In an interview with PharmaShots, Dietrich Stephan, Ph.D., CEO of NeuBase Therapeutics shared his views on the importance of preclinical in vivo data for PATrOL-enabled anti-gene for myotonic dystrophy type 1.

Shots:

• NeuBase announced in vitro and in vivo data for its DM1 program, demonstrating the potential of its genetic medicine platform to target the disease-causing mutation without negatively impacting the gene's function
• Data showed that NeuBase's candidate both rescues mis-splicing across key gene transcripts that are dysregulated in DM1 and bring DMPK mRNA back to baseline levels
• The new data provide significant support for NeuBase's DM1 program and broadly demonstrate the unparalleled precision of its novel genetic medicine platform

Tuba: Discuss the specifications of the company's PATrOL platform. How is this technology different from other precision genetic platforms?

Dietrich: NeuBase can uniquely target and drug the genome  the three billion letter blueprint of life with exquisite precision, so as to turn genes on, off, or even change their function and thus resolve the majority of causal insults behind most diseases. This includes not only what we usually think of as genetic diseases (also known as Mendelian diseases), but also cancers and other common human diseases that will touch most of us. As every human disease has a genetic component, we strive to make a large positive impact on suffering and death on a global scale.

Targeting the genome allows us to address the root causality of disease, which is very different than what we as an industry have historically done through targeting proteins. Drugging the genome with high precision allows us to minimize or even eliminate engagement of our drugs with other healthy and normally functioning genes in the genome to minimize side effects  something that was not easily done when targeting proteins as we could not predict their structures across the entire proteome.

Relative to other precision genetic medicine platforms in this nascent, yet already transformational, cohort of companies, the PATrOL platform is a new approach that combines capabilities of all of the precision genetic medicine companies - RNA silencing companies (which turn toxic disease-causing genes off), gene replacement companies using gene therapy and mRNA approaches (which turn genes on) and gene editing companies (which change the function of mutated genes) -  into a single unified technology approach and without the limitations of ribose-based backbones. We have spent the past several years quietly validating the capabilities of this platform and are now accelerating into a pipeline of programs addressing these various disease-causing mechanisms in diseases of high unmet need.

The platform is made of three buckets of parts: our proprietary scaffolds, re-imagined nucleobases, and delivery technology, which, when combined, culminates in drugs that conceptually look like short stretches of single-stranded nucleic acids, also termed oligonucleotides, but behave very differently. We use specially engineered nucleobases, like the A's, C's, G's, and T's that make up our genetic code with which we can tune precise target engagement and reduce off-target sequence engagement, which we believe will translate into tolerability advantages in patients. The scaffolds to which we couple these nucleobases (in the appropriate sequence to recognize a target of interest) are rigid and made of modified peptides as opposed to derivatives of natural sugar-phosphate backbones. Consequently, our drugs can be designed to target the sequence of any gene as well as its 3-dimensional geometry, allowing for unparalleled specificity. Since our drugs are uncharged, they also do not aggregate in the body nor do they elicit an immune response. Finally, we have developed delivery technology that can be coupled to our compounds and allow them to achieve broad biodistribution after systemic administration, including into hard-to-reach tissues. This opens us opportunities to treat diseases that strike various tissues and organs. These unique technical features boil up to a few likely benefits for patients with a variety of diseases: reduced adverse events due to off-target drug engagement, increased tolerability, and ease of administration.

Q2. What would be the peculiarity of PATrOL-enabled therapies?

Dietrich: Unlike other precision genetic medicines, PATrOL-enabled therapies can be used to turn up or down gene expression and even change a gene's function to address root causality across a nearly unlimited number of rare and common diseases. We can perform this by directly engaging the double-stranded genome and also at downstream targets such as in mRNAs.

Q3. Can we have a highlight of in vitro & in vivo preclinical data for PATrOL-enabled anti-gene therapies to treat DM1?

Dietrich: First, a bit on the pathogenesis of myotonic dystrophy, type 1 (DM1) to orient ourselves. DM1 is caused by a long sequence of trinucleotide repeats in the DMPK gene. When the messenger RNA (mRNA) is made from that mutant gene, it becomes misfolded due to the nucleotide repeats. This mutant mRNA traps essential proteins, known as splicing factors. As a result, other mRNA molecules throughout the cell aren't spliced correctly, leading to catastrophic changes in cellular physiology.

