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Today, Underdog Pharma, a spin-off company of SENS Research Foundation, was officially launched with the lofty goal of eradicating atherosclerosis.

Atherosclerosis is the leading cause of death worldwide and currently has no effective solution. Current medicine has three broad approaches towards it: lifestyle changes, such as diet and exercise; drugs that reduce the accumulation of cholesterol and thus slow down the rate of plaque formation; and surgical procedures, such as bypass surgery and the fitting of stents, which attempt to solve the problem with brute force.

None of these approaches is particularly effective in the long term, and none of them offers an actual cure for the disease. This is why Underdog is developing a therapeutic approach that could potentially address atherosclerosis by removing a harmful lipid known as 7-ketocholesterol from the arterial walls to halt progression of the disease and potentially even reverse it.

If successful, this could help pave the way for the repair approach to be accepted, and because it uses a more familiar drug format, it could also reduce approval time. If this age-related disease can be demonstrated to be modifiable, it would be a world first and could be transformative for healthcare.

We had the opportunity to talk with Dr. Matthew O’Connor from the Underdog team about this new company and the exciting work that it is doing.

Can you briefly explain the 7-ketocholesterol story and how it drives atherosclerosis?

7KC is a toxic oxysterol formed by the reaction of a cholesterol molecule with an oxygen free radical. 7KC has no redeeming qualities and is difficult to clear once it has become lodged in a cell. It is highly toxic to cells and is a fundamental damage molecule implicated in many diseases of aging, including atherosclerosis (and therefore heart attacks and strokes), Alzheimer’s disease, and macular degeneration. When an atherosclerotic lesion begins to form, immune cells called macrophages respond and try to clean up the lipids and cell debris in the arterial wall. Macrophages cannot metabolize 7KC, however, and that eventually shuts down lysosomal function in the macrophage, rendering the macrophage unable to properly metabolize lipids. They keep eating, however, and eventually get engorged with lipids. At this point, they become what are called “foam cells”: giant zombie cells that make up a large part of mature atherosclerotic plaques. They thus become part of the problem rather than the solution. 7KC has been known to be extremely atherogenic since the 1990s, but now we think we finally have a way to fight it.

You suggest that 7-ketocholesterol has no biological function and is a useless molecule that is very harmful and thus removing it should have little to no side effects. How have you reached the conclusion that this molecule serves no function?

Believe it or not, 7-KC has actually been studied since the 1940s. Your body doesn’t make 7KC enzymatically, only “accidentally” when a free radical damages a cholesterol molecule. It is not a nutrient that you need to eat. It acts like cholesterol in that it can integrate into cell membranes, but instead of helping to create the proper mechanical properties of the cell, it damages the cell membrane, resulting in leaky membranes. Neither is it a useful signaling molecule like most enzymatically created oxysterols are. 7KC has no redeeming qualities. You’d be better off without any of it.

You are planning to create a variant of an existing drug that is modified to get rid of 7-ketocholesterol; how does it work? 

We created a computational and a robotic drug screening system to test thousands of possible cyclodextrin variations. We studied what helps them bind 7KC and what helps them bind cholesterol.

Being a modified existing drug, presumably this means a shorter time to market?

That is absolutely our hope. This class of drug is known to the FDA; there are versions that are extraordinarily safe, and we are working with the regulatory experts who have gotten cyclodextrins approved before. We have learned what makes a cyclodextrin safe and have built those properties into our new CDs. We have a detailed plan to get our drug into clinical trials in 3-4 years. We are working on a clinical plan that will hopefully minimize the time in clinical trials as well.

What stage of research are you currently at; have you conducted mouse testing successfully?

We have many drug candidates and are narrowing down on which few to put through the rigorous process of pre-clinical safety and quality testing. We are starting animal testing now.

Is there anything you would like to tell people about Underdog that we haven’t already covered here?

We are a mission-driven company through and through – a true SENS company targeting a fundamental aging damage molecule. That’s why our drug won’t just help with atherosclerosis but also other diseases and disabilities of aging – perhaps aspects of aging that we haven’t even thought of yet. Mike and I have been in this field for a long time, and if there is a way we can contribute to building a new way of treating age-related disease, we intend to find it.

