Research Partnership Archives - Sanford Burnham Prebys

Tag: Research Partnership

Institute News

First supercentenarian-derived stem cells created

AuthorMonica May
Date

March 19, 2020

telomere DNA illustration

Advance primes scientists to unlock the secrets of healthy aging.

People who live more than 110 years, called supercentenarians, are remarkable not only because of their age, but also because of their incredible health. This elite group appears resistant to diseases such as Alzheimer’s, heart disease and cancer that still affect even centenarians. However, we don’t know why some people become supercentenarians and others do not.

Now, for the first time, scientists have reprogrammed cells from a 114-year-old woman into induced pluripotent stem cells (iPSCs). The advance, completed by scientists at Sanford Burnham Prebys and AgeX Therapeutics, a biotechnology company, enables researchers to embark on studies that uncover why supercentenarians live such long and healthy lives. The study was published in Biochemical and Biophysical Research Communications.

“We set out to answer a big question: Can you reprogram cells this old?” says Evan Snyder, MD, PhD, professor and director of the Center for Stem Cells and Regenerative Medicine at Sanford Burnham Prebys, and study author. “Now we have shown it can be done, and we have a valuable tool for finding the genes and other factors that slow down the aging process.”

In the study, the scientists reprogrammed blood cells from three different people—the aforementioned 114-year-old woman, a healthy 43-year-old individual and an 8-year-old child with progeria, a condition that causes rapid aging—into iPSCs. These cells were then transformed into mesenchymal stem cells, a cell type that helps maintain and repair the body’s structural tissues—including bone, cartilage and fat.

The researchers found that supercentenarian cells transformed as easily as the cells from the healthy and progeria samples. As expected, telomeres—protective DNA caps that shrink as we age—were also reset. Remarkably, even the telomeres of the supercentenarian iPSCs were reset to youthful levels, akin to going from age 114 to age zero. However, telomere resetting in supercentenarian iPSCs occurred less frequently compared to other samples—indicating extreme aging may have some lasting effects that need to be overcome for more efficient resetting of cellular aging.

Now that the scientists have overcome a key technological hurdle, studies can begin that determine the “secret sauce” of supercentenarians. For example, comparing muscle cells derived from the healthy iPSCs, supercentenarian iPSCs and progeria iPSCs would reveal genes or molecular processes that are unique to supercentenarians. Drugs could then be developed that either thwart these unique processes or emulate the patterns seen in the supercentenarian cells.

“Why do supercentenarians age so slowly?” says Snyder. “We are now set to answer that question in a way no one has been able to before.”

The senior author of the paper is Dana Larocca, PhD, vice president of Discovery Research at AgeX Therapeutics, a biotechnology company focused on developing therapeutics for human aging and regeneration; and the first author is Jieun Lee, PhD, a scientist at AgeX.

Additional authors include Paola A. Bignone, PhD, of AgeX; L.S. Coles of Gerontology Research Group; and Yang Liu of Sanford Burnham Prebys and LabEaze. The work began at Sanford Burnham Prebys when Larocca, Bignone and Liu were members of the Snyder lab.

The study’s DOI is 10.1016/j.bbrc.2020.02.092.

Institute News

Parkinson’s research benefits from powerful collaboration

AuthorDeborah Robison
Date

June 19, 2017

Mayo Clinic Collaboration

Medical discoveries may languish in laboratories for years without the necessary tools and means to drive findings further toward the development of novel therapeutics. This could have been the case for Dr. Pamela McLean, a Parkinson’s disease expert at the Mayo Clinic in Jacksonville, Fla., had a collaboration with SBP’s drug discovery team in Lake Nona not emerged.

McLean’s deep clinical experience and unique insights into the molecular basis of the disease, combined with SBP’s screening technology and drug discovery expertise, produced promising findings and attracted a significant grant from The Michael J. Fox Foundation (MJFF). Just recently, the researchers were awarded a special MJFF bridge grant to ensure that the science continues to move forward.

