THE NEUBASE PIPELINE

NeuBase is developing precision genetic medicines targeting rare, monogenic diseases, for which there are no approved therapies, as well as more common genetic disorders, including cancers and complex genetic disorders that are resistant to current therapeutic approaches. NeuBase's pipeline includes therapeutic candidates for the treatment of myotonic dystrophy type 1 (DM1), Huntington's disease (HD), and cancer-driving point mutations, such as KRAS G12V and G12D which are involved in many tumor types. The company expects to file an IND application for DM1 by the end of 2022.

NT-0200: Myotonic Dystrophy Type 1 (DM1)

CTG repeats in DMPK causing splice dysfunction and haploinsufficiency

NT-0100: HUNTINGTON'S DISEASE (HD)

CAG repeats in HTT causing polyglutamine aggregates

NT-0300: KRAS (G12D & G12V)

Cancer-driving mutations KRAS G12D and G12V

preclinical

ind

clinical

NT-0200: Myotonic Dystrophy Type 1 (DM1)

DM1 is a multi-system, progressive disorder characterized by weakness of smooth and skeletal muscles that can range from mild to severe, myotonia, cardiac conduction defects, cognitive deficits and shortened lifespan. Current treatment options include therapies to manage the symptoms, physical therapy, and assistive devices. No treatments are currently FDA approved that slow or stop the progression of DM1.

Show more

DM1 is caused by a single inherited copy of a trinucleotide repeat expansion in the 3′ untranslated region of the DMPK gene. When transcribed into RNA, the expanded trinucleotide repeat creates a molecular hairpin structure that is toxic in that it results in broad mRNA splicing abnormalities in hundreds to thousands of mRNAs in the cell. In addition to not forming a functional DMPK protein, which appears to be important for the correct functioning of various tissues, this RNA hairpin “traps” critical splicing proteins making them unavailable for normal mRNA splicing activities. This alters the correct production of a range of proteins, resulting in DM1’s numerous symptoms beyond muscle and including the brain. NeuBase’s drug candidate for the NT-0200 program is designed to engage with the toxic RNA hairpin structure and release the splicing proteins to restore normal RNA splicing and downstream protein production. Preclinical data demonstrate NeuBase’s drug candidate maintains similar DMPK protein levels to untreated patient-derived cell lines and rescues splicing across significantly mis-spliced muscle mRNA transcripts in the HSALR mouse model. Because NeuBase’s peptide backbone is non-immunogenic and our delivery shuttles achieve broad tissue distribution, the DM1 drug candidate has the potential for subcutaneous dosing and long-term use.

NT-0200 targeting pre-mRNA releases splicing factors to restore mRNA splicing
NT-0200: Myotonic Dystrophy Type 1 (DM1)

Different from other approaches, NeuBase's DM1 drug candidate is designed to specifically target and not degrade the mutated DMPK RNA, thus maintaining DMPK protein production. By restoring mRNA splicing and downstream correct protein production, including DMPK, NeuBase's precision genetic approach has the potential to be disease-modifying.

NT-0100: HUNTINGTON'S DISEASE (HD)

HD is a fatal neurodegenerative disease characterized by neuronal death in deep brain structures culminating in progressive impairments in movement and cognitive control followed by death. Current treatment options attempt to lessen involuntary movement and psychiatric symptoms, but disease-modifying treatments have yet to successfully advance through clinical trials.

Show more

HD is caused by a single inherited copy of a trinucleotide repeat expansion in the coding region of the Huntington gene (HTT). The expanded trinucleotide repeat is transcribed into RNA and translated into an abnormally sticky version of the Huntingtin protein. This mutant protein leads to toxic accumulation in neurons and eventual neuronal cell death – and death of cells throughout the body over time. The goal of NeuBase’s NT-0100 program is to advance a drug candidate that selectively binds the mutated mRNA to reduce or prevent production of the mutated protein. Preclinical data from patient-derived cell lines and animal models demonstrate the ability of NeuBase’s candidate compounds to inhibit the production of toxic protein while maintaining production of normal Huntingtin protein after subcutaneous administration. Preclinical animal studies show that NeuBases’s delivery shuttle has the ability to cross the blood-brain barrier and reach the deep brain at potentially efficacious levels after systemic administration.

NT-0100D targeting DNA inhibits transcription into mRNA
NT-0100D targeting DNA inhibits transcription into mRNA
NT-0100R targeting mRNA inhibits translation into mutant protein
NT-0100R targeting mRNA inhibits translation into mutant protein

NeuBase’s therapeutic approach is to maintain normal huntingtin protein function while eliminating the toxic protein and is focusing on systemic dosing routes, which offers the potential for uniform brain distribution.

NT-0300: KRAS (G12D & G12V)

NeuBase’s oncology program targets KRAS G12D and G12V gene mutations, which are the two most common and historically “undruggable” KRAS driver mutations, together representing more than 50% of KRAS-driven tumors. There are no approved therapies for KRAS G12D or G12V mutations, which account for approximately 55% of all KRAS mutations.

Show more

NeuBase designed novel PATrOL-enabled compounds to selectively engage with the mutant transcript at either the DNA or RNA level to inhibit downstream signaling and protein production. In addition, these compounds targeting KRAS codon 12 mutations have potential to work against NRAS and HRAS mutations. Preclinical studies have shown tumor growth inhibition after intra-tumoral administration and reduction of downstream signaling, validating that the compounds can engage the target.

NT-0300D targeting DNA inhibits transcription into mRNA
NT-0300D targeting DNA inhibits transcription into mRNA
NT-0300R targeting mRNA inhibits translation into mutant protein
NT-0300R targeting mRNA inhibits translation into mutant protein

RAS-driven cancers are common, severe, and largely untreatable. Normal KRAS protein is essential for cellular function. NeuBase is designing compounds for the allele-selective target engagement of KRAS G12D and G12V at the DNA or RNA level.