An international team of scientists including CureLab Oncology, Inc. (Boston), University of Camerino (Italy), and Boston University have serendipitously discovered a DNA vaccine, which systemically alleviates chronic inflammation in the body. Since osteoporosis is an inflammatory disease, preventive and therapeutic effects of the new vaccine were demonstrated on mouse models with osteoporosis. A paper reporting these results is published in the latest issue of the journal Gerotarget (the geriatric section of Oncotarget). An online preprint of the paper is available on the journal's website.
The international CureLab consortium has developed a plasmid (circular DNA) encoding gene for p62-SQSTM1 as an anti-cancer DNA vaccine. Previous publications on p62 in Oncotarget have demonstrated anti-cancer effects of the plasmid in melanoma, sarcoma, mammary carcinomas and lung cancer in mouse models. Also, publication of the pilot study revealed the vaccine's great potential for treating dogs with spontaneous mammary carcinomas. The team, so enthused by the anti-cancer promise of this product, named it Elenagen® after the wife of Dr. Alex Shneider, CureLab Oncology founder and CEO.
P62 is an intracellular protein constituted of at least nine domains. It plays a key role in autophagy, the intracellular utilization of misfolded proteins. Cancer cells use excessive amounts of autophagy to protect themselves from radiation and chemotherapy. Moreover, a cancer cell cannot form a tumor if p62 is not expressed in the cell. This means that application of the p62 DNA vaccine will not lead to selection of p62-negative cells, which would escape the vaccination's effect since cells lacking p62 would be vulnerable and not form tumors. Based on these facts, Dr. Alex Shneider of CureLab Ocnology and his collaborators including Franco Venanzi of University of Camerino and Michael Sherman of Boston University have decided to use p62 as a targeted anti-cancer vaccine. Today, this vaccine is in phase I clinical trials in Russia, funded by a Technology Transfer program of the Pharma 2020 initiative.
"It is easy to mobilize yourself in a search for an alternative hypothesis if your results refute your original thinking," says Shneider, a corresponding author of the paper "Still, the history of science is teaching us that we have to ask ourselves 'Weren't we right for wrong reason?' when our observations seem to support our first idea." In addition to serving as a key component in autophagy and clearing the cell of dysfunctional proteins, p62 also functions as a signaling hub of the cell by controlling expression of many genes. Thus, the p62-encoding DNA vaccine could be administered as an intramuscular injection and serve as a gene therapy pushing the cells to express and release certain proteins. The research team tested this hypothesis and observed sharp down-regulation of master inflammatory cytokines by bone-marrow stromal cells. This molecular discovery implies that the p62 DNA vaccine could possess a positive effect on reducing or eliminating osteoporosis and other known inflammatory diseases.
A generally accepted animal model of induced osteoporosis is ovariectomy. Surgical removal of ovaries in mice leads to a depletion of estrogen;this facilitates and mimics the aging process including systemic chronic inflammation and osteoporosis. Of note, ovariectomies are used as a medical procedure which requires compensatory therapy to reduce its negative side effects. In their paper, Shneider, Venanzi and their co-authors report that intramuscular delivery of p62 DNA exerts a powerful anti-osteoporotic action in mouse models with inflammatory bone loss (i.e, ovariectomy). This data provides a solid rational to apply the p62 DNA vaccine as a safe, new therapeutic for treatment of inflammatory related bone loss.
"I do not believe in panaceas, still chronic inflammation manifests itself in almost every disease associated with age," says author, Prof. Franco Venanzi. "The more we test our p62 vaccine and its derivatives on different models of inflammatory diseases, the more excited and hopeful we are." At present, CureLab Oncology and its associated academic centers constituting the worldwide CureLab consortium are pursuing preclinical and clinical development programs for anti-cancer and anti-osteoporosis application of the p62 DNA vaccine as well as performing pre-clinical research on alternative anti-inflamatory applications of the product and its derivatives.