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A new generation of RNA therapeutics

Our Science

Latest Generation PMOs Peptide Delivery Technology

RNA therapeutics built on latest generation PMOs (Phosphorodiamidate morpholino oligomers)

  • RNA is the molecular code your cells use to transcribe the genetic code in your DNA, process that information, and translate it into proteins.
  • RNA therapeutics alter the way RNA is processed, and hence how genetic messages are translated to proteins, to alter disease processes.
  • PMOs are synthetic chemical structures modelled on RNA. PMOs are a type of Antisense Oligomer, and function similarly to Antisense Oligonucleotides (ASOs).
  • PMOs and ASO both contain nucleic bases which bind the complementary strand of RNA to have an effect on how the cell will process that target RNA strand.
  • PMOs can be designed to have many effects on the target RNA, including:
    • Alternative splicing
      This approach is used to up- or down-regulate the production of proteins, or to alter the function of the protein by changing the splicing.
    • Modulating and stabilising mRNA
      PMOs can help to modulate and stabilise pre-mRNA splicing. This process prevents naturally occurring non-productive alternative splicing and promotes the generation of productive mRNA.
    • Translation suppression
      PMOs can prevent the cellular machinery from translating mRNA into a protein. As a result, the PMO inhibits translation of an undesirable protein or viral DNA.
  • RNA PMO’s are clinically and commercially validated molecules. The first approved PMO for the treatment of Duchene muscular dystrophy, Exondys51, was co-invented by our Chief Scientific Officer, Professor Sue Fletcher.

 

Revolutionary peptide delivery technology

While PMOs and other RNA therapeutics, including ASOs and siRNAs, have shown early promise, efficient delivery of these therapies to cells remains the single largest barrier for the technology.

  • Cell-penetrating peptides (CPPs) are a clinically validated solution to this problem.
  • Peptides are short chains of amino acids which due to their sequence and properties can deliver drugs safely and effectively across a cell membrane.
  • We leverage our proprietary libraries – constructed out of the genomes of bacteria, viruses, and archaea – to identify the optimal sequences designed by these organisms to safely enter human cells.
  • Using our CPP platform technology, we have identified a CPP for our lead drug program VP-001, to deliver a PMO to the very back of the retina in an eye.
    PPMOs/ CPP-PMOs
  • We are developing next-generation PPMO-based (Peptide-PMO) chemistries for advanced RNA-targeted therapeutics. Our PPMO-based chemistries are designed to enhance tissue targeting, delivery into the cell, safety and drug potency.

PYC’s therapeutic approach

RNA Therapeutics

RNA therapeutics are at the forefront of the precision medicine revolution. Our RNA therapeutic of choice, a phosphorodiamidate morpholino oligomer (PMO), can alter the way a cell interprets a gene to correct many genetic diseases.

PMOs are assembled in precise sequences that correspond to the specific target RNA. These therapeutic candidates bind selectively to the target RNA and modulate its function to increase or decrease the production of a protein involved in a disease.

The protein synthesis pathway involves the DNA being transcribed into an immature form of RNA called precursor messenger RNA (pre-mRNA). Pre-mRNA is spliced — or processed — into messenger RNA (mRNA), which is then translated into a protein.

Pre-mRNA splicing is a uniquely attractive drug target as it allows you to modulate protein production with high precision while keeping the process under the endogenous control of the cell.

PMO-based drug development has the potential to address diseases that otherwise could not be treated with traditional small molecule or biologic drugs.

Professor Sue Fletcher, our Chief Scientific Officer, a pioneer in the world of RNA biology and PMOs, co-invented the first approved PMO, Exondys51, a treatment for Duchenne muscular dystrophy. Sue and her dedicated team of scientists at PYC are designing the next generation of life-altering PMO therapeutics — including our lead drug candidate, VP-001.

PMOs are uncharged antisense agents that are composed of moieties with a morpholino base (versus RNA, whose moieties have a ribose base) linked through methylene phosphorodiamidate. PMOs inhibit gene expression and alter pre-mRNA splicing by binding with the transcript, thus blocking the protein-translational processes.

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PYC’s delivery advantage

The greatest challenge for the realization of all genetic therapies, and especially RNA therapies, has been delivery. ASOs and PMOs have been limited to applications which have easy local delivery or where there is an existing delivery mechanism, such as the liver. There is great potential in unlocking delivery to tissues and cells beyond these areas, including the deepest cells in the back of the eye.

Our CPPs have a unique advantage over other delivery CPPs and mechanisms: they are derived from our proprietary library of CPPs. Our peptide library is constructed from the genomes of microorganisms, including bacteria, viruses and archaea, which have evolved methods of interacting with the human body over millions of years of evolutionary pressure.

Our screening methods identify the highest potential sequences to validate in our high throughput nuclear delivery assays. This ensures we only move CPPs forward that functionally deliver the target cargo to the RNA-target site. Our initial focus has been on identifying a clinical lead CPP to deliver a PMO to the deepest cellular layer in the retina – the retinal pigment epithelium.

PYC’s screening methods identify the highest potential sequences to validate in our high throughput nuclear delivery assays. This ensures we only move CPPs forward that functionally deliver the target cargo to the site of action.

Therapeutic application

Our CPP-PMO technology is being translated into a pipeline of drugs for high unmet need inherited disease. Our initial focus is to deliver to market a CPP-PMOs which treats an inherited retinal disease called Retinitis Pigmentosa, the leading cause of childhood blindness.

Our results

Ocular Systemic

Our lead CPP has demonstrated safe and highly effective, dose dependant delivery of PMOs to the deepest cellular layer in the mouse retina – the Retinal Pigment Epithelium (RPE) – at 28day post single intravitreal (IVT) injection. Effective delivery has been demonstrated at doses significantly lower than what other ASOs or PMOs are required to be dosed at in the mice via IVT injection.

We have identified other CPPs with differentiated distribution systemically, demonstrating meaningful delivery of PMOs to critical organs such as the heart. Importantly this highly effective CPPs show a safe systemic delivery profile, overcoming a major challenge in the clinical development of systemically administered CPPs to date.

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Explore the future applications

CPP-PMOs have significant potential beyond the eye. We are building a platform to deliver PPMOs to other target tissues and cells, including the brain and certain systemic applications. View Our Pipeline to learn more about our ocular and expansion programs.

Our Pipeline

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or email info@pyctx.com