Researchers have identified the previously uncharacterized microtubule-severing enzyme, Fidgetin-like 2 (FL2), as a potential therapeutic target
Researchers have identified the previously uncharacterized microtubule-severing enzyme, Fidgetin-like 2 (FL2), as a potential therapeutic target for regenerating and repairing cutaneous wounds. FL2, according to the new study's authors, is “a fundamental regulator of cell migration that can be targeted in vivo using nanoparticle-encapsulated siRNA to promote wound closure and regeneration.”
They found, in vitro, FL2 depletion from mammalian tissue culture cells increased cell movement rate by more than two-fold. The researchers clinically translated their findings by locally depleting FL2 in murine full-thickness excisional and burn wounds. That’s where they found that topical application of FL2 siRNA nanoparticles to either wound type significantly improved the rate and quality of wound closure--clinically and histologically--relative to controls.
Charafeddine: When we started working on this, we noticed that most of the therapeutic targets were components of complex extracellular signaling pathways. These targets might have potent effects on wound healing, but they can also result in numerous unintended and difficult to predict side effects because these pathways alter cell behavior on so many different levels. With FL2, we have an intracellular target that specifically affects a subset of the cell’s structural migration machinery. Instead of flooding the system with regenerative and proliferative agents, we are fine tuning it for a more productive healing without changing the broader signaling milieu within the wound.
Rate and quality of wound closure
Charafeddine: When we looked at these wounds closely, we noticed that re-epithelialization and collagen deposition and organization occur days earlier than normal. This makes sense, since by depleting FL2, we are changing the internal skeleton of the cell, generating an optimal architecture for keratinocytes and fibroblasts to move productively fast into the wound. Moreover and most surprising to us was the fact that not only do the cells move more quickly into the wound, they know what to do when they get there. We see the rapid restoration of higher-order structures, like hair follicles, at time points at which they would never occur in control wounds. So cells … move into the wound, function and differentiate appropriately. It’s real regeneration.
Charafeddine: Topical application of nanoparticle siRNA was the way we went in the paper and that gave very nice results. And of course, from a regulatory standpoint, topical delivery is ideal. Ultimately for clinical use, we envision applying a cell permeable Fidgetin-like 2 inhibitor (like nanoparticle-siRNA or LNA) in a controlled-release gel or dressing. It’s actually something that we’re discussing in detail with drug delivery experts.
Charafeddine: In terms of our science, we would like to understand whether FL2 can be targeted to enhance the healing of chronic wounds like diabetic ulcers, which are devastating conditions. We actually have had some promising preliminary results in that regard. We are also looking at FL2 in other regenerative models like spinal cord injury and myocardial infarction. And of course we would like to push this into clinical trials as quickly as possible. To that end, my mentor and the senior author on the paper, Dr. David Sharp, started a company called MicroCures, which is working to commercialize this technology as well other novel therapeutic agents.
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Charafeddine RA, Makdisi J, Schairer D, et al. Fidgetin-Like 2: A Microtubule-Based Regulator of Wound Healing. J Invest Dermatol. 2015.