Underdog Pharmaceuticals Launched

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, evidence-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]

Identification and Targeting of Noncanonical Death Resistant Cells

SENS Research Foundation Research Center

Forever Healthy Foundation Fellowship in Rejuvenation Biotechnology

Principal Investigator: Tesfahun Admasu / Alexandra Stolzing

When cells age, they lose their proliferative capacity and stop dividing in a phenomenon called senescence. Cellular senescence decreases the regenerative capacity of cells and tissues.

Throughout the aging process, senescent cells accumulate and secrete a characteristic set of proteins, called a senescence-associated secretory phenotype (SASP). Although SASPs act as tumor suppressors and recruit immune cells to repair damage, they also exacerbate the deleterious effects of senescence in the development of pathologies such as cancer, neurodegenerative diseases, and diabetes. Furthermore, SASPs can induce senescence in surrounding cells (called ‘secondary senescence’ or ‘paracrine senescence’), which can aggravate the effect. While primary senescent cells are fairly well characterized at this point, not much is known about secondary senescent cells and how they are arise in vivo.

Project Goals

This project seeks to confirm the hypothesis that secondary senescent cells are different from primary senescent cells, and would therefore need a different senolytic to eradicate them. In addition, the project will study how SASP components mediate the spread of senescence. This work could provide us with the basis for a new, therapeutically viable hypothesis for stopping the spread.

Job Opportunity: Research Assistant (Immunology)

SENS Research Foundation (SRF) is hiring a Research Assistant for our Research Center (RC) located in Mountain View, CA. SRF is an exciting, cutting edge non-profit dedicated to transforming the way the world researches and treats age-related disease.

We are seeking a Research Assistant in our Senescence Immunology group for a project geared toward developing therapeutic interventions to rejuvenate immune clearance of senescent cells. This project involves working with human blood samples and primary human cells. This is a full-time position.

Qualified candidates will have a BS or MS in the chemical/biological sciences and substantial bench experience. Duties will include mostly bench work in a small team-oriented environment.

Candidates should have experience in WBC purification, culturing primary cells, quantitative real-time PCR, western blot, immunofluorescence, ELISA, micro plate readers, FACS analysis, and data analysis. Candidates with experience in 2nd and 3rd generation lentivirus system are particularly encouraged to apply.

Interested candidates should submit a cover letter and resume to [email protected].

We offer an excellent benefits package including paid vacation and sick leave, fully covered health insurance (inclusive of dependents), an FSA program, and a company matched 401(k) plan, all of which is offered after a 90-day introductory period. SENS Research Foundation is an equal opportunity employer.

The position is available now and will be filled as soon as the qualified candidate is found. Salary is commensurate with job title.

Job Type: Full-time
Salary: $48,000 to $50,000/year

SRF Research Center Immunologist Application Form

UPDATE: This post has been filled.

Immunologist

SENS Research Foundation (SRF) is seeking a full-time researcher for a Scientist position to work at our Research Center located in Mountain View, California. The position is to lead a new intramural research project geared toward performing translational research studying aging as it relates to the immune system, with a possibility of developing a new therapeutic. This is a collaborative effort between SRF and the Campisi Lab at the Buck Institute for Research on Aging, located in Novato, CA. The collaboration allows the researcher to work with two institutions at the forefront of the anti-aging field, and allow for mentorship from experts in the field. The successful applicant will work with, and be guided by, senior researchers at both SRF and the Buck, and as such this position is available to new PhDs as an alternative to doing a Postdoc (or a 2nd postdoc). The position offers the opportunity for upward mobility into a more senior, PI level position. Leading a team at SRF is an exciting career opportunity in a team environment where everyone is dedicated to discovering new treatments for the diseases and disabilities of aging.

Required Experience

  • PhD or equivalent doctoral degree in the chemical/biological sciences
  • Expertise in the innate immune system

Desired Capabilities

  • Independent planning and project design
  • NK cell knowledge or experience
  • Proficient at the bench and with data analysis
  • Management / mentoring experience
  • Comfortable working in a small team environment and with collaborations with other institutions

Compensation

SRF is proud to offer a competitive salary of $65-75,000/yr for this position, which includes paid vacation and sick leave, fully covered health insurance, inclusive of dependents, an FSA program, and a company matched 401(k) plan offered after a 90-day introductory period. SRF is an equal opportunity employer.

Interested candidates should apply by email to Dr. Matthew O’Connor, taking care to include all of the information and documentation listed below.

Applicants moving onto the second phase of the application process will be contacted by email by a SRF representative for an interview.

