Scaffolds Instead of Solutions — Safe and Effective RNA Therapy for Peripheral Arterial Disease
By Adrienne Mueller, PhD
September 4, 2020
Peripheral arterial disease (PAD) is a disorder that affects a significant proportion of the population. If you are over 60, you have a one in twenty chance of having PAD. By the time you are in your 70s, your likelihood increases to one in ten. PAD occurs when the vessels that carry blood to your arms and legs narrow or become blocked, which is often the result of plaque buildup. Although PAD sometimes only presents with mild discomfort, it can also cause debilitating pain, limit your ability to walk, and in severe cases, even result in tissue death.
Limitations of Gene Therapy
One of the most promising new strategies to treat PAD is to improve vascular growth. If your vessels are shrinking or dying, regenerating new arteries will help keep your tissue supplied with blood. New vessels develop in response to growth factors, which are molecules that signal to your tissue to create new cells. One approach to stimulate the production of growth factors is gene therapy—having a virus deliver a growth factor gene (DNA) into your cells, so your cells' own machinery makes growth factor proteins. Unfortunately, gene therapy has its challenges. If the virus-delivered growth factor is not integrated into your genome, it may have limited access to your cells' machinery and very little of it will be produced. If the growth factor DNA is integrated into your genome, it may overwrite your existing genes. Also, once the growth factor DNA is integrated into your genome, it will continuously promote the synthesis of new growth factors, which risks causing abnormal tissue growth.
mmRNA — Full of Promise, but Hard to Deliver
Synthetic modified mRNA (mmRNA) is new method that has been developed to overcome the challenges of gene therapy. Your cells' machinery can more readily synthesize growth factors from free-floating RNA than DNA. Also, unlike DNA that is incorporated into your genome using gene therapy, there is no risk of RNAs overwriting your existing genes, and they will only promote growth factor synthesis for as long as they are present in the tissue. Currently, mmRNAs are delivered in a lipid-based solution, not using a virus. However, there are two drawbacks to using a solution to deliver mmRNAs: 1) Using a solution means that there is a lot of variability in the spread of the mmRNA, and tissue adjacent to the target tissue could also be exposed to it, and 2) solutions are also very easy for the body to clear, so the tissue will only be exposed to mmRNAs very transiently.
Treating PAD — Scaffolds Instead of Solutions
Using a biomaterial, like a scaffold, instead of a solution, could overcome these drawbacks. Firstly, mmRNAs embedded in a scaffold cannot spillover to adjacent tissues. Secondly, scaffolds also allow the slow release of mmRNA, as the scaffold material slowly degrades over a period of weeks. An additional benefit of scaffolds is that they closely mimic the structure of existing tissue, which helps tissue regenerate by giving newly growing cells a substrate to attach to.
In their recent study, first author Tatiana Zaitseva, PhD, of Fibralign Corporation and Stanford Cardiovascular Institute-affiliated senior author Ngan Huang, PhD, report on a nanofibrillar scaffold they developed to help deliver mmRNA to limbs with PAD. The researchers loaded mmRNA for a growth factor that promotes new blood vessel formation into a new, slow-releasing scaffold. As they report in their paper in Regenerative Medicine, the authors found that their delivery mechanism works—the cells placed next to the scaffold do in fact synthesize more growth factors. Further, when they tested the scaffold in pigs with simulated PAD, they succeeded in helping to repair the damaged tissue. Five weeks after implanting the scaffold, the tissue showed clear and significant regeneration of new vessels.
Use of scaffolds to deliver mmRNAs promises to be a safer and more effective method to treat PAD than traditional gene therapy. This novel approach could also improve treatments for other disorders of soft tissue that have used gene therapy approaches in the past—cardiovascular, nervous, musculoskeletal, or otherwise.
This work was performed in collaboration with an industry partner, Fibralign Corporation. Additional CVI-affiliated authors who contributed to this study include Guang Yang, Maedeh Zamani, Richard L Hallett and Dominik Fleischmann.