Our preclinical data clearly show that we can use our technology to invade into the misfolded RNA structure formed by the sequence of repeats in the mRNA, free the splicing factors and restore normal RNA splicing to the entire cell. We have shown this in vivo in an animal model of the disease, which contains the human mutation after a single intravenous dose of our therapy.

We are now engaged in the IND-enabling activities and plan to dose our first patient next year.

Q4. Can we have a glimpse of the NeuBase pipeline portfolio? What are the other additional indications the company plans to address using this platform?

Dietrich: In addition to DM1, we are exploring the potential of our technology for the treatment of Huntington's disease. Given the potential of the PATrOL platform to address many or most disease with a genetic basis, we are also exploring the potential applications in a wide variety of diseases including certain cancer indications which have not been druggable at the protein level historically.

Q5. When can we expect the IND submission of your two preclinical programs (NT0100 & NT0200)?

Dietrich: We are currently engaged in the IND-enabling preclinical activities in both programs. We have been pleasantly surprised at the pace of progress of our DM1 program, which has accelerated recently. We plan to have at least one of these programs in the clinic in 2022 and continue to focus on our critical path to the clinic for both.

Q6. Which all would be targeted geographies for the clinical studies for NT0100 & NT0200?

Dietrich: Since we are initially focused on rare diseases, we would aim to capture patients from a broad geographical footprint for our clinical trials. This would allow us to reach the most patients as well as expedite enrollment. We have enjoyed our conversations with the patient advocacy groups and clinical trial organizations which focus on these indications and are, we believe, well-positioned for not only rapid recruitment but also intelligently designed trials that will initially focus on both safety and efficacy readouts.

Q7. Are you looking for collaborations or license agreements to utilize the PATrOL platform across multiple organ systems and disease indications?

Dietrich: We are convinced that the PATrOL platform has near limitless potential for patient impact and shareholder value creation. In fact, we have audacious aspirations for our company in the mid-to-long term. Our team has been thoughtful in prioritizing indications in which we are uniquely capable of addressing disease causality and this will form the basis of our pipeline roll-out over the coming months and years. We are engaged in conversations with potential partners with an emphasis on co-developing non-core programs in our portfolio.

Q8. Please explain about Myotonic dystrophy type 1 (its symptoms, geographical distribution, etc.)

Dietrich: DM1 is a dominantly inherited progressive genetic disorder that affects 1 in 8,000-20,000 in the general population. The disease is caused by a mutation in one copy of the DMPK gene. This disease falls into a unique category of diseases terms trinucleotide expansion disorders, named because a three-letter repeat that is normally quite small in repeat size becomes unstable in certain individuals and 'expands' in repeat number through successive generations, until it increases in size from the 'pre-mutation range' to the 'mutation range' and causes the disease. This progression through generations is termed 'anticipation' and is unique to trinucleotide expansion diseases. In each generation, 50% of the children of an affected individual will carry the expanded copy of the gene, and the disease will become worse through the generations culminating in the congenital form of the disease in which affected often are unable to reproduce due to severity of the disease.  It is characterized by progressive muscle wasting and weakness, myotonia (uncontrolled contractions), cardiac conduction defects, cognitive dysfunction, and, in many cases in a reduced lifespan. There is currently no cure for DM1, and treatment is usually targeted at managing symptoms as much as possible. Preclinical work has shown that at least some of the clinical signs and symptoms may be reversible. There does not appear to be any specific geographic clustering of the disease. 

Main Image Source: National Human Genome Research Institute

About Author:

Dietrich A. Stephan is the Chairman and CEO of NeuBase Therapeutics. Dr. Stephan is an industry veteran who is considered one of the fathers of the field of precision medicine, having trained with the leadership of the Human Genome Project at the NIH and then going on to lead discovery research at the Translational Genomics Research Institute and serve as professor and chairman of the Department of Human Genetics at the University of Pittsburgh.

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