UCLA researchers have developed ways to chemically modify NELL-1, an osteoinductive factor, that significantly prolong the in vivo circulation time of the protein and retain its osteoblastic activity without any appreciable cytotoxicity.
Osteoporosis is a progressive bone disease due to low osteoblast activity and/or high osteoclast activity. With the aging population, the biomedical burden of osteoporosis is significantly elevating, with no novel therapeutic to address systemic bone loss. In the United States, osteoporosis is a major public health threat for 24 million Americas. Roughly 1 in 4 women more than age 50 has osteoporosis. The cost of hip fractures alone is projected to reach $62 billion in the United States by the year 2020.
NELL-1 is an osteoinductive factor recently discovered to induce bone formation and reverse osteoporotic bone loss when administrated intravenously. However, similar to other protein drugs, the bioavailability of NELL-1 is limited by its in vivo half-life and rapid clearance from body. Unmodified NELL-1 requires an impractical 48hr injection frequency and thus limits NELL-1’s translation into a clinical setting. Currently, one of the most popular technologies to prolong the half-life time of protein is to use water-soluble polymers as a macromolecular carrier. PEG is a water-soluble polymer with excellent biocompatibility but without immunogenicity. As it is approved for human use by FDA, the non-toxic PEG molecule is widely used in numerous biomedical applications.
UCLA researchers PEGylated NELL-1 by random conjugation using 3 different PEG sizes. The thermal stability, cytotoxicity, in vivo bioactivity and pharmacokinetic behavior of the multiple forms of PEGylated NELL-1 were evaluated and the most effective forms were selected. Specific forms of PEGylation of NELL-1 significantly increases the elimination half-life of the protein from 5.5h to 15.5h while distributing more than 2-3 times the amount of protein to bone tissue in vivo. Systemic NELL-PEG therapy administered every 4-7 days significantly increases not only percent bone volume but also new bone formation throughout the overall skeleton after 4 weeks of treatment.
A principal application of this invention is for treatment of osteoporosis.
Patent Pending
Nell-1, osteoporosis, PEGylation, bioavailability, circulation time