The Question: Are intracellular targets still intractable for macromolecules ?

There are many validated intracellular targets and novel treatment modalities - but a lack of efficient delivery.

This means:

Host of well characterized intracellular targets are not amenable to small molecule development in a multitude of therapeutic areas.

Endosomal entrapment is a as major limitation to deliver large biomolecules to cytoplasmic/nuclear targets.

Intracellular targets are mostly intractable for large biomolecules, as it requires traversing cellular membranes

  • Proteins payloads: typically, do not escape endosome and quickly degrade.
  • Oligonucleotides: >99% are trapped in endosomes.

Cancer

  • 19.3 million registered new cases worldwide and almost 10.0 million deaths in 2020 [1]
  • More than 385,000 children and adolescents (age 0–19) develop cancer each year [2]
  • By November 2017, around 2600 clinical trials were conducted on gene therapy, more than 65% of them associated with cancer [3]
  • Until August 2019, 22 gene products were approved for the treatment of different disorders, five of them against cancer [4]
  • Endosomal escape enhancers augment efficacy and lead to tumor regression [5]

References:
[1] https://doi.org/10.3322/caac.21660,
[2] https://doi.org/10.1016/s1470-2045(17)30186-9,
[3] https://doi.org/10.2147/BTT.S302095,
[4] https://doi.org/10.1016/j.biotechadv.2019.107502,
[5] https://doi.org/10.3390/biomedicines5020014

Hemophilia B

  • Hemophilia B is the second most frequent coagulation disorder with a frequency of 1 in 30,000 males [1]
  • Current treatment consists of frequent injections of recombinant factor IX (FIX) and has several drawbacks [2]
  • Adeno-associated virus-mediated delivery of the FIX coding sequence (gene therapy) showed promising results but still suffers from several limitations [3]

The ENDOSCAPE-based non-viral DNA delivery opens new therapeutic opportunities for gene therapy, and could be applied to many other liver disorders. Endosomal escape enhancers strongly augment transfection efficiency in cellular models.

References:
[1] https://doi.org/10.1016/S0140-6736(03)13405-8,
[2] https://doi.org/10.1186/1750-1172-7-24,
[3] https://doi.org/10.1055/s-0041-1722862

The Solution: Endosomal Escape Enhancer (EEE) for Intracellular Delivery of Macromolecule Compound

EEE Enables Efficient Payload Delivery From Endosomes

EEE mediates increased release of polymeric drugs in target cells

>> lowering dose + reduced off-target tox

EEE Mode of Action: Endosomal Low pH Driven Activity

EEE mediates efficient endosomal escape from acidified endosomes

Mechanism

  • The endosomal escape enhancer activity
    • Is dependent on clathrin-mediated uptake of cargo.
    • Can be blocked with endosomal acidification inhibitors.
  • Proteins that do not route through late endosomes are not amenable to improvement through endosomal escape enhancement.

Powered by Evolution: Natural Intracellular Delivery Compounds

  • Plants produce protein toxins 10–100 fold more potent than small molecule toxins
  • These proteins do not cross endosomal membranes
  • Plant metabolites evolved to enhance release of toxins from endosomes – enabling access to cytosol

The ENDOSCAPE Symposium gives answers

  • Gene Therapy – Where We Stand Today
  • Endosomal Escape – The Strategies
  • Carriers of Endosomal Escape Enhancers and Genes
  • Endosomal Escape – What Happens?
  • GMP Production and Market
  • Gene Therapy – Clinical Applications and Future Perspectives

register at our Symposium