A single injection of SOD1-targeting RNA into the subpial space, which is below the innermost meningeal layer, was able to spread throughout the spinal cord and, via retrograde delivery, into brain centers that project to the spinal cord in several animal models, including primates.

Silencing of SOD1 in the spinal cord of mice was able to halt or prevent the development of amyotrophic lateral sclerosis (ALS) when delivered after or before the onset of symptoms, respectively.

Researchers at the University of California at San Diego reported those results in the Dec. 22, 2019, online issue of Nature Medicine.

Senior author Martin Marsala, professor in the Department of Anesthesiology at UC San Diego School of Medicine and a member of the Sanford Consortium for Regenerative Medicine, called the results “remarkable.”

“We were recording these mice every month for open-field running,” he told BioWorld. “And my technician just came every month and said, ‘No disease. No disease. No disease,’” long after all of the untreated control animals had succumbed to ALS.

The approval of Spinraza (nusinersen, Biogen Inc.)and Zolgensma (onasemnogene abeparvovec-xioi, Novartis AG) for type 1 spinal muscular atrophy has demonstrated that gene therapy can deliver profound benefits in neuromuscular disorders.

However, what has been “missing in industry and in the field of gene therapy for ALS,” Marsala said, is a delivery method that is effective in adults.

Spinraza and Zolgensma are delivered intravenously, or into the cerebrospinal fluid (CSF) via intrathecal injection.

Both methods, though, leave them outside of the pia mater, the innermost of the three protective layers that surround the brain.

And it turns out that “the pia mater is really doing an incredible job of screening out an awful lot of stuff that you would think would be getting into the spinal cord” from the CSF, Michael Krupp told BioWorld.

Krupp and Marsala are co-founders of startup Neurgain Technologies Inc., which operates under the tagline: “Hits the spot.” The company is developing a device for subpial delivery of therapeutics.

The pia mater’s toughness is a problem for treating most neurodegenerative diseases, including ALS, which are mostly sporadic and first start showing symptoms in adulthood.

In the work now published in Nature Medicine, Marsala and his colleagues showed that delivery into the subpial space at the level of the cervical spinal cord allowed the vector to spread throughout the spinal cord, and into the motor centers of the brain via retrograde transport in large animals.

In a mouse model of ALS, “disease can be completely blocked from developing if treatment is done in 120-day-old mice, [and] after 50 percent motor neuron loss, we were able to block progression of disease,” Marsala said.

Postmortem assays of the animals showed no neurodegeneration, and gene correction in up to 95% of cells.

Krupp, who is Neurgain’s CEO, said the company would be interested in taking the ALS work forward “if we find the right partner interested in doing it with us.”

However, Neurgain’s initial target is pain, where the company’s strategy is to rewire excitatory into inhibitory circuits via highly localized delivery of a two-gene combination.

And “the real power of this company is the delivery technology coupled with some smart targets,” Krupp said.

“The key to the company is that we have both delivery technology, which is the subpial injection technology… but also uniquely, we can deliver to the entire spinal cord or to just discrete sections.”

While it desirable to treat the entire spinal cord in diseases like ALS, for pain treatment, “you only want to hit a discrete segment.”

Neurgain is working on getting its device approved independently from any particular program, which would enable the company to collaborate with various partners looking for a delivery technology.

The company has been “working diligently on a prototype design,” he said, and has had two meetings with the FDA to discuss the development plan.

“We have the ability to deliver genes, and we could deliver oligonucleotides, small-molecule drugs, and we can also do stem cells,” Krupp said. “The technology has a tremendous amount of potential.”

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