Right to the bone

 

In-vitro study results showed that CSA-90 increased matrix mineralization and potentiated rhBMP-2 (recombinant human bone morphogenetic protein-2) activity in cultured osteoblasts. When CSA-90 was administered locally to mice that had bone fractures and were then injected with Staphylococcus aureus, CSA-90 increased rhBMP-2-induced bone formation. In addition, the mice receiving N8’s compound were able to prevent the establishment of infection. Most mice that were not treated with CSA-90 were euthanized because of infection-induced localized osteolysis and poor health.

 

“The effects of the combination provided a serendipitous observation,” notes Dr. Michael Triplett, CEO of N8 Medical, which emerged from work done at Brigham Young University and the University of Utah via a grant from the National Institutes of Health. Ceragenins are synthetic, non-peptide small-molecule mimetics of naturally occurring (hence innate, or N8) host defense peptides, critical components of the innate immune system that possess antimicrobial, anti-inflammatory, immunomodulatory and anticancer activities. This patented portfolio of small molecules may exhibit a broad range of utility in a number of healthcare fields, with the primary focus being respiratory infectious disease.

 

“This study, and many like it, demonstrate the versatility of our ceragenin platform and encourage us to explore multiple applications for their use,” Triplett says. “We have been investigating ceragenins for use in bone unions, particularly in the presence of infections and co-administration with low-dose rhBMP-2, and believe this is an extremely positive step forward in our pursuit of orthopedic applications. These data are confirmation of our decision to continue to pursue broad clinical orthopedic applications for this technology including open fractures, spinal fusions, bone cement for orthopedic implants and many others.”

 

“We are working with a team in Australia to evaluate the extent of the synergy between our ceragenins CSA-13 and CSA-90 and rhBMP-2,” Triplett observes, “There are safety concerns with rhBMP-2 at higher doses. If the dose can be lowered via CSA-90, we’ll be very encouraged. The article in the Journal of Bone and Joint Surgery has generated immense interest.”

 

Among the important findings presented in the journal article are that “CSA-90 enhanced matrix mineralization in cultured osteoblasts and increased rhBMP-2-induced bone formation in vivo. All animals in which an open fracture had been inoculated with Staphylococcus aureus and not treated with local CSA-90, including those treated with rhBMP-2, had to be culled prior to the experimental end point (six weeks) because of localized osteolysis and deterioration of overall health, whereas CSA-90 prevented establishment of infection in all open fractures in which it was used. Increased union rates were seen for the fractures treated with rhBMP-2 or with the combination of rhBMP-2 and CSA-90 compared with that observed for the fractures treated with CSA-90 alone.”

 

Also, “Ceragenins, or cationic steroid antibiotics (CSAs), are synthetically produced small-molecule chemical compounds that mimic the actions of cationic antibacterial peptides (CAPs). One of the best-described CAPs is LL-37, a peptide derived from the C-terminal region of hCAP-18. A broad range of bacteria are inhibited by LL-37, which is bactericidal via disruption of bacterial membranes. CSAs are able to replicate the broad antibacterial activities of CAPs but are designed to have reduced cytotoxicity and improved in-vivo stability compared with the endogenous peptides. CSA-13 and the related compound CSA-90 have been shown to have antibacterial properties against a range of Gram-positive and Gram-negative bacteria associated with oral and respiratory tract infections.”

 

N8 Medical is a privately held, emerging pharmaceutical company focused on the development of a broad-spectrum anti-infective therapy based upon ceragenins, a portfolio of synthetically produced small-molecule chemical compounds that mimic the activities of endogenous cationic antibacterial peptides that comprise the innate immune system. The company is currently focused on several applications for the ceragenin platform, including treatment of chronic cystic fibrosis, pulmonary infections and the development of antimicrobial devices and coatings for the prevention of medical device-related hospital-acquired infections.