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.
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.
- 19.3 million registered new cases worldwide and almost 10.0 million deaths in 2020 
- More than 385,000 children and adolescents (age 0–19) develop cancer each year 
- By November 2017, around 2600 clinical trials were conducted on gene therapy, more than 65% of them associated with cancer 
- Until August 2019, 22 gene products were approved for the treatment of different disorders, five of them against cancer 
- Endosomal escape enhancers augment efficacy and lead to tumor regression 
- Hemophilia B is the second most frequent coagulation disorder with a frequency of 1 in 30,000 males 
- Current treatment consists of frequent injections of recombinant factor IX (FIX) and has several drawbacks 
- Adeno-associated virus-mediated delivery of the FIX coding sequence (gene therapy) showed promising results but still suffers from several limitations 
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.
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
- 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