We would like to thank Dr. O’Connor for taking the time to speak with us about the exciting work that Underdog is doing, and we wish these researchers the best of luck in their endeavors. We will be watching their progress eagerly in the coming years and are hopeful that a solution to heart disease will be found. You can find a copy of the official press release below.

Novel therapeutic approach to cardiovascular disease from SENS Research Foundation flagship research program graduates from laboratory to the biotech world

  • Kizoo Technology Capital leads seed round financing at Underdog Pharmaceuticals
  • SRF announces leadership appointments

MOUNTAIN VIEW, Calif., Nov. 14, 2019 (GLOBE NEWSWIRE): Underdog Pharmaceuticals, Inc. (Underdog), and SENS Research Foundation (SRF) today announced the launch of Underdog and the completion of its seed round, providing $3.95 million to promote Underdog’s development of disease-modifying treatments for atherosclerosis and other age-related diseases. SRF also announced two senior appointments.

The Underdog round is led by Michael Greve’s Kizoo Technology Capital, part of the Forever Healthy Group and one of the premier organizations focusing on accelerating rejuvenation biotechnologies. It also includes Oculus co-founder Michael Antonov through Tubus, LLC, and financier Harald McPike through Chambray Worldwide, Ltd.

Underdog was built from an SRF flagship program that has driven two years of applied development designed to explore and repair the underlying causes of cardiovascular disease. Its co-founders are Matthew O’Connor, Ph.D. and Michael Kope, formerly the V.P. of Research and the founding CEO, respectively, of SRF.

“We’ve taken a well-known and extremely safe compound,” said O’Connor, “and have created novel derivatives that can specifically target the toxic biomolecule that drives the development of atherosclerosis, the cause of most heart attacks and strokes.”

Underdog’s research has combined computational and synthetic chemistry programs to create custom-engineered cyclodextrins (polysaccharides with known industrial and pharmaceutical excipient uses) to capture, and remove from cells, oxidized cholesterol derivatives such as 7-ketocholesterol, which are broadly toxic molecules with no known biological function. “Underdog will take a classic pharmaceutical approach and use it to attack the root causes of cardiovascular disease,” said Kope.  “If we’re successful, we won’t just be ameliorating the disease, but reversing it.”

Underdog’s advisors include world-renowned cyclodextrin expert Dr. Lajos Szente. “This elegant approach has the potential to be truly revolutionary,” Szente said. “I’m delighted to be working with them on this important advancement in the field.”

“I came to Aubrey de Grey years ago so that we could work together to accelerate the availability of human rejuvenation therapies,” said Greve. “I am proud to help SRF grow a flagship research program into a genuine company and to help unlock the required capital to develop a true rejuvenation therapy. I’m gratified that we’ve done this while continuing to allow for the health and growth of SRF itself, one of our most important engines for the rejuvenation pipeline.”

The agreement between the organizations will provide equity, royalties, and milestones for the future support of SRF programs.

As Underdog spins out, the V.P. of Research position at SRF has been assumed by Prof. Alexandra Stolzing. Stolzing, a long-standing SRF Research Advisory Board member, received her PhD from the Humboldt University in Berlin, was a postdoctoral fellow at Sheffield University, UK, group leader at the Fraunhofer Institute for Cell Therapy and Immunology, Germany, and then Professor for Biogerontological Engineering at Loughborough University, UK. With over 70 peer-reviewed publications, she has participated in several international research consortia in areas including regenerative medicine, cell and gene therapy development, and neurodegenerative diseases. Her industry experience includes startup CSO and VP of Research roles. Said Stolzing, “I’ve always been passionate about translational research in aging, and I’m very excited to join SRF, where I look forward to translating SRF’s basic science projects, initiating new projects, and helping generate the next wave of healthspan spinouts.”

Science and technology investor and longtime SRF board member Jim O’Neill has stepped in to lead the SENS Research Foundation as interim CEO. He will also spearhead the search for the incoming permanent CEO. O’Neill has advised, invested in, and nurtured more than sixty science and technology companies. While running the Thiel Foundation, he co-founded the Thiel Fellowship and helped create deep science fund Breakout Labs. Previously, he helped lead the U.S. Department of Health and Human Services as the principal associate deputy secretary, where he was responsible for overseeing policy and regulations at NIH, FDA, and CDC and led two major reforms of FDA. He supported the creation of the Armed Forces Institute for Regenerative Medicine, served on the steering committee of the Biomedical Advanced Research and Development Authority, and represented the United States on the U.S. delegation to the World Health Assembly. “Over the past decade, Mike and Aubrey built a team of scientists dedicated to damage repair and turned skeptics into advocates along the way,” said O’Neill. “The growing interest in technologies that can reverse aging is proof of their vision and determination. I’m excited to advance SRF’s vision to bring the benefits of such technologies to the public.”

