The Endosomal Escape Vehicle Platform of Cyclic Cell-Penetrating Peptides Enhances the Delivery of Oligonucleotides
Leo Qian, PhD;Co-Founder and Vice President, Discovery Research, Entrada Therapteutics
Oligonucleotide medicines have the potential to treat diseases for which there are currently no options. The question is, according to Entrada Therapeutics, how best to ensure peptide drugs can hit intracellular targets.
Entrada CEO Leo Qian, Ph.D., set out his view of the oligo space at TIDES Asia, telling delegates that developers who are not focused on getting drugs into cells are limiting the number of diseases they can target.
“There is a huge amount of disease targets in the cell, and most of them are undruggable. So I think a lot of these targets, whether they are at the DNA, RNA, or protein level, could really benefit from a powerful delivery platform,” Qian said.
Qian pointed to Entrada’s endosomal escape vehicle (EEV) technology as an example of such a platform. The firm’s approach is to attach a cyclic peptide to the drug that binds to the cell membrane with low affinity at which point it enters the cell via a process called endocytosis. Once in the cell the therapeutic migrates to the cytosol.
“One way to induce cell uptake is by using these so-called cell penetrating peptides [CPPs], which were first discovered in 1988. In fact, many viruses use CPPs so that they can reach intracellular compartments.
“Entrada’s peptides have been modified to enhance cellular uptake. We improved a lot on the stability side, as well as other properties related to their binding with the phospholipids,” he said.
The EEV technology has already been used to deliver a range of cargos, including peptides, antisense oligos, as well as mRNA and other larger biomolecules, according to Qian, explaining that flexibility is foundational to the platform.“So we really need to build our fit for purpose engine to demonstrate the activity as well as discover and engineer the best EEVs for the specific target. It’s very much like a medicinal chemistry approach.”
Making DMD therapies deliver
Duchenne muscular dystrophy (DMD) is one of the best-known diseases for which the therapeutic target is within the cell. The disease is caused by a mutation in a gene encoding a protein called dystrophin, which is vital to the normal functioning of muscle cells.
DMD is not undruggable per se. At present several treatments are approved, based on the principle of exon skipping.
However, Qian said current commercially available DMD drugs are less effective than they could be because it is difficult to reach their intracellular targets.
“There are already four drugs approved in the U.S. by the FDA, but their efficacy is very limited. Usually, they only achieve 1% to 6% of the dystrophy correction, even after weekly IV injections,” he said.
“At Entrada, we have built our Duchenne franchise with our initial focus to treat the patients who are amenable for exon 44 skipping, followed by exon 45 skipping, and 50 and 51.”
The company’s exon 44 skipping oligo candidate, ENTR-601-44 has shown some promise, Qian said.
“In the preclinical data package, we have seen robust exon skipping in different models, both in mice as well as in monkey as well as a protein correction and some of phenotypical correction as well.”
The drug is also being examined in a Phase 1 study that is expected to produce data in the first half of 2024.