DEB is a terrible disease. It’s a disease of collagen 7 which is in the skin and if you don’t make collagen 7 essentially your skin is easily peeled off. So a baby being born and going through the birth canal might have parts of their skin pulled off by the friction or in life any friction can cause blistering or skin loss. These people spend their whole lives trying not to produce any stress or strain on their epidermis—it’s like potentially having burns on your entire body. What the team is trying to do here is make a functional copy of collagen 7A1, from a non-functional copy that these people have inherited. In the disease state it has a mutation in it that doesn’t allow it to perform the anchoring function that collagen 7A1 takes on in healthy people. So by skipping a bad exon you can create a functional collagen 7A1. It may be a little shorter, it might not have the number of turns that a collagen 7A1 helix would have, but it has most of them. The hope there is that you can create a situation that a patient’s skin will gain some of the tensile strength that your skin and my skin have so that every time these patients rub their hands they’re not going to have the blistering or loosening of that top layer of skin from the dermis.
DDD: Where are these drugs in the regulatory pipeline?
Art Levin: LCA has an IND that has been accepted and ProQR is getting ready to enroll their first patients. It’s a very exciting time for the company. The cystic fibrosis program is well into clinical trials and due to report out shortly. It’s a very exciting drug and I think the industry at large is waiting for that to come out.
[Editor’s note: ProQR received orphan drug designation from the FDA for their drug candidate QR-313 for Dystrophic Epidermolysis Bullosa following our interview with Dr. Levin.]
DDD: What are the challenges of RNA therapeutics?
Art Levin: Some of these disease have multiple mutations and each of those mutations would require a unique RNA therapeutic. This is something that differs from other therapeutic areas. For instance, in muscular dystrophy there are at least 17 different exons that need to be skipped so each of those patient classes would require a different drug. Same thing with LCA, Ushers, and DEB. Each of those diseases have patients that may ultimately require a different sequence—same philosophy or same mechanism of action—but you want to make the change at a different place on the RNA for each of the different patient classes with respect for which mutation they may hold.
That said, there will be variations in individuals. Take muscular dystrophy for example, most parents know what their son’s genotype is, so you know which drug, or which exon you want skipped. For some of these debilitating, genetic disorders, sequencing is now the norm. Right now, would it be important to know what your DEB mutation was? Maybe not, but as we get closer to getting different formulations for different patient subtypes then you’ll see that the patients will get the sequencing done and you’ll know which specific sequence drug you’ll have to take.
Moving forward the oligonucleotide field and companies like ProQR will develop novel ways to utilize RNA targets for modifying disease processes as we learn more about RNA biology and you should expect to see advancements in how we deliver these important new drugs to the right cell types to make the process safer and more efficacious.
Arthur A. Levin, Ph.D.
Scientific Advisory Board Member, ProQR Therapeutics, Leiden, the Netherlands
Arthur A. Levin, Ph.D. has been a scientific advisor for ProQR since its founding. Dr. Levin has nearly 20 years of experience in the research and development of RNA-targeting therapeutics and 30 years of experience in the pharmaceutical industry. He has been involved in the development of more than 20 oligonucleotide therapeutics in clinical trials. In addition to the Scientific Advisory Board for ProQR, Art is Avidity Bioscience’s Executive Vice President of Research and Development and sits on the SABs of Rigontec, CiVi Therapeutics and Cardior, and is a Director at Stoke Therapeutics. Prior to joining Avidity, Dr. Levin ran Research and Development at miRagen Therapeutics and was Chief Development Officer at Santaris Pharma (Copenhagen) where he led the efforts on the first microRNA targeting therapeutic in clinical trials.
Before joining Santaris Pharma, Dr. Levin consulted for leading biotechnology and pharmaceutical companies, conducting research and development in RNA-based therapies such as mRNA, microRNA, and siRNA. Dr. Levin’s began his work in oligonucleotide therapeutics at Isis Pharmaceuticals, where he was Sr. Vice President of Drug Development and responsible for the development of Isis’ products across a range of therapeutic areas. His expertise was instrumental in advancing more than a dozen oligonucleotide drugs from basic research to clinical development in areas such as neuromuscular diseases, infectious diseases, metabolic disorders, cardiovascular disease and cancer. He joined Isis from Hoffmann-La Roche Inc. where he was Research Leader and made fundamental discoveries in retinoid therapeutics.
Dr. Levin holds a Ph.D. in Toxicology from the University of Rochester School of Medicine and Dentistry, New York and a B.S. in Biology from Muhlenberg College. He completed his post-doctoral work at the Chemical Industry Institute of Toxicology in Research Triangle, North Carolina. He the author of more than 70 papers and book chapters.