“This is an historic moment for SENS Research Foundation,” said Dr. Aubrey de Grey, co-founder and Chief Science Officer of SRF. “Underdog may well become one of the most significant endeavors in the rejuvenation biotechnology industry, and Mike and Oki are the perfect team to make it a success. And with Jim’s deep experience in investment and policy, and Alex’s brilliance in research and teaching, I’ve no doubt our mission is in good hands. I’m delighted to have their leadership and expertise at SRF.”

About Underdog

Underdog Pharmaceuticals, Inc. is pursuing a mission to treat the underlying causes of age-related disease. The company develops simple and direct interventions targeting toxic forms of cholesterol using rationally designed molecules to provide the first true disease-modifying treatments for age-related diseases such as atherosclerosis, hypercholesterolemia, heart failure, and macular degeneration. Its products are based on novel derivatives of a well-known, safe compound and a new way of looking at cardiovascular disease created through a SENS Research Foundation program. For more information, please visit underdogpharma.com.

About SENS Research Foundation

SENS Research Foundation is a 501(c)(3) nonprofit that works to research, develop and promote comprehensive regenerative medicine solutions for the diseases of aging.  SRF supports research projects focused on a damage repair paradigm at universities and institutes around the world with the goal of curing such age-related diseases as heart disease, cancer, and Alzheimer’s disease. SRF educates the public and trains researchers to support a growing regenerative medicine field through advocacy campaigns and educational programs. For more information, please visit sens.org.

About Kizoo

Kizoo provides mentoring and seed and early-stage financing with a focus on rejuvenation biotechnology. Having been entrepreneurs, VCs, and mentors in both high-growth tech and biotech companies for many years, with multiple exits and massive value created for the founders, Kizoo now brings this experience to the emerging field of rejuvenation biotech – a young industry that will eventually become much bigger than today’s largest technology markets.

As part of the Forever Healthy Group, Kizoo directly supports the creation of startups turning research on the root causes of aging into therapies and services for human application. Investments include AgeX, FoxBio, Turn.bio, Elevian, Oisin Biotechnologies, LIfT BioSiences, MAIA Biotechnology, and others. Forever Healthy’s other initiatives include the evaluation of new rejuvenation therapies, evidenced-based curation of the world’s cutting-edge medical knowledge, funding research projects on the root causes of aging, and hosting the annual Undoing Aging Conference. For more information, please visit: kizoo.com and forever-healthy.org.

Notice 

This press release is not an offer to sell or a solicitation of an offer to buy securities in any jurisdiction.  No securities commission or regulatory authority has approved or disapproved the information contained herein.

Media contacts:

For Underdog: [email protected]

For SRF: [email protected]

For Kizoo: [email protected]

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.
  1. November 15, 2019

    Great, article, Steve, many thanks.

  2. December 3, 2019

    Is this a treatment but not a cure?

    What I mean is, would a person have to take
    the anti-7KC drug the rest of his/her life?

    If yes, wouldn’t a treatment using CRISPR be a more permanent cure? Or the short term use of sonolytics?

    • mm
      December 4, 2019

      Even if you had to take it every few years or decades it is way better than current standard of care. Senolytics might have some effect but it would unlikely stop the disease. CRISPR modification of the macrophages might be a viable approach and Repair Biotechnologies is working on modifying our macrophages so that they can absorb 7KC. I will take either approach to be quite honest given the lack of solutions now.

  3. December 11, 2019

    Robert Kane Pappas
    Steve, I think this is a case of removing the scratches from David Sinclair’s DVD
    comparison with regards to the cause of aging. If you remove a scratch yo will move the epigenetic needle back.Sinclair Interview Excerpts
    YouTube
    https://youtu.be/uA9z8K5snOk

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