No matter how many molecules he threw at them, Paul Tesar couldnt get the brain cells to survive. Or he got them to survive, but then to everyones bafflement they still couldnt do what they were supposed to.

Tesar, a professor of innovative therapeutics at Case Western University, had spent years building stem cell models for multiple sclerosis, growing brain organoids in dishes and then seeing what small molecules restored myelin production. Now he was trying to do the same for other myelin diseases, particularly an ultra-rare genetic condition called Pelizaeus-Merzbacher disease, where a single mutation leads to the death of the myelin-producing neurons, called oligodendrocytes, and can kill patients in infancy.

Weve screened many thousands of small molecule compounds, Tesar toldEndpoints News. But we could not get them to restore function.

Then Tesar got an email from Ionis, the California biotech that had just used an RNA-modifying technology called antisense to build Spinraza, the first FDA-approved drug for the genetic neurological disorder spinal muscular atrophy.

Now, in a study published inNature,Tesar and Ionis have shown they can use a single dose of drug built from that technology to keep those neurons both alive and well-functioning and treat the disease at least in mice. The publication isnt groundbreaking, antisense researchers say, but it shows for the first time that antisense can be used to effectively target oligodendrocytes, an insight its authors hope will open up other rare myelin disorders to therapy.

Its not that its different than everything thats been done before, but it goes further than everything thats gone before, Jon Watts, a professor at the RNA Therapeutics Institute at UMass Medical School who is not affiliated with Ionis or the paper, told Endpoints, both in terms of duration of effect after a single dose, and the real focus in getting the biology, the therapeutic effect in oligodendrocytes.

The applicability to the most famous and common of myelin disorders, multiple sclerosis, is limited, researchers say, both because the therapy relied on having a specific gene to target and because the paper doesnt prove you can get an effect on the peripheral nervous system. Still, Berit Powers, an assistant director at Ioniss neurology research department and a co-author, pointed to several other genetic myelin disorders, known as leukodystrophies. That includes an Ionis program on Alexander disease, a rare childhood condition with Parkinsons-like symptoms.

Were certainly exploring the potential of ASOs in non-monogenic conditions like MS, Powers told Endpoints, using a shorthand for antisense oligonucleotides. But that work is very new.

This is hardly Tesars first foray into biotech. In 2015, he showed in Naturehow certain small molecules could regenerate myelin the holy grail for an MS therapy and founded Convelo Therapeutics around that work. Last year, they partnered with Genentech for an undisclosed sum and an exclusive option to acquire the company.

Myelin is a fatty substance that coats neurons, insulating them and helping electric currents pass through. Tesars lab was broadly interested in the question of why myelin fails, both in MS and rare diseases, and about 7 years ago he got a grant to work from the PMD Foundation.

First, Tesar built stem cell models of the disease, figuring out how different mutations in a single gene, called PLP1, lead oligodendrocyte progenitor cells (the stem cell-like cells that will become oligodendrocytes) to create a toxic RNA and a mutated protein that kills them soon after they differentiate. Then, he tried to suppress that gene with different chemicals, eventually testing over 3,000 different compounds.

He was able to eventually get the oligodendrocytes to survive, but to his surprise, they didnt produce myelin as they should. The surviving cells still couldnt properly function, revealing, he wrote in a 2018 Cell paper a second phase of pathology. A hypothetical treatment, he argued, would have to both keep progenitor cells alive and then treat the survivors in a way that induces myelination.

With antisense, he and Powers Ionis team were able to do both. Antisense oligonucelotides consist of strands of RNA that are a mirror image of the RNA you want to target. The mirror binds to and silences, or turns off, that gene. In the study, the researchers confirmed that PLP1 was disease-causing by knocking out the gene in cell lines with CRISPR. Then they injected mice with antisense strands through the spinal cord, the same way Spinraza is delivered. (You cant use CRISPR to treat the disease in humans, because theres no good way yet of delivering it.)

Powers and Tesar were unsure if they would be able to target oligodendrocytes and progenitor cells. What they found, though, was complete restoration of oligodendrocytes and a profound rescue of neurological function. Myelin, too, was finally restored. Mice that died after 3 weeks now lived for over 200 days.

Ionis hasnt licensed the drug and its unclear yet the implications for other diseases, but researchers say the results could translate into humans quickly, at least by drug development standards.

I do think its very rapidly translatable, Watts said. Based on the data theyre showing here, and based on the unmet need, this appears to be something that could be translated pretty quickly into a Phase I trial.

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Ionis, leading MS researcher throw antisense at a new type of brain cells - Endpoints News