Changing The Paradigm For A Rare Genetic Disease That Is Currently Contraindicated For Surgery and Lacks Alternative Treatments
Charles Hwang, BS1, Michael Sorkin, MD1, Serra Ucer, PhD1, Sidra Kader, BS1, Anita Vaishampayan, none1, Michael T. Chung, MD2, Christopher Breuler, BS1, Caitlin Priest, BS1, Nicole Patel, BS1, John Li, MD1, Kaetlin Vasquez, MS1, Haichun Pan, PhD1, Aris Economides, PhD3, Shailesh Agarwal, MD1, Yuji Mishina, PhD1, Benjamin Levi, MD1.
1University of Michigan, Ann Arbor, MI, USA, 2Stanford University, Stanford, CA, USA, 3Regeneron Pharmaceuticals and Genetics Center, Tarrytown, NY, USA.
PURPOSE: Heterotopic ossification (HO) is a debilitating formation of ectopic bone restricting joint mobility and causing chronic pain. Fibrodysplasia Ossificans Progressiva (FOP) is a congenital variant of HO caused by a genetic mutation in a bone morphogenetic protein receptor that causes severe, progressive lesions resulting in immobility and often fatal mechanical respiratory failure at a premature age that currently lacks a cure. With increased proclivity for osteogenesis at baseline, surgical excision of bony lesions is contraindicated in FOP patients due to universal recurrence. We have previously shown that rapamycin is a powerful drug which can eliminate lesions in mouse models of FOP. Here, we demonstrate that combination therapy with low-dose rapamycin and the BMP receptor inhibitor LDN-212854 presents an option to prevent both primary HO and post-excision HO in an FOP mouse model.
METHODS: Within the recurrence study arm, ACVR1R206H/+ P21 mice received inductive Ad.cre and cardiotoxin (CTX) injection in bilateral hindlimbs. Three weeks later, mice were live-scanned with in vivo ÁCT, reinjected with Ad.cre bilaterally, and underwent HO excision at the 3 week timepoint. These mice were randomized to daily rapamycin (5 mg/kg, n=12) or PBS (n=8) for 3 weeks with endpoint ÁCT. For low-dose rapamycin and LDN adjunctive therapy, 16 mice were stratified into low dose rapamycin (0.5 mg/kg, n=10, both hindlimbs of 5 mice), rapamycin and LDN212854 (0.5mg/kg and 0.6mg/kg respectively, n=8), and injection control (PBS, n=14) cohorts for daily injections. They were subsequently induced as previously described, with additional second and third CTX booster series on post-operative day 3 and 7. Mice were scanned with ÁCT 3 weeks later. Contours were drawn manually by blinded experts around HO to compute total volumes (800HU). Recurrence cohorts were analyzed by log-transform/ANOVA/post-hoc Hochberg and low-dose results were analyzed similarly with restriction to right legs only.
RESULTS: In post-surgical mice, PBS injection showed statistically similar HO volumes to baseline volumes of pre-excision mice (p=0.054). However, rapamycin treatment significantly reduced the post-surgical HO volume 11-fold (p=.044, Fig: left). In the primary HO model treated with low-dose rapamycin/LDN, mice treated with rapamycin for 21 days showed 17-fold less ectopic bone (p=0.001) compared to PBS vehicle injection, paralleling a 9-fold reduction (p=.003) when treated with rapamycin plus LDN212854 adjunct (Fig: right).
CONCLUSIONS: These studies demonstrate that rapamycin prevents primary development of HO and is also effective in preventing post-surgical recurrence in a FOP mouse model. Furthermore, rapamycin with and without LDN adjunct remains effective at preventing primary development of HO even at lower concentrations. This study further corroborates rapamycin as a promising candidate for primary and post-surgical HO prophylaxis in children with FOP, with opportunities for subsequent dosing studies and adjunct therapies to minimize prohibitive adverse effects. Existing literature implicates similar molecular mechanisms among various etiologies of HO, suggesting a putative role for rapamycin even beyond FOP in post-traumatic and post-surgical HO patients.
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