Synthetic Molecules Hold Potential To Cure Many Diseases

Hong Moulton

In a grassy field north of Philomath sits an industrial building that houses Gene Tools LLC, where former OSU Professor Jim Summerton develops and manufactures his invention: custom-designed synthetic molecules called Morpholino antisense oligomers. Commonly known as Morpholinos, these molecules hold the potential to treat a wide variety of human health issues, from muscular dystrophy to influenza.

Morpholinos work by binding to sequences of RNA, a major component of all living cells. They can be tailored to bind onto specific parts in the RNA, thereby preventing other molecules from interacting with it. This can either prevent the manufacture of proteins that cause health issues or induce desired protein production by correcting genetic errors caused by mutations. 

Although they show great promise, there is no FDA-approved Morpholino-based drug that doctors can prescribe. One of the major hurdles for Morpholinos is their poor delivery into cells.  Currently, in order for a drug to easily travel into human cells, the size of the drug molecule needs to be small. Morpholinos are plus-sized molecule, many times the weight of small molecules.  In the Department of Biomedical Sciences at the OSU College of Veterinary Medicine, Associate Professor Hong Moulton is focused on the problem of getting the big molecules into cells.

“Morpholino oligomers have revolutionary potential for treatment of a broad range of human diseases, including viral, bacterial, age-related and genetic diseases,” she says. “But they suffer from poor delivery across the cell membrane into cells. My long-term research interest has been in inventing and improving delivery of Morpholinos.”

Moulton grew up in central China where her mother was a geochemist “I saw my mom doing chemistry and I watched the changing of the color and the state of the things she was working on, and that is how I got interested in chemistry,” she says. She attended Chongqing Normal University and became a chemistry teacher. “At that time, once you graduate you get a job assigned to you,” she says. “So I got a job in the Chongqing College of Education teaching organic chemistry.” While on a teacher exchange program in Seattle, Moulton met a professor at Portland State University who encouraged her to enter their doctoral program, where she did her PhD. research in the field of biochemistry and biophysics.  This led to her meeting Dr. Jim Summerton and he offered her a job at AVI Biopharma (now named Sarepta Therapeutics), founded by Dr. Summerton.

Moulton worked at AVI Biopharma, a Corvallis company, for thirteen years. While there she invented a technology that uses cell-penetrating peptides to improve the delivery of Morpholinos into cells. This technology has made it possible to carry out gene knockdown studies with Morpholinos, in cell culture and in animals, without using other methods to assist their delivery. For example, she demonstrated that the technology improved the delivery of Morpholinos into muscle cells of mice with muscular dystrophy, improving their symptoms and survival. Unfortunately, in the financially tricky realm of drug development, Summerton’s company went through many transformations, and eventually the research part of the company moved to Seattle.

 Moulton chose to stay in Corvallis and now works as a Senior Research Associate Professor in the OSU College of Veterinary Medicine. She is currently working on several Morpholino projects. One involves the use of a color-switchable zebrafish specially engineered for her at the Mayo Clinic. “This fish has a piece of DNA integrated into it that has genes coding for two proteins: one is for blue fluorescent protein and one is for red fluorescent protein.” she says. Moulton then designed a Morpholino that binds to that gene’s RNA, allowing her to manipulate the color of the fish. This technique gives her a tool for testing her theories of improved delivery of Morpholinos. “If I am able to deliver the Morpholinos into the nucleus of the cells, every cell in that fish will turn off the blue gene and turn on the red gene so the fish will turn from blue to red under a fluorescent microscope,” she says “That allows me to quantify how much material is getting to the cells.”

It also allows her to see where the Morpholinos are most effective. “Is it going to the brain? Is it going to the muscles? I can look at distribution of these molecules.” Moulton has already used her custom-designed fish to demonstrate that a peptide-enhanced Morpholino can be delivered into specific tissue in juvenile fish. The next step begins this summer when OSU veterinary student Brandy Finney will be helping her test the process on adult fish.

The second big project in Moulton’s lab is an NIH-funded study of Morpholino’s effect on  the influenza virus. She is a co-investigator on a multi-million dollar grant, working with several teams across the U.S. to identify which host genes interact with influenza. One of the goals at the end of the five-year project is to have a Morpholino that will inhibit the influenza virus. “We then will want to develop this into a therapeutic product that goes to drug development,” she says.

One big difficulty in treating viruses and bacteria is their rapid mutation and development of drug resistance. Because ‘small molecule’ drugs take many years to develop, and only effect a specific gene and protein function, these rapid mutations can significantly decrease their.  Morpholinos, on the other hand, can be easily adapted to each mutation.  “The beautiful thing about this technology is . . .  Let’s say we have an influenza outbreak and mutation occurs in the virus; influenza mutates quickly, and you don’t have time to develop a small molecule drug because you have to go through many steps, including determination of the structure of the new protein, screening a small-drug chemistry library, etc., which is a long and costly process.  But with Morpholinos we can quickly sequence the DNA , design a compound to accommodate the mutation, make the compound, and put the right delivery component on it in about three weeks.”

All Morpholinos are composed of four subunits in a sequence; rearranging those units determines where they will bind to the RNA and which protein’s manufacture they inhibit. That provides a huge advantage to their use in medicine, because, if Morpholinos are approved by the FDA as a drug class, a sequence can be tweaked without having to go through the traditional approval process again.  “We call it platform technology because you can design the Morpholino sequence on a computer, and when you know where a mutation occurs, you can just change the sequence and synthesize a new Morpholino in a few weeks,” Moulton says. “Except for vaccines, FDA hasn’t approved such a “class” drug yet but I can see how it would work in the future. It’s very exciting.”