McLean studies the role of alpha-synuclein, a protein that misfolds and aggregates in the brain regions that are critically involved in Parkinson’s disease. She brought her cell-based models of alpha-synuclein protein “clumping” to SBP where the drug discovery team screened through 800,000 chemical compounds for substances that were capable of removing the abnormal protein and protecting the cells. Results from the initial study identified eight compounds as potential inhibitors of alpha-synuclein aggregation.

“Our current investigation will enhance the effectiveness of the drug candidates that we previously identified and advance them to pre-clinical development on the road to patient treatment,” said Dr. Layton Smith, director of SBP at Lake Nona Drug Discovery.

During this phase, chemistry teams will validate and refine the drug candidates’ biological activities. The process will likely eliminate some candidates in a testing funnel designed to narrow the compounds to those that exhibit the desired properties, such as inhibiting protein aggregation in the brain. Concurrently, McLean will explore the drug candidates’ mechanism of action to understand if the compounds work by blocking aggregation, enhancing removal of the clumps or by some other means. New therapies are critically needed to treat the more than 1 million Americans afflicted with Parkinson’s disease. Current medicines treat symptoms but do not reverse the effects of the disease.

Institute News

What SBP Scientists are Researching to Battle Skin Cancer

AuthorHelen I. Hwang
Date

May 16, 2017

Nevus sample from Peter D. Adams' lab

Skin cancer is one of the most common of all cancers, and melanoma accounts for about 1 percent of skin cancers. However, melanoma causes a large majority of deaths from that particular type of cancer. Alarmingly, rates of skin cancer have been on the rise in the last 30 years. Here in Southern California, our everlasting summer comes with a price. Exposure to sun increases our risk to melanoma.

Melanoma occurs when the pigment-producing cells that give color to the skin become cancerous. Symptoms might include a new, unusual growth or a change in an existing mole. Melanomas can occur anywhere on the body.

At Sanford Burnham Prebys Medical Discovery Institute (SBP), we have several researchers working on the causes of melanoma and discovering new ways to treat this deadly disease.

Here is a roundup of SBP’s latest research:

Key findings show how melanoma develops in order to identify potential therapeutic targets

Ze’ev Ronai, PhD
Professor and SBP Chief Scientific Advisor

Ronai’s laboratory has been studying how rewired signaling networks can underlie melanoma development, including resistance to therapy and metastatic propensity. One player in that rewiring is a protein called ATF-2, which can switch from its usual tumor-preventive function to become a tumor promoter when combined with a mutation in the human gene called BRAF.

Ronai’s work on a protein, ubiquitin ligases, led to the identification of RNF125 as an important regulator of melanoma resistance to a common chemotherapy drug. RNF125 impacts melanoma resistance by its regulation of JAK2, an important protein kinase which could play an important role in melanoma resistance to therapy.

Work on the ubiquitin ligase Siah2 identified its important role in melanoma growth and metastasis, and its contribution to melanomagenesis. Melanoma is believed to be a multi-step process (melanomagenesis) of genetic mutations that increase cell proliferation, differentiation, and death.

Work in the lab also concern novel metabolic pathways that are exploited by melanoma for their survival, with the goal of identifying combination drug therapies to combat the spread of melanoma. Earlier work on the enzyme PDK1 showed how it can be a potential therapeutic target for melanoma treatment.

Immunotherapy discovery has led to partnership with Eli Lilly

Linda Bradley, PhD
Professor, Immunity and Pathogenesis Program, Infectious and Inflammatory Diseases Center

Bradley’s group is focused on understanding how anti-tumor T cells can be optimized to kill melanoma tumors. They discovered an important molecule (PSGL-1) that puts the “break” on killer T cells, allowing melanoma tumors to survive and grow. Using animal models, they removed this “break” and T cells were able to destroy melanoma tumors. They have extended their studies and found that in melanoma tumors from patients, T cells also have this PSGL-1 “break”. Bradley’s lab has partnered with Eli Lilly to discover drugs that can modulate PSGL-1 activity in human disease that may offer new therapies for patients.

