Drugging the Genome

Company to Watch – NeuBase Therapeutics

In the first of four features on NeuBase Therapeutics, Big4Bio spoke with Founder and CEO Dietrich Stephan and CFO Todd Branning about the spark behind founding of the company, and how it is drugging the genome with precision genetic medicine. The second feature will provide an in-depth focus on its technology and pipeline, and plans moving forward.

by Marie Daghlian

Genetic medicines have enormous potential as nearly all diseases are driven by genetic mutations, but many genetic medicines in development are restricted due to issues of delivery, immunogenicity, and the ability to redose.

Dietrich Stephan, Founder and CEO of NeuBase
Dietrich Stephan, Founder and CEO of NeuBase

“The big ‘why’ of NeuBase is that we can directly drug the genome without the issues of early genetic medicines and address disease at the base level,” says Dietrich Stephan, founder and CEO of NeuBase Therapeutics.

Stephan’s background includes being part of the Human Genome Project and a career spent finding disease causing genes across a variety of diseases. He founded NeuBase in 2018 to translate research, first invented in Denmark by Peter Nielsen and moved forward by researchers at Carnegie Mellon University in Pittsburgh into precision genetic medicines to treat rare and common diseases.

The NeuBase platform, PATrOL, or peptide-nucleic acid (PNA) antisense oligonucleobase, is a fully differentiated synthetic platform engineered to overcome the hurdles of delivery, tolerability, selectivity, manufacturability, durability, and scalability that can limit other genetic medicine technologies.

“We’re not an ASO, we’re not an antisense RNA, we’re not a viral gene delivery technology. We’re very different, and our PATrOL platform technology delivers compounds that can wedge into the double stranded human genome and engage with a mutant gene with single base selectivity to neutralize it before it makes a mutant mRNA and a broken protein, and manifests in disease,” Stephan says.

Most genetic medicines, including ASOs and mRNAs, target RNA. Only a handful of companies can directly drug the genome.

“Ourplatform is designed to directly drug the genome and turn genes on if we need to, turn them off if we need to, and even edit them in vivo with excellent fidelity,” says Stephan. “Nearly every disease is driven by genetic changes, and we can address the major mechanisms that drive genetic disease. So, we believe our unified platform can have a broad impact across rare and common diseases.”

NeuBase can temporarily drug the genome to modulate gene function. NeuBase’s “PNA” looks like an oligonucleotide in that it has a backbone, it has nuclear bases, and it has a delivery shuttle tagged on the end of it, but it acts very differently. For example, NeuBase has shown that its PATRoL-enabled drug candidates can stop expression of a mutated toxic gene by blocking the RNA polymerase that reads that gene at the DNA level so no mRNA is made and thus no toxic protein is made. NeuBase can also design drug candidates that can also do the opposite by turning on a gene if it needs to increase its function to resolve a disease. But the mechanism of action is very different from base editing in that these gene modulations are temporary.

NeuBase can also permanently edit a mutation out.  While similar to some of the new base editing and prime editing technologies, Stephan says its PATrOL platform is in a class of its own.

Drugging the genome
“Drugging the genome”

“We use a series of these PNAs to open up the DNA double helix and slip in a DNA donor strand on top of the mutation,” says Stephan. “The cell recognizes this complex that’s sitting there on top of a mutation and uses its own nucleic acid repair enzymes to resolve the mutation. We don’t have to deliver modified CRISPR Cas9 bacterial enzymes, but we can leverage the cell’s natural machinery that has evolved through millennia to correct genes. That’s a very different strategy than other base editors and we have seen exquisite fidelity with our technology in vivo by utilizing these multiple layers of selectivity and the cell’s own high fidelity repair machinery.”

Proprietary chemistry enables the company’s therapies to be delivered systemically and achieve broad tissue distribution or be targeted, overcoming another issue with many genetic medicines, many of which are constrained to the liver or directly into the tissue of interest. NeuBase has engineered its PNAs to be delivered systemically by intravenous or subcutaneous injection that can get into every cell and tissue in the body, including in the brain. And because the PNAs are completely synthetic, the body doesn’t recognize them and can’t mount an immune reaction against them, promising the ability to be able to dose repeatedly and maintain the therapeutic effect over time.

NeuBase recently presented at the 2022 MDA Clinical & Scientific Conference and showed positive proof of concept in preclinical data for its lead compound targeting myotonic dystrophy type 1 (DM1) . The data also provided validation of the overall platform, says Chief Financial Officer Todd Branning.

“What we showed with this recent data presentation is that NeuBase has a differentiated approach to treating DM1. And we’ve talked about that conceptually, but now we’ve supported that with some significant data,” said Branning.

“People know that mRNAs can be a drug now. People don’t yet know that PNAs can be a drug. This data really crystallized two things,” says Stephan. “One is that our PATrOL-enabled PNAs work as drugs in vivo, directly addressing the genetic mutation, and secondly, that we can deliver these drugs via a patient-friendly route and get them to very difficult tissues, to targets such as skeletal muscle.”

NeuBase hopes to submit an Investigational New Drug Application for its experimental DM1 therapeutic to the U.S. Food and Drug Administration in the fourth quarter of 2022.


NEXT: Further exploring of NeuBase’s technology, pipeline, and future plans


This is part of the Big4Bio Company to Watch program for April 2022: NeuBase Therapeutics
For more information on the series, click here