocity. But the stop signals become a problem in the context of remyelination.”

Outside of the cell, there are remyelination inhibitors deposited among and around areas where myelin has been degraded. Presumably, these exist to prevent damage from spreading. “There’s the disease-associated proteoglycans, chondroitin sulfate proteoglycans, and hyaluronan, for example,” says Caprariello. “There’s even just the break down of myelin. Myelin debris itself is an impediment to the regeneration of myelin.” Adding to the complexity of trying to stimulate remyelination are the scavenger cells of the brain. They must clear the inhibitory signals before remyelination can take place. “As you age, [these cells] become compromised in their ability to clear garbage. That is yet another impediment,” notes Caprariello.

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Despite the barriers, clemastine has performed well in promoting remyelination in animal models where myelin damage is a prominent feature. Indicators of remyelination have been seen in experimental autoimmune encephalomyelitis in 2014; in 2015, a group in China saw remyelination after mice were fed cuprizone, a toxin that selectively destroys oligodendrocytes in certain areas of the brain; and in 2018, clemastine promoted remyelination alongside exercise after lysolecithin was injected into myelin rich areas of the spinal cord. Lysolecithin degrades lipid-rich structures like myelin.

A clinical trial for clemastine as a remyelinating therapy for multiple sclerosis began in 2014. The trial, called ReBUILD, was a 150-day, double-blind, randomised, placebo-controlled, crossover trial. The patients admitted into the trial had relapsing remitting multiple sclerosis with chronic demyelinating optic neuropathy—a clinical condition where the nerve fibers between the eyes and the brain become inflamed and lose their myelin. Treating patients with clemastine reduced the time it took a signal received by the eye to travel to the visual cortex—an indication of myelin repair on the optic nerve. The results were published in the journal Lancet in 2017.

Clemastine created a lot of optimism for researchers studying remyelination and for people with multiple sclerosis, spinal cord injuries, traumatic brain injuries, and other demyelinating disorders. And it is far from the only remyelinating drug being developed. “Preclinically, right now as a field, we’re up to about 80. In clinical trials in various diseases? Probably about 25% of that. So, we’re doing pretty well,” says Caprariello.

Two others currently in clinical trials are bexarotene and opicinumab. Bexarotene is an oral medication currently used to treat certain types of skin cancer. It binds to the retinoid X receptor on oligodendrocytes and promotes myelin formation. Bexarotene is being tested in patients with relapsing remitting multiple sclerosis as an add on to their existing therapy. The results are expected in the spring of 2020. Opicinumab was specifically designed to target the LINGO protein. LINGO is expressed on neurons and oligodendrocytes and interfering with it promotes myelin repair.

A phase 2 clinical trial of opicinumab called AFFINITY began in 2017 and is expected to be completed in 2022. AFFINITY builds on previous trials like the SYNERGY study. The SYNERGY study involved patients with relapsing remitting multiple sclerosis and tested the effectiveness of opicinumab as an add on therapy in patients already using a disease-modifying therapy. Unfortunately, opicinumab did not meet its primary endpoint of improving patients’ ability to walk, their upper limb coordination, their cognitive function, or their overall disability. Careful analysis of the data, however, has allowed the researchers to pinpoint patients in the study who responded best to the treatment as well as hone in on dosage and outcome measures that will better indicate remyelination in the AFFINITY trial. Like the SYNERGY study, AFFINITY will test the effectiveness of opicinumab in relapsing remitting patients in combination with their existing therapy. This trial will focus on patients with clinical features more conducive of myelin repair. The participants will have experienced their first disease symptom within the last twenty years and will have met brain imaging criteria indicative of myelin damage and intact nerve fibers that can be remyelinated.

The trial design of drugs like bexarotene and opicinumab highlight the utility of remyelination as an add on therapy working alongside an existing treatment. “Modulating immune function does a fantastic job for reducing clinical relapses, but the disease seems to progress nevertheless. That’s instructive that there needs to be an additional element that targets the brain. Is that remyelination? I hope,” says Caprariello.