Knocking out a specific protein can slow melanoma growth 

William Stallcup, PhD
Professor, Tumor Microenvironment and Cancer Immunology Program

The danger of melanomas is their metastasis to organs, such as the brain, in which surgical removal is not effective. By injecting melanoma cells into the brains of mice, we have shown that the NG2 protein found in host tissues makes the brain a much “friendlier” environment for melanoma growth.

Specifically, NG2 is found on blood vessel cells called pericytes and on immune cells called macrophages. The presence of NG2 on both cell types improves the formation of blood vessels in brain melanomas, contributing to delivery of nutrients and thus to accelerated tumor growth. Genetically knocking out NG2 in either pericytes or macrophages greatly impairs blood vessel development and slows melanoma growth.

Mysterious molecule’s function in skin cancer identified

Ranjan Perera, PhD
Associate Professor, Integrative Metabolism Program

Ranjan’s research uncovered the workings of a mysterious molecule called SPRIGHTLY that has been previously implicated in colorectal cancer, breast cancer and melanoma. These findings bolster the case for exploring SPRIGHTLY as a potential therapeutic target or a biological marker that identifies cancer or predicts disease prognosis.

 Drug discovery to help babies has led to a clinical trial at a children’s hospital

Peter D. Adams, PhD
Professor, Tumor Initiation and Maintenance Program

Approximately 1 in 4 cases of melanoma begins with a mole, or nevus. Genetic mutations can cause cells to grow uncontrollably. By investigating how this occurs, we can understand why melanoma develops from some moles, but not others.

Babies born with a giant nevus that covers a large part of the body have especially high risk of melanoma, and the nevus cells can spread into their spine and brain. Adams’ research identified a drug that deters the cells from growing. The drug identified will be used in a clinical trial at Great Ormond Street Children’s Hospital in London, England that may help babies with this debilitating disease.

Discovery of a receptor mutation correlates with longer patient survival

Elena Pasquale, PhD
Professor, Tumor Initiation and Maintenance Program

Pasquale’s work has included whether mutations in the Eph receptor, tyrosine kinases, play a role in melanoma malignancy. Eph receptor mutations occur in approximately half of metastatic melanomas. We found that some melanoma mutations can drastically affect the signaling ability of Eph receptors, but could not detect any obvious effects of the mutations on melanoma cell malignancy.

Bioinformatic analysis of metastatic melanoma samples showed that Eph receptor mutations correlate with longer overall patient survival. In contrast, high expression of some Eph receptors correlates with decreased overall patient survival, suggesting that Eph receptor signaling can promote malignancy.

Institute News

On the map: doing business in Medical City

AuthorKyle Ziegler
Date

April 13, 2017

Lake Nona aerial view

More than a hundred central Florida business leaders gathered in Lake Nona’s Medical City to learn about the latest life sciences and health innovations during Orlando Business Journal’s “Doing Business in Medical City” event on April 13, 2017. Leaders from anchor institutions Guidewell Innovation Center, Nemours Children’s Hospital, Sanford Burnham Prebys Medical Discovery Institute (SBP) and Tavistock touted numerous examples of collaborations and tech innovations all unique to the area’s health ecosystem.

Panelists highlighted several important collaborative projects taking shape inside of Medical City research labs. “The way we approach basic science and biomedical discovery is through interaction,” said Layton Smith, PhD, director of drug discovery and pharmacology at SBP. “We need to be—and are—interacting with partners like the University of Central Florida, the University of Florida and more. So essentially, what we’ve built here is a node in a network of biomedical research.” One of the recent collaborations he described involves a project with UCF researchers on Zika. Also discussed was an ongoing partnership with the Mayo Clinic and the Michael J. Fox Foundation on personalized medicine approaches for Parkinson’s disease.

