Intracellular Target Program
For its intracellular target program Phylogica uses protein transduction domains to get phylomers into cells. It has so far validated several intracellular phylomers in a number of in vivo models, including for the treatment of acute burn wounds, traumatic brain injury, and stroke.
The company’s extracellular target program focuses on blocking growth factors and receptors, with one of the most promising targets being CD40 signaling ligands involved in multiple chronic inflammatory diseases. Phylogica has validated several hits against this target and has matured these to the low-nanomolar range. Another area of interest is developing phylomers as antimicrobial agents.
Dr. Watt points to the small size and simple chemistry of phylomers as additional advantages of the technology, making phylomers relatively easy to synthesize. “We have made 17 grams of a 29-amino acid phylomer at 96 percent purity in partnership with Genzyme,” Dr. Watt stated.
In terms of noninjectable delivery, phylomers have been applied directly to acute burn sites in which the dermis is absent. The company has also demonstrated biological effects of phylomers following inhaled delivery in a lipopolysaccharide-induced acute respiratory distress model, blocking neutrophil influx into the lungs.
In rodent models, the in vivo half-life of phylomers is about 100 minutes without the use of pegylation or any type of controlled-release delivery method, “which is compatible with acute delivery regimes,” Dr. Watt explained. “We have also pegylated one of our phylomers for half-life extension and have shown that it retains biological activity.”
Escoublac is a start-up company that is part of the Biogen Idec. It was founded by Gerard Karsenty, M.D., Ph.D., Columbia University College of Physicians and Surgeons (www.cumc.columbia.edu), after he and his colleagues discovered that osteocalcin, a protein secreted by bone-forming osteoblasts, has a role in energy metabolism and related disorders. Dr. Karsenty’s group postulated, based on gene knock-out experiments, that osteocalcin is involved in cross-talk between osteoblasts, pancreatic beta cells, and adipocytes.
Osteocalcin is post-translationally modified to include three gamma-carboxy-glutamic acid residues. The majority of osteocalcin circulates in the fully carboxylated form, with a smaller fraction under-carboxylated or noncarboxylated; the under- or noncarboxylated forms bind less tightly to bone. Dr. Karsenty determined that ostocalcin’s role in mediating this crosstalk depends on the ratio of the noncarboxylated to carboxylated form.
When pancreatic islet cells and adipocytes grown in culture are exposed to osteocalcin, the beta-cell mass increases, beta cells express and secrete more insulin, and adipocytes express and secrete more adiponectin, resulting in improved insulin sensitivity. Giving noncarboxylated osteocalcin to mice produces the same effects as seen in tissue culture.
If these results translate to humans, increasing the ratio of noncarboxylated to carboxylated osteocalcin in the body, “could be a new way to approach type 2 diabetes and possibly obesity,” reported Nils Bergenhem, Ph.D., CSO of Escoublac, which licensed the osteocalcin technology from Columbia.
Escoublac is developing noncarboxylated osteocalcin as an injectable appetite suppressant. The company is exploring both biological and chemical synthesis routes to produce osteocalcin. Dr. Bergenhem envisions a once-daily or twice-daily dosing regimen possibly by modifying or derivatizing the endogenous form of the peptides.