Application Information

Contact Information:

  • Last Name / Surname
  • First Name / Given Name
  • Email Address
  • Phone Number
  • Full Mailing Address

Academic Information:

  • Graduate Institution
  • Program or Department
  • Graduation Date
  • First available date to begin position

Documents:

Attach documents in PDF, DOC or DOCX format.

  • CV or Resume.  Please limit your CV or resume to a maximum of 2 pages. Highlight any prior laboratory or research experience. A brief 1- or 2-line description of your specific contribution to each research project is particularly helpful. For instance, the statement “created the expression construct that allowed us to determine protein localization” quickly clarifies your role in the project.
  • Cover Letter.  A cover letter describing your knowledge of SRF’s damage repair approach to aging as well as your experience in immunology; please limit your letter to one page.

A Small Molecule Approach to Removal of Toxic Oxysterols as a Treatment For Atherosclerosis

This research program has successfully spun-out into a company! Visit the Underdog Pharmaceuticals, Inc. website for more information on their transformative approach to atherosclerosis.

SENS Research Foundation Research Center

Principal Investigator: Matthew O’Connor
Research TeamAmelia Anderson, Carolyn Barnes, Angielyn Campo, Anne Corwin, Sirish Narayanan

Many diseases of aging are driven in part by the accumulation of “junk inside cells:” stubborn, damaged waste products derived from the metabolic processes particular to specific cell types. The accumulation of these wastes disables the cell type in question and leads to their dysfunction; when, after decades of silent accrual, a critical number of these cells become dysfunctional, diseases of aging characteristic of that tissue erupt. For example, atherosclerotic lesions form when immune cells called macrophages take in 7-ketocholesterol (7-KC) and other damaged cholesterol byproducts in an effort to protect the arterial wall from their toxicity, only to ultimately fall prey to that same toxicity themselves. These macrophages – now dysfunctional “foam cells” – become immobilized in the arterial wall and spew off inflammatory molecules that in turn promote advanced atherosclerosis, heart attack, and stroke. In other organs, the accumulation of damaged molecules inside vulnerable cells drives Alzheimer’s and Parkinson’s diseases, as well as age-related macular degeneration.

Dr. O’Connor’s team have identified a family of small molecules that may be able to selectively remove toxic forms of cholesterol from early foam cells and other cells in the blood. If effective, these small molecules could serve as the basis for a groundbreaking therapy that would prevent and potentially reverse atherosclerosis and, possibly, heart failure.

Research Highlights:

A lead compound was identified following evaluation of data from human blood sample tests in conjunction with computer modeling to predict the likely behavior of rationally-designed molecules. Preliminary testing has indicated performance consistent with enhanced activity relative to the existing family of compounds: specifically, the candidate molecules exhibit selective targeting of toxic cholesterol byproducts, with significantly reduced affinity for native cholesterol. A patent application for this lead compound and others to be derived from it has now been submitted.

The team is now working to refine their original assay with the expectation that it will more accurately reflect the desired activity on toxic and native cholesterol, and also on an entirely different chemical approach to improved molecules derived from the original family. We are also working with a potential contract laboratory to test the absorption, circulation to tissues, and disposal of our lead candidate, and to perform toxicity assays. SRF has recently acquired a new robotic system to run the assay, which our in-house engineer, Anne Corwin, is now working to set up and program; the end result will be an increase in throughput that allows more rapid testing of more molecules.

Engineering New Mitochondrial Genes to Restore Mitochondrial Function (MitoSENS)

SENS Research Foundation Research Center

Principal Investigator: Amutha Boominathan
Research Team: Nana Abena Anti, David Begelman, Bhavna Dixit, Caitlin Lewis, Sanjana Saravanan

Mitochondria are the tiny cellular “power plants” in our cells, which take energy from our food and convert it into a form that can be used to power the cell’s energy-intensive processes. Unfortunately, like actual power plants, they generate waste – in this case called free radicals, which damage mitochondrial DNA (mtDNA) over time. As a result, some cells become burdened by these dysfunctional mitochondria and can accumulate in the body as we age. These damaged cells in turn export toxic molecules to far-flung tissues, contributing to Parkinson’s disease, age-related muscle dysfunction, and other conditions.

The MitoSENS goal is to engineer a solution to the accumulation of cells with these mutation-bearing mitochondria via allotopic expression.  Allotopic expression involves placing “backup copies” of all the protein-coding genes of the mtDNA in the cell’s nucleus. From this “safe harbor,” the copied genes can then direct the cell’s machinery to produce engineered versions of the missing mitochondrial proteins and deliver them to the correct location. With their full complement of proteins restored, mitochondria can resume producing energy normally – despite lacking functional copies of these genes to produce them on their own.