Panelists also emphasized the role of people partnerships in broadening community health and wellness initiatives in the area.

Jim Zboril, president of Tavistock Development Co. LLC, described collaboration as a hallmark of Lake Nona and highlighted the built environment as a foundation for residents to live, work, and play. The Lake Nona Life Project, for example, allows “citizen scientists” who live and work in Lake Nona to take part in research studies happening in their backyard. He also provided a glimpse of the latest projects taking place inside of Lake Nona Town Center, which will include a new fitness center and cable water park, as well as new developments in the adjacent Lake Nona Sports and Performance District, which is home to the USTA’s National Campus and Orlando City Soccer’s training facility.

Additionally, new tech innovations are fast-tracking a “wellness without walls” approach to healthcare delivery. Renee Finley, president of GuideWell Innovation, described how new wearable sensor technology displayed in Lake Nona’s intelligent home WHIT (Wellness, Health, Innovation, and Technology), can track activities of daily living, including how many times the refrigerator is opened in a day and movements in the home. ‘Those things can be indicators of other health conditions,” she said.

Meanwhile, Nemours’ telehealth services are making the demand for access to healthcare easier by providing a gateway for the consumer to get in touch with a specialist. “We have an app where you can access any one of our pediatric providers for urgent consultation any time of the day or night—24/7,” said Andre Hebra, MD, chief medical officer of Nemours Children’s Hospital. “And beyond that, we have telehealth services to provide specialty consultations to some of our partnership hospitals.”

Institute News

Nanowire arrays allow electrical recording of neuronal networks

AuthorJessica Moore
Date

April 12, 2017

nanowire array, neuron

To examine a neuron’s health, activity and response to drugs, scientists record its electrical activity. Current methods of recording are destructive, so they can only be used to study a neuron for a brief period, and can only measure the activity of one cell at a time. But neurons don’t function individually—they act in networks, and commonly used systems for detecting the electrical activity of complex groups of neurons aren’t as sensitive as they could be.

A new technology developed through a collaboration between Anne Bang, PhD, director of Cell Biology in the Conrad Prebys Center for Chemical Genomics at the Sanford Burnham Medical Research Institute, and Shadi Dayeh, PhD, associate professor at UC San Diego, makes high-sensitivity recording possible in neuronal networks. Publishing in Nano Letters, the team describes nanowire arrays that could accelerate drug development for neurological and neuropsychiatric diseases.

“We envision that this nanowire technology could be used on stem-cell-derived brain models to identify the most effective drugs for disorders like bipolar disorder and Alzheimer’s,” says Bang.

The nanowire technology developed in Dayeh’s laboratory is nondestructive and can simultaneously measure potential changes in multiple neurons — with the high sensitivity and resolution achieved by the current state of the art.

The device consists of an array of silicon nanowires densely packed on a small chip patterned with nickel electrode leads that are coated with silica. The nanowires poke inside cells without damaging them and are sensitive enough to measure small potential changes that are a fraction of or a few millivolts in magnitude. Neurons interfaced with the nanowire array survived and continued functioning for at least six weeks.

Another innovative feature of this technology is it can isolate the electrical signal measured by each individual nanowire. “This is different from existing nanowire technologies, where several wires are electrically shorted together and you cannot differentiate the signal from every single wire,” Dayeh says.

Dayeh noted that the technology needs further optimization for brain-on-chip drug screening. His team is working to adapt the arrays for heart-on-chip drug screening for cardiac diseases and in vivo brain mapping, which is still several years away. “Our ultimate goal is to translate this technology to a device that can be implanted in the brain.”

This story is based on a press release from UC San Diego.

