A cholesterol advance, AI tools, the growth of RNAi, patient advocacy. Live coverage from Charles River’s World Congress

The 2019 World Congress: Delivering Therapies to the Clinic Faster got underway on Monday with two poignant talks from the camp driving rare disease research these days: the families. In keeping with the theme of the meeting, speakers also looked at how 21st century tools like AI and RNA interference are helping us identify targets and silence malfunctioning genes more efficiently, and overcoming un-druggable targets. Here is a snapshot of some of the talks.

Searching for a novel, affordable cholesterol-lowering drug

For most people with high cholesterol statins do the trick. Unfortunately, for patients with high baseline LDL cholesterol levels, statins are not enough. Four years ago regulators approved a new class of cholesterol-busting drugs that many doctors believed would lead to a reduction in the incidence of strokes and heart attacks.

The new injectable medications were known as PCSK9 inhibitors because they blocked a substance that hinders the liver’s ability to remove bad (or LDL) cholesterol from the blood. The problem was that the antibody drug, while effective, was also wildly expensive and insurers were reluctant to cover the cost of the drug. Thus a drug that holds great promise for patients languishes on the sidelines.

“To make a drug that works and then price it in a way that you know artificially limits access is a misalignment of goals,” said Dr. Brian Hubbard, PhD, CEO of Dogma Therapeutics, who delivered the keynoter at the World Congress. “I have no issue with making profit, but as we just hear if people need it you should find a way to get it to them and that has not happened yet.”

Dogma Therapeutics, which is based in Cambridge, MA, thinks it has arrived at a solution to the pricing problem. The tiny biotech discovered small molecule inhibitors that directly bind to a novel, cryptic binding pocket in PCSK9. Guided by dozens of crystallized structures of inhibitors bound to the PCSK9 protein, these molecules have been optimized to have more binding affinity. The preclinical data looks good so far. In large-animal studies, the drug elicited significant and robust reductions in LDL cholesterol by 55% after multiple weeks of dosing.

Dogma began working on the project in 2012, and identified the molecule in 2015, but it took four years to refine it to identify the right animal model to test the drug, said Dr. Hubbard.  

Charles River contributed medicinal chemistry, structural biology and biophysics, cell biology and PK/PD studies.

 “I will freely admit this is luck, but I tell my team luck came because we kept going,” Dr. Hubbard said.

Running Interference in the Age of Precision Medicine

RNA interference or RNAi is a naturally occurring process that regulates gene expression in many organisms. Powerful new algorithms and expression vectors give us the ability to generate reliable RNAi tools, which can be exploited experimentally to effectively and reversibly silence nearly any gene or gene combinations not only in vitro but also in live mice. As proof of RNAi, the US Food and Drug Administration approved Onpattro, the first drug that acts by RNAi interference, for a neurological disorder called amyloidosis.

Onpattro is designed to interfere with RNA production of an abnormal form of the protein TTR and, by preventing its production, to help reduce accumulation of amyloid deposits in peripheral nerves. The FDA had granted the application fast track, priority review and breakthrough therapy designations, along with orphan drug designation.

Dr. Peter Smith, PhD, CEO at Alnylam Pharmaceuticals, which developed Onpattro, said they are gradually overcoming many of the obstacles that have held back progress in using RNAi to develop drugs. These include delivering the RNA molecules to cells, and improving their stability.

“If you look at the evolution of these molecules over time it is really pretty amazing,” says Dr. Smith.

Accelerating Drug Discovery Through the Power of Microscopy Images

Dr. Anne Carpenter, Institute Scientist from the Broad Institute of Harvard and MIT, made a strong case for making better use of microscopy image analysis during the early stages of drug development. Using what they call “cell painting,” her group uses multiple stains on one sample to mine all available data from the smallest number of cells.

Microscopy images can be multidimensional – they can be 3D or time lapse, each with its own advantages depending on the research needed. Comparing normal and diseased cells can offer valuable insights into the mechanism of disease, especially when compared across multiple stains and image resolutions.

Dr. Carpenter described images as a quantitative data source. As we develop more and better biological models, images can offer a wealth of data down to the level of a single cell’s nucleus. For example, a researcher could take an image of normal cells, then an image of diseased cells. If they can use a drug compound to make the diseased cells look the same as normal cells, that is a strong data point in favor of the effectiveness of that drug.

Dr. Carpenter emphasized that the best use of precious biological samples is to measure everything and ask questions later. Forming a detailed morphological and cytological profiles first, before deciding which parts of the data you are most interested in, gives a research a richer picture of the cells under review. The theme of getting the most value out of each available piece of data was carried through many presentations of the day.

Target Identification for NASH Using Machine Learning

AI startup nference uses public domain data to predict associations in disease modeling and drug discovery. Dr. Tyler Wagner, the Head of Cardiovascular Research at AI at nference, used the liver disease NASH to show how AI can be uniquely useful in in developing treatment. In his example, the nference Biomedical Knowledge Synthesis Platform (nferX), a deep learning tool, was able to make connections between NASH and genetic markers that had not explicitly been made in the literature, but which turned out later to be an area of interest for NASH drug development.

In simple terms, Dr. Wagner explained that if the literature (including journal articles, blogs, FDA requests, medical databases, etc.) had many references to a strong relationship between A and B, and between B and C, the tool could extrapolate a relation between A and C even if they are never mentioned together in the real world. In terms of drug discovery, the relation between A and C could be the next big research arena, which the computer could predict before it is discovered by human researchers.

Nference uses natural language processing to create knowledge maps, which can then be divided into relevant categories and queried by experts to find novel associations. The company only uses public domain literature for now, but the logical next step is to offer their services to companies with proprietary knowledge, which can then be categorized and queried in new ways. This should offer new insights into data that has already been collected, saving time and money by unearthing valuable connections lurking unseen in the literature.

The Voices of Parents

Patient advocates shared their stories on how they are opening up the doors to research in rare diseases by starting foundations, raising money and pushing for research on all fronts. Matt Wilsey, who along with his wife, Kristen, started a foundation to find a cure for the rare genetic disorder, NGLY1 deficiency, that afflicts his young daughter Grace, received the Charles River Research Models in Drug Discovery Award. The Grace Science Foundation is modeled after the Manhattan Project, but for a single disease. Animal researchers, cell and systems biologists, chemists, geneticists, and scientists from many other fields working simultaneously on the foundation’s one goal: cure Grace and patients like her.  Read our Eureka blog to learn more about their foundation.

The day closed with a dynamic presentation from the Jake and Beth Burke, their son, Jack who was born with neurofibromatosis, and the Burke’s other two children, Luke and Grace. The Burkes started Cure NF with Jack to raise money for the rare condition, which causes tumors to form on nerve tissue anywhere in the body. Their talk received a standing ovation. Both the Grace Science Foundation and Cure NF with Jack served as a reminder to the largely scientific crowd of how urgent the needs are.

“The status quo isn’t working for people with rare diseases,” says Wilsey. “We are taking more risk, pursuing multiple therapies at once because we don’t have the luxury of time. That means trying some things won’t work but some that will. We aren’t setting the timeline or the rules, NGLY1 is setting them.”