Finding the Blood: Exploring New Avenues to Improve Pro-angiogenesis Therapeutics
A study was recently published1 which claimed that there is a lack of association between cardiovascular disease (CVD) and total cholesterol; the authors even went on to claim that higher levels of cholesterol may prolong life and suggest that lowering cholesterol via medication is useless. This view is not only extreme, but also garnering a lot of criticism. Statins are commonly prescribed to mitigate symptoms associated with many different disorders, such as hypertension, diabetes and peripheral artery disease (PAD). For now, the jury is out on whether or not the study carries any weight, as a substantial amount of evidence will need to be collected before physicians give up on statins.
Statins have become part of the daily medication routine for many suffering from a variety of different disorders; however, they carry with them a host of undesirable side effects. Perhaps researchers may use this publication as inspiration to search for other targets for CVD therapeutics. One currently under-utilized avenue may be the promotion of angiogenesis—the creation of new blood vessels—as it has the potential to mitigate both hypertension and PAD. In the past, pro-angiogenesis therapeutic research has been fraught with problems, including the technological limitations within monitoring and analyzing data. Many of these previous therapeutics hinged on the delivery of single angiogenic growth factors. Although they produced promising results at the bench, they failed miserably in clinical trials. This poor performance is likely due to: an inability to provide sustained growth factors over a period of time to allow for maturation of the new vessels; difficulties accurately targeting desired tissues; and poor experimental design.2 Fortunately, through recent advances in technology and knowledge, these issues can be circumvented.
New Delivery Methods Assist in Mitigating Negative Results Associated with Pro-Angiogenic Therapies
New delivery methods may improve drug efficacy. Within recent years a number of scaffolds have been developed to localize and prolong the delivery of single angiogenic growth factors, such as vascular endothelial growth factor (VEGF). VEGF is associated with tumorigenesis, which causes grave concern when it cannot be accurately targeted to the correct tissue. One group has provided evidence that its release can be localized and sustained for two weeks through the use of self-assembling peptide nanofibers.3 This addresses two of the major concerns associated with VEGF: an inability to maintain a therapeutic dose and accurate targeting.
In a similar manner, another group has used Gelfoam to deliver recombinant periostin peptide (rPN). Although this is a peptide rather than a single growth factor, this system also showed improved release by the non-fibrotic fibrin encapsulation of the Gelfoam. These delivery systems will require more research and additional delivery systems will be developed, but it is clear that the process will be streamlined if this innovation is driven by collaboration. By sharing data and feedback, it will allow each party to have a better perspective regarding the side of this research that they seldom see.
Another approach that is gaining steam is the use of cell therapies. Primarily, the cell therapies used in angiogenesis promotion use human umbilical vein endothelial cells (HUVECs) and mesenchymal stem cells (MSCs). Cell therapies pose challenges and side effects, similar to angiogenic growth factors, in terms of localization and delivery; additionally, there are undesirable paracrine effects that can result from stem cell treatments. Researchers found that using HUVECs in tandem with hyaluronic acid (HA) prolonged the degree of cell retention and increased angiogenesis in comparison with material or cells alone, as compared at four weeks.4 Although HUVEC treatment is still in its infancy, accurately collected and analyzed data will help assess risks associated with this cell therapy in the future.
Researchers are also focused on directing the action of the autologous bone-marrow derived MSCs by injecting it coupled with a collagen hydrogel. Through a series of carefully crafted and recorded controls, the authors were able to identify although collagen may improve capillary density, the mature vessel density and elevated oxygen saturation could be attributed to the MSCs themselves.5 In a similar manner to the aforementioned study using nanofibers, a group used a synthetic hydroxyapatite nanoparticle system to deliver cells which displayed an increase in angiogenesis, arteriogenesis and cell survival after seven days.6 As compared to the early days of cell therapy, new technology is making it easier to sift through mass amounts of data allowing researchers to “fail” potential therapeutics faster. This allows for issues to be nipped in the bud before more R&D dollars are wasted moving forward with therapies that are unlikely to survive clinical trials.
Advances in Digital Technologies Assist Scientists in Designing Targeted Therapeutics
The prevalence of bioinformatics and in silico analysis has grown substantially the past few years. Many researchers are choosing to entirely plan and project the effects of possible therapeutics on computers. This requires technology that did not exist during the initial trials with single growth factors. One group designed a VEGF-mimetic peptide system. This system has a similar epitope to that of VEGF attached to a network of self-assembling filaments. It successfully promoted angiogenesis in vivo. In a similar manner to previously mentioned studies, this is another system that relies on the addition of scaffolding for higher levels of success in angiogenic activity.7 As other groups choose to move forward bearing these things in mind, better predictive analytics will be essential.
Knowledge and technology are swiftly adapting to improve the development of pro-angiogenesis therapeutics. With skyrocketing operational costs and high failure rates, there is a great deal of pressure on researchers to deliver better results. BIOVIA Designed to Cure enables scientists to be more productive by supporting innovation and delivery of therapeutics. This platform integrates different portions of the research process enhancing decision making, accelerating the design of therapeutics, increasing accessibility of information and allowing for better collaborations. Please contact us today to learn more about how our software options can support the efforts of your lab.
- “Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review,” June 12, 2016, http://bmjopen.bmj.com/content/6/6/e010401.full ↩
- “Instructive Nanofiber Scaffolds with VEGF Create a Microenvironment for Arteriogenesis and Cardiac Repair,” August 8, 2012, http://stm.sciencemag.org/content/4/146/146ra109.long ↩
- “Intrapericardial Delivery of Gelfoam Enables the Targeted Delivery of Periostin Peptide after Myocardial Infarction by Inducing Fibrin Clot Formation,” May 10, 2013, http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0036788 ↩
- “A cellular delivery system fabricated with autologous BMSCs and collagen scaffold enhances angiogenesis and perfusion in ischemic hind limb,” February 29, 2012, http://onlinelibrary.wiley.com/doi/10.1002/jbm.a.34081/abstract ↩
- “Enhancement of Cell-Based Therapeutic Angiogenesis Using a Novel Type of Injectable Scaffolds of Hydroxyapatite-Polymer Nanocomposite Microspheres,” April 18, 2012,
- “Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair,” August 1, 2011, http://www.pnas.org/content/108/33/13438 ↩
- “Concise Review: Injectable Biomaterials for the Treatment of Myocardial Infarction and Peripheral Artery Disease: Translational Challenges and Progress,” July 10, 2014, http://stemcellstm.alphamedpress.org/content/3/9/1090 ↩