Institute News

Florida Translational Research Program funding re-fuels drug discovery collaborations with leading research institutions

AuthorDeborah Robison
Date

January 18, 2017

robotic arm at the Prebys Center in Lake Nona

Reinstatement of Florida Translational Research Program (FTRP) funding has provided scientists at Florida universities and medical research institutes with renewed access to the world-class drug discovery technology housed within Sanford Burnham Prebys Medical Discovery Institute at Lake Nona (SBP). The FTRP offers investigators the chance to work with drug discovery experts to translate their research advances into potential new medicines. The facility’s high-tech resources, including high-throughput robotics that screen tens of thousands of chemical compounds per day, combined with expert advice from faculty that have decades of experience in the pharmaceutical industry, make for powerful collaborations that benefit the statewide life science industry.

Funded by the state of Florida and administered by SBP, the program’s most recent call for proposals netted 16 projects—some new and some ongoing—from all Florida universities with biomedical research programs, including the University of Florida, Florida State, Florida International University, University of Central Florida, University of South Florida and University of Miami, as well as the Mayo Clinic and Moffitt Cancer Center.  

All projects focus on major unmet medical needs: aggressive cancers, Alzheimer’s, diabetes, heart disease and drug-resistant infections. While some teams are testing drug libraries to find compounds with desired properties, others are refining active compounds for potency and specificity. The collaborations aim to identify drug candidates with clinical benefits such as reducing tumor size, halting aggressive breast cancer metastasis, reducing inflammation in diseased brains or treating antibiotic-resistant pathogens.

“Our intent is to replicate success stories like that of Pamela McLean, associate professor of neuroscience at the Mayo Clinic,” says Layton Smith, PhD, director of drug discovery at SBP’s Lake Nona campus. “The initial results from her FTRP project led to her receiving the biggest grant ever awarded by the Michael J. Fox Foundation. Similarly, our work with Kirk Conrad, professor of physiology at the University of Florida on a potential heart failure drug has attracted the interest of a major pharmaceutical company.”

“Our approach to collaborative drug discovery has brought more research funding to the state,” adds Smith. “But more important, our work may lead to new therapeutics that reduce the burden of disease around the world.”

Institute News

Consortium awarded $15 million to unravel bipolar disorder and schizophrenia

AuthorSusan Gammon
Date

August 31, 2016

Anne Bang, PhD

Sanford Burnham Prebys Medical Discovery Institute (SBP), the Johns Hopkins University School of Medicine, the Salk Institute for Biological Studies, and the University of Michigan will embark on a $15.4 million effort to develop new systems for quickly screening libraries of drugs for potential effectiveness against schizophrenia and bipolar disorder, the National Institute of Mental Health (NIMH) has announced. The consortium, which includes two industry partners, will be led by Hongjun Song, PhD, of Johns Hopkins and Rusty Gage, PhD, of Salk.

Bipolar disorder affects more than 5 million Americans, and treatments often help only the depressive swings or the opposing manic swings, not both. And though schizophrenia is a devastating disease that affects about 3 million Americans and many more worldwide, scientists still know very little about its underlying causes — which cells in the brain are affected and how — and existing treatments target symptoms only.

With the recent advance of induced pluripotent stem cell (iPSC) technology, researchers are able to use donated cells, such as skin cells, from a patient and convert them into any other cell type, such as neurons. Generating human neurons in a dish that are genetically similar to patients offers researchers a potent tool for studying these diseases and developing much-needed new therapies.

“IPSCs are a powerful platform for studying the underlying mechanisms of disease,” says Gage, a professor of genetics at Salk. “Collaborations that bring together academic and industry partners, such as this one enabled by NIMH, will greatly facilitate the improvement of iPSC approaches for high-throughput diagnostic and drug discovery.”

A major aim of this collaboration is to improve the quality of iPSC technology, which has been limited in the past by a lack of standards in the field and inconsistent practices among different laboratories. “There has been a bottleneck in stem cell research,” says Gage, a professor of genetics at Salk. “Every lab uses different protocols and cells from different patients, so it’s really hard to compare results. This collaboration gathers the resources needed to create robust, reproducible tests that can be used to develop new drugs for mental health disorders.”

The teams will use iPSCs generated from more than 50 patients with schizophrenia or bipolar disorder so that a wide range of genetic differences is taken into account. By coaxing iPSCs to become four different types of brain cells, the teams will be able to see which types are most affected by specific genetic differences and when those effects may occur during development.

First the researchers must figure out, at the cellular level, what features characterize a given illness in a given brain cell type. To do that, they will assess the cells’ shapes, connections, energy use, division and other properties. They will then develop a way of measuring those characteristics that works on a large scale, such as recording the activity of cells under hundreds of different conditions simultaneously.

“SBP’s Conrad Prebys Center for Chemical Genomics will play a key role in this initiative,” says Anne Bang, PhD, a director at the Center. “We will be developing assays and testing prototype drug compounds to see if they induce the desired response in iPSC disease models from the consortium. Our goal is to establish assays suitable for high throughput drug screening, ultimately leading to discovery of drugs for preclinical and clinical studies.”

Once a reliable, scalable and reproducible test system has been developed, the industry partners will have the opportunity to use it to identify or develop drugs that might combat mental illness. “This exciting new research has great potential to expedite drug discovery by using human cells from individuals who suffer from these devastating illnesses. Starting with a deeper understanding of each disorder should enable the biopharmaceutical industry to design drug discovery strategies that are focused on molecular pathology,” says Husseini K. Manji, MD, F.R.C.P.C., global therapeutic area head of neuroscience for Janssen Research & Development.

The researchers also expect to develop a large body of data that will shed light on the molecular and genetic differences between bipolar disorder and schizophrenia. And, since other mental health disorders share some of the genetic variations found in schizophrenia and bipolar disorder, the data will likely inform the study of many illnesses.

The National Cooperative Reprogrammed Cell Research Groups program, which is funding the research, was introduced by the National Institute of Mental Health in 2013 to overcome barriers to collaboration by creating precompetitive agreements that harness the unique strengths of academic and industry research.

Institute News

SBP seeks renewed funding for Florida Translational Research Program to ensure breakthrough discoveries continue

Authorjmoore
Date

February 18, 2016

Header image

The Florida Translational Research Program (FTRP), an early drug discovery initiative funded by the state of Florida, has proven crucial in advancing research and securing out-of-state funding for investigators at SBP and collaborating institutions. During the current legislative session, SBP is seeking renewed funding of the three-year program after a budget hiatus in 2015 put numerous investigations on hold. Continue reading “SBP seeks renewed funding for Florida Translational Research Program to ensure breakthrough discoveries continue”

Institute News

Existing compound holds promise for reducing Huntington’s disease progression

Authorsgammon
Date

December 7, 2015

Header image

Currently, there is no treatment to halt the progression of Huntington’s disease (HD), a fatal genetic disorder that slowly robs sufferers of their physical and mental abilities. In a new collaboration between SBP’s Conrad Prebys Center for Chemical Genomics (Prebys Center) and the University of California, San Diego School of Medicine, researchers have discovered that an existing compound, previously tested in humans for diabetes, offers hope for slowing HD and its symptoms. Continue reading “Existing compound holds promise for reducing Huntington’s disease progression”

Institute News

New collaboration strives to find novel treatment approaches for cardiovascular disease

Authorpbartosch
Date

May 28, 2015

Header image

Sanford-Burnham today announced it has signed a two-year partnership agreement with Takeda Pharmaceutical Company Ltd. of Japan to study the potential role of several gene regulatory proteins as targets for the treatment of heart failure. Based on research conducted in Sanford-Burnham laboratories, the collaborating scientists will screen and develop molecules that have the potential to improve the metabolism and function of the failing heart. Continue reading “New collaboration strives to find novel treatment approaches for cardiovascular disease”