NeuBase is developing the next-generation of gene silencing therapies using its proprietary Peptide-nucleic acid AnTisense OLigonucleotide (PATrOL™) platform.
Modular and highly specific, the PATrOL platform has the potential to significantly improve upon current gene silencing technologies by combining the specificity of antisense approaches with the intracellular penetration and broad organ distribution capabilities of small molecule therapeutics.
The next generation of gene silencing therapies
Key features of our PATrOL-enabled therapies include:
- Modular molecular design
- High mutant RNA sequence specificity
- Even distribution throughout all tissue types
- Ability to cross the blood-brain barrier
- Endosome-independent cell permeability
- Resistant to premature degradation throughout the body
- No toxic self-aggregation
- Potential to address dominant and recessive genetic diseases
- Ability to open up and bind to double-stranded RNA
In all cells, genetic information that is encoded in DNA is transcribed into RNA, which in turn is translated into protein.
When DNA mutations occur in gene sequences, they are passed on to mutant RNA and, subsequently, to mutant protein. These mutant proteins can be harmful to cells, becoming the cause of many genetic diseases.
Gene silencing is a powerful approach used to address many genetic diseases. Specialized molecules designed to prevent the translation of mutant proteins called antisense oligonucleotides (ASOs) can bind to and inactivate mutant RNA before it can produce disease-causing protein, potentially delaying or even preventing genetic disease onset, symptoms or progression.
After DNA is transcribed into RNA, a process known as splicing, which removes intervening sequences to form messenger RNA (mRNA), occurs. That mRNA is then translated into a protein.
In addition to gene silencing, if designed properly, ASOs are capable of modifying gene splicing to address recessive genetic diseases. ASOs can bind to a very specific sequence on the RNA and modify the pattern of splicing so as to skip or eliminate disease-causing mutations from the mRNA and downstream protein. Similar to gene silencing, modifying gene splicing has the potential to delay or prevent genetic disease onset.
NeuBase’s Peptide-nucleic acid Antisense Oligonucleotide platform, or PATrOL™ platform, utilizes short sequences of engineered ASOs: peptide-nucleic acids (PNAs). While NeuBase’s PNAs are designed to bind mutant RNA to prevent translation or alter splicing to remove harmful protein like traditional ASOs, PATrOL-enabled therapies represent the next-generation of antisense technology, demonstrating superior gene silencing capabilities in preclinical studies.
The PATrOL platform yields therapeutics with the even and broad tissue distribution that is the hallmark of small molecules, while maintaining the highly specific targeting that is characteristic of antisense oligonucleotide therapies.
Unlike traditional ASOs which have a sugar backbone, NeuBase’s PNA therapies are designed with a peptide backbone. The peptide backbone enables the PATrOL platform to be truly modular and highly scalable, permitting rapid development of PATrOL-enabled therapies for many different genetic diseases.
NeuBase can develop its PATrOL-enabled therapies using multiple different types of nucleic acid bases, including those that are natural or engineered, allowing for increased selectivity and optimization of the therapy for the target disease. NeuBase is the first and only company to successfully create bifacial Janus bases, engineered bases that target double-stranded DNA or RNA by engaging both strands at once.
NeuBase has developed a proprietary chemistry to decorate its antisense candidates, which allows the therapies to be delivered systemically and achieve broad tissue distribution. With this targeting advantage, we are able to deliver our candidates into the cell bodies of neurons in every brain structure with systemic administration. This opens up new frontiers to not only address diseases of the brain in a manner that is preferable to patients, but also concurrently address disease pathologies outside of the brain.
NeuBase chemists have invented a method to develop short antisense oligonucleotides, as short as only three nucleotides in length, which gives NeuBase ASOs the advantages of small molecule therapies. These PATrOL-enabled drugs have proprietary “linkers” on each end, which enable cooperative binding across the RNA target. This self-assembly capability confers the selectivity of long antisense oligonucleotide therapies on very small molecules.