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2014 Director's Messages

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Jan. 14, 2014: RNA Interference for All: Transformative Technology to Speed Translation

The Human Genome Project revolutionized science, not only because it identified all 3 billion letters of the human genome sequence, but also because all data from the project were made freely available to the public — a revolutionary idea at the time. The availability of these data has enabled scientists to develop better ways of understanding, diagnosing, treating and preventing disease, and it led to the development of entirely new areas of science. The Project’s success encouraged the public release of other large data sets, including from the International HapMap Project, an effort to create a map of variations in genome sequences among different people, and ENCODE, a project to catalog of all the functional elements in the human genome sequence.

One of the first steps of scientific translation is called “target validation,” when investigators try to determine whether a particular molecule will be a good “target” on which a drug can act. Choosing a good target out of the thousands of possibilities is difficult, and the lack of available data for comparison makes this step even more challenging. However, on Dec. 11, 2013, NCATS and Life Technologies Corp. announced that, for the first time, large-scale data on the biochemical makeup of small interfering RNA (siRNA) molecules are available to the public. siRNAs are small pieces of ribonucleic acid (RNA) that block the activity of genes through a natural process called RNA interference (RNAi). Discovered only a decade ago, RNAi has rapidly become a key tool for target validation. Because each siRNA molecule can block a different gene, RNAi can tell us about the role of any gene in maintaining health or causing disease.

Until now, a major limitation for RNAi researchers has been the lack of publicly available data on the chemical sequences for siRNAs. Historically, the companies that own these molecules have not published this information. To address this obstacle, NCATS and Life Technologies are providing all researchers with access to siRNA data from Life Technologies’ Silencer Select siRNA library, which includes 65,000 siRNA sequences targeting more than 21,000 human genes. At the same time, NCATS is releasing complementary data about the effects of each siRNA molecule on biological functions. Scientists from the NIH-wide RNAi initiative, part of NCATS’ Division of Pre-Clinical Innovation, use high-tech robots to introduce siRNAs into human cells to block the activity of each gene, one at a time. This process, called a genome-wide siRNA screen, can produce a complete list of all genes involved in a particular biological function or disease process — an invaluable step in target validation. Life Technologies’ siRNA sequence library and data from the RNAi initiative are available to the public free-of-charge through the National Library of Medicine’s public database PubChem.

Consistent with NCATS’ mission, the RNAi initiative is designed to improve the technology and efficiency of genome-wide RNAi for target validation. Before the initiative, screens produced unreliable results for reasons that were poorly understood. During the past two years, the RNAi team has published findings describing the source of unreliability and new approaches to overcome it. These advances, now combined with the public release of siRNA screening data, promise to turbocharge the identification of new targets for drug development.

A great example of how the RNAi initiative is producing new insights about genes involved in disease as well as new targets for therapies was announced in November. RNAi experts at NCATS, collaborating with a team from the National Institute of Neurological Disorders and Stroke, performed a genome-wide siRNA screen that revealed dozens of genes that may represent new targets for treating Parkinson’s disease. The network of genes appears to regulate the disposal of defective mitochondria, the structures that produce energy for cells. The findings, which were published online in Nature, also may be relevant to other neurological diseases caused by damage to mitochondria.

The development of new genome-wide RNAi technologies and the production and public release of genome-wide RNAi data are increasing our understanding of the role of individual genes in basic cell functions and aiding discovery of new therapeutic targets. In the “3Ds” vernacular we use at NCATS, we have developed new technologies for genome-wide RNAi, demonstrated their effectiveness in Parkinson’s disease, and now are publicly disseminating our results to the scientific community. I look forward to sharing more about the RNAi initiative’s successes as NCATS and our collaborators continue to make target validation, and translational research as a whole, more efficient and effective.

Christopher P. Austin, M.D.
Director
National Center for Advancing Translational Sciences


Feb. 4, 2014: Advancing Rare Diseases Research, Honoring a Long-Serving Champion for Patients

As many as 25 million people in the United States are suffering from one of more than 6,500 rare diseases. Although each rare disease affects fewer than 200,000 Americans, in total, these illnesses affect a large part of our population. With NCATS’ emphasis on identifying commonalities among diseases as a route to accelerating the translational process, we are tackling the problems of rare disorders in an integrated way.

Obstacles to rare disease treatments include difficulties in diagnosis, widely dispersed patients and scientific experts, and the high perceived risk of developing such treatments.  NCATS’ rare disease initiatives, including the Office of Rare Diseases Research (ORDR) Therapeutics for Rare and Neglected Diseases (TRND) program, are directly addressing these obstacles and thus making rare disease translational research easier and more efficient for all.

Two events this month have caused me to reflect on the enormous progress made in rare diseases research over the past several decades. First, ORDR Director Stephen C. Groft, Pