The skin is arguably one of the easiest of the large organs in the body to target for delivery of gene therapies, via established microneedle approaches. Nonetheless, much of the initial thrust of gene therapy clinical development focused instead on the liver, one of the other more tractable targets. Most material injected into the bloodstream ends up in the liver, and a single injection is logistically easier than coverage of large amounts of skin via microneedle patches, among other reasons.
Given the advent of messenger RNA (mRNA) encapsulated in lipid nanoparticles (either artificial or repurposed extracellular vesicles) as a proven gene therapy vector, however, adjusting the behavior of skin cells to generate elastin or collagen to reverse some of the loss of structure and elasticity in aged skin seems a practical goal at the present time. This while bearing in mind that elastin structure is complex, and any solution there will probably look more like adjusting the regulation of correctly structured elastin deposition rather than just expressing more elastin.
LNP-delivered mRNA lasts only a short time in tissues, a matter of a few days at most. This is a big advantage for any therapy one might hope to deliver to very large numbers of people, given the way that regulators such as the FDA think about risk and safety. From a regulatory point of view, one of the (many) issues with the early gene therapy technologies, such as viral vectors, is that they last for a very long time. This dramatically limits the potential applications.
Given an mRNA therapeutic that actually works, one or more genes that when upregulated will dramatically improve the structural integrity of aged skin, such a treatment could be adopted and widely used by the established "anti-aging" clinical infrastructure. That ecosystem that already uses microneedle techniques extensively to deliver marginal or useless treatments. One can hope that the good will chase out the bad in the long term, and snake oil will give way to effective therapies.
Intradermally delivered mRNA-encapsulating extracellular vesicles for collagen-replacement therapy
Recent developments in messenger RNA-modification techniques have enhanced the therapeutic efficiency of mRNA delivery and its potential for near-term clinical applications, including protein-replacement therapy and vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. However, the intrinsic inability and potential immunogenicity of mRNAs require that they be encapsulated within delivery vehicles. Current mRNA-delivery modalities centre on the usage of lipid nanoparticle (LNP) carriers for encapsulation and transport.
Extracellular vesicles (EVs), including exosomes and microvesicles, play a major role in the transport of biomolecules and nucleic acids, including mRNAs, within the human body. As a result, in recent years, EVs have emerged as promising carriers for nucleic-acid-based therapeutics owing to their intrinsic biocompatibility, their ability to cross physiological barriers and their low immunogenicity. Unlike LNPs, EVs, including exosomes, are endogenously produced by the body's cells and lead to lower levels of inflammatory responses. Moreover, strategies to cheaply and easily produce large quantities of exosomes have been developed.
We previously reported a cellular nanoporation (CNP) method in which transient nanometric pores were created on the surface of source cells to allow for the large-scale loading of full-transcript mRNAs into secreted EVs. Here, by using a mouse model of acute photoaging that closely mimics the pathophysiological features of aging-damaged skin in humans, we show the utility of exosome-based COL1A1 mRNA therapy to replace dermal collagen-protein loss as an anti-aging treatment for photoaged skin. To improve the efficiency of mRNA delivery and retention, we also show that the delivery of collagen mRNA via a hyaluronic acid (HA) microneedle (COL1A1-EV MN) patch allows for a more efficient distribution of mRNA in the dermis, resulting in durable collagen-protein engraftment and in an improved treatment of wrinkles in photoaged skin.
View the full article at FightAging
