[Author: Laura Cowen]
Drugs that selectively induce apoptosis of senescent cells may be effective candidates for the treatment of fibrodysplasia ossificans progressiva (FOP) flare-ups via the inhibition of tissue reprogramming and subsequent prevention of endochondral heterotopic ossification (HO), preclinical study findings indicate.
Writing in the Journal of Bone and Mineral Research, Robert Pignolo (Mayo Clinic, Rochester, Minnesota) and colleagues say their data “suggest a way-forward for a randomized clinical trial with senolytics for FOP.”
Pignolo and team carried out a series of experiments using cellular and animal models to investigate the role of injury-induced senescent cell accumulation in FOP.
First, they demonstrated that cardiotoxin-induced muscle injury in Acvr1Q207D mice, which serve as a model for FOP, results in senescent cell accumulation at a level that was over 12-fold higher than that recorded in non-injured, vehicle-injected muscle from these mice.
This finding was substantiated by an analysis of biopsied lesions from a FOP patient, which also showed the presence of senescent cells, as well as a gene expression analysis that identified overexpression of genes associated with senescence (eg, p15 and p16), and components of the senescence-associated secretory phenotype (SASP) in cardiotoxin-injured muscle of Acvr1Q207D mice.
Next, the researchers developed an in vitro model to evaluate the impact of the SASP on tissue reprogramming after muscle injury.
They observed that in the presence of senescent cell co-culture, FOP myoblasts preferentially express genes consistent with reprogramming (eg, Nanog) and chondrogenesis (eg, aggrecan) whereas wild-type myoblasts are directed toward a myogenic fate.
Furthermore, injured muscle from FOP Acvr1Q207D mice had a gene expression profile consistent with tissue reprogramming as early as 3 days after cardiotoxin injury, and by day 6 there was a more than 20-fold upregulation of genes associated with reprogramming and chondrogenesis.
“These data indicate that tissue reprogramming is in close temporal proximity to chondrogenesis in FOP,” Pignolo et al remark.
Finally, the team looked at whether the senolytic drugs dasatinib 5 mg/kg and quercetin 50 mg/kg affect senescent cell burden and reprogramming factors.
They found that senescent cell burden and several senescence-associated genes, including p16 and components of the SASP, were diminished following dasatinib plus quercetin treatment of injured muscle cells.
In addition, both dasatinib and quercetin, individually and together, reduced HO to negligible levels and preserved joint mobility when given as a daily prophylactic regimen beginning 2 days before cardiotoxin injection, with the greatest effect seen with the combined regimen.
Pignolo and co-authors note that currently “there are no approved therapies for FOP, either for the prevention of flare-ups or for their episodic treatment when they occur.”
“The likelihood for senolytic drugs to become part of the therapeutic management of FOP seems possible in the near future, due both to our encouraging preclinical data and the availability of senolytics as nutraceuticals or repurposed drugs,” they say.
Moreover, “[l]egitimate concerns about adverse events and risks of long-term undesirable outcomes related to senolytics are diminished by the need for infrequent administration, owing to the quick removal of senescent cells and their time to re-accumulation,” the team concludes.