Searching for a lymphedema drug

Wed, 11 Aug 2021 00:00:00 +0000

More than 20 years ago, I cloned the VEGF-C cDNA into an adenovirus shuttle vector. Even though we had the vectors for the AdEasy system from Bert Vogelstein’s lab to make adenoviruses in-house, we preferred to team up with gene therapy expert Seppo Ylä-Herttuala to make the first adenovirus with VEGF-C cargo (AdVEGF-C). This and other VEGF-C-expressing adenoviruses have been used by Seppo and us in several preclinical studies to show that VEGF-C can be successfully used to treat the underlying cause of certain types of lymphedema.In 2018, Herantis Pharma started Phase 1 clinical trials with AdVEGF-C, which was branded under the name Lymfactin. After Eiger Biopharmaceuticals ’ Phase-2-trials with bestatin failed to show any effect on lymphedema, Lymfactin was the only drug in clinical trials that was aimed at lymphedema. This spring, Herantis announced that it is discontinuing the clinical trials with Lymfactin in order to focus on their neurodegenerative ( CDNF ) drug pipeline. On top of this bummer came the news that the assignment of patients for the phase-2 trial had been non-random and that the Phase-2 results are therefore inconclusive . This is bad news for lymphedema patients just when gene therapy, on the whole, is making a comeback after an almost two-decade-long hiatus.What is the way forward? Even though the small molecule drug bestatin was shown to increase VEGFR-3 expression and activation , it was never a pro-lymphangiogenic therapy. The mouse experiments had shown clearly that it merely supports the endogenous lymphatic repair that is naturally kicking in after acute lymphatic damage. It specifically counteracts too high leukotriene B4 levels, which inhibit lymphangiogenesis, but it does not carry any own lymphangiogenic signal.The strategy to inhibit an inhibitor was also used in mouse studies that were published today in Science Signaling by Kataru et al.: Kataru et al. Kataru et al. used genetic modification of lymphatic endothelial cells to block PTEN, an intracellular inhibitor of VEGFR-3 signalling. The results are convincing: Lymphangiogenesis without any of the drawbacks that are inevitably associated with growth factor therapy, such as having too high growth factor concentrations at the site of delivery, which can lead to vessel leakiness and other unwanted responses. Small molecule PTEN inhibitors do exist, but they are pretty toxic. If a reasonably non-toxic PTEN-inhibitory compound could be found, all that is left is to specifically target it to lymphatic endothelial cells. However, neither finding nor targeting are easy tasks, although there are enough ideas that could be followed if funding was available. Read more about this topic in our opinion piece about searching for a lymphedema drug in Science Signaling: doi-link , e-print link for those who have no access to the full text.

Protein Drug Discovery & Development

Wed, 09 Sep 2020 00:00:00 +0000

Yesterday, I had my first Zoom lecture about protein drug discovery and development. I hope that the students did get at least something out of it. My goal is to cc-license the complete presentation but there are still a few images that I need to replace. A first attempt is rarely a great performance, and we had our fair share of technical problems. My headset failed for the first time since I bought it at the beginning of the Covid-19 pandemic. And the Zoom polling functionality disappeared before the students had any chance to use it and we did not manage to bring it up again.Here is the link to the live Google Slides: https://mjlab.fi/pddd . These will keep changing (= improving). Below you find the PDF snapshot of the presentation from the actual lecture day. The whole presentation is CC-licensed. So feel free to reuse it. All source files (mostly in Inkscape SVG format) are also available from here: https://mjlab.fi/pddd-files . I have done all the SVG files in Inkscape , but you can also open them in any browser or edit them in Adobe Illustrator. If you want to edit or extract images, the easiest is perhaps to download the presentation in Microsoft PowerPoint, LibreOffice Impress, or PDF format. I still have not figured out how to share the Google Slides presentation without making the original editable for everyone (after all, I need some control over the content of my lectures).Be aware, that at this moment, the presentation still contains eight images on Fair Use or with unknown licensing terms (even though the legal concept of fair use does not really exist outside the USA). All image sources (excluding my own images) are listed in the file README.txt with their respective licenses and source URLs. Some images are so old that I was not anymore able to locate their original URLs. Hence I am not sure about their licensing terms. I will replace these over the next few weeks when I manage to get hold of CC-licensed or public domain equivalents.

Drug Development on Michael’s Domain

Searching for a lymphedema drug

Protein Drug Discovery & Development