Systemic Therapy of Inactivated-Bisphosphonate-Conjugated PEGylated NELL-1 (BP-NELL-PEG) for Spaceflight-Induced Osteoporosis

Osteoporosis affects more than 200 million people worldwide. Therapeutic approaches to osteoporotic bone loss have focused primarily on anti-resorptive agents but with significant clinical limitations. Therefore, there is pressing need to develop new agents, particularly anabolic therapies that promote bone formation. Microgravity-induced bone loss is an important medical consideration of long-duration space flight and has been measured to degrade bone at a rate up to four times faster than disuse atrophy on Earth. As such, the microgravity model of osteoporosis serves as a proxy for extreme cases of disuse osteoporosis on the ground.NELL-1 is a potent pro-osteogenic protein most studied for its local bone forming effects. Studies have demonstrated that recombinant NELL-1 acts as a combined anabolic and anti-osteoclastic agent to protect against osteoporotic bone loss. In addition, through PEGylation, we successfully increased the circulation half-life of NELL-1 (NELL- PEG) to be up to six times longer. In this study, the therapeutic effects of NELL-PEG were further amplified by conjugation with inactivated bisphosphonate (BP) to increase bone binding affinity. We verified inactivated BP acts only as a targeting molecule to optimize NELL-PEG deposition in bone and does not exert its own anti-osteoclastic effect. This has led to my central hypothesis that systemic BP-NELL-PEG therapy will prevent bone loss and promote new bone formation in long-duration spaceflight. This study was a part of the Rodent Research 5 spaceflight mission and supported by the Center for the Advancement of Science in Space (CASIS) and the National Aeronautics and Space Administration (NASA).I tested my hypothesis through two AIMs: (1) Pre-Flight Ground Operation to optimize the delivery route and dose of systemic BP-NELL-PEG for the reversal of ovariectomy (OVX)-induced osteoporosis in mice; (2) Flight Operation to examine the effects of optimized systemic delivery of BP-NELL-PEG for the reversal of microgravity-induced osteoporosis in mice. Results showed that systemic BP-NELL-PEG therapy successfully prevented bone loss from long-duration spaceflight by promoting new bone generation. Furthermore, our findings with inactivated BP conjugation introduce a promising platform for improving skeletal delivery of systemic therapeutics for bone diseases