Research Highlights:

In 2019, the MitoSENS team achieved a major breakthrough in successfully demonstrating transient allotopic expression for all 13 mtDNA genes. This work was recently published in Redox Biology, 30 (2020) 101429. Several of these genes can be expressed stably and the team was further able to demonstrate a functional utility for these exogenous proteins in rescuing patient cell lines with specific mutations in the mtDNA genes ATP8, ATP6, and ND1 (Nucleic Acids Res. 44(19) 2016; 9342-9357 and Redox Biology 30 (2020) 101429).  

Our current efforts are focused on validating this strategy in rescuing some of the more common inherited disease conditions observed as a result of mutations to mtDNA, such as Leber’s Hereditary Optic Neuropathy (LHON) and Leigh’s syndrome. We are also exploring alternative strategies and software based prediction models to optimize the expression of all 13 mtDNA genes and the transport and integration of their corresponding proteins into the mitochondria.

The MitoSENS team also has ongoing experiments to demonstrate efficacy in living, breathing mice – specifically,  a transgenic ATP8 mouse derived from the Maximally Modifiable Mice (MMM) created through the SENS Research Foundation-funded work at Applied StemCell. The new MMM-derived mouse model will have the allotopic ATP8 copy engineered into their nuclear genomes but will inherit functionally compromised mitochondria (and thus mitochondrial DNA) from a cross with FVB mice, which have a specific mutation in the mitochondrial ATP8 gene. This work is being done in collaboration with the Brand lab at the Buck Institute and will include biochemical and behavioral assays to evaluate if the allotopically expressed ATP8 gene can rescue the phenotype.

Enhancing Innate Immune Surveillance of Senescent Cells

Buck Institute for Research on Aging

Principal Investigator: Judith Campisi
Research Team: Abhijit Kale

SENS Research Foundation Research Center

Principal Investigator: Amit Sharma/Alexandra Stolzing
Research Team: Elena Fulton

When normal cells lose their ability to replicate, they become senescent cells. Over time, senescent cells accumulate in aging tissues, spewing off a cocktail of inflammatory and growth factors, as well as enzymes that break down surrounding tissue and cause inflammation. This cocktail is the “senescence-associated secretory phenotype” or SASP. Senescent cells – and the downstream impact of the SASP – are now implicated in a remarkable litany of the diseases of aging.

On a more encouraging note, multiple studies have now documented that senolytic drugs and gene therapies that destroy senescent cells exert sweeping rejuvenating effects in aging, both in laboratory animals and animal models of multiple diseases of aging. In theory, however, senolytic therapies shouldn’t be necessary. The body’s immune system is on continuous patrol against senescent cells: our natural killer (NK) cells recognize senescent cells as abnormal, bind to them, and release substances that trigger the senescent cells to self-destruct.

An SRF-donor-funded collaboration between Dr. Judith Campisi’s lab at the Buck Institute and the SRF Research Center seeks to discover why senescent cells accumulate with age, and what might we do to enhance immune surveillance and elimination of these cellular saboteurs?

Research Highlights:

The Campisi lab has recently published three papers describing the underlying mechanism of immune evasion by resistant senescent cells (Pereira et al., 2019, Munoz et al., 2019, and Kale et al., 2020). Dr. Campisi has found that a significant proportion of senescent cells manage to evade destruction, even by fresh NK cells. These ‘resistant’ cells escape immunosurveillance and accumulate in aging tissues. Senescent cells moreover shed decoy ligands binding to NK cell receptors; another aim of this work is to screen for more such ligands shed by senescent cells.

The Buck-SRF-RC collaboration is now seeking to drill further into the mechanism of senescent cell accumulation, and test interventions. At the SRF-RC, we are currently perfecting the method of co-culturing NK and senescent cells and controlling the killing process;  next, we will begin testing therapeutic interventions.

The SRF-RC scientists are also working for the first time with NK cells derived directly from aged human donors (rather than long-cultured lines of NK cells, or NK cells artificially “aged” by exposure to oxidative stress or extensive replication in culture, as has been done in the past). Using these cells will allow them to observe any direct effects of aging on NK cell senolytic activity.

Use of this Web site constitutes acceptance of the Terms of Use and Privacy Policy.

© 2020 SENS Research Foundation – ALL RIGHTS RESERVED

Thank you for Subscribing to the SENS Research Foundation Newsletter.

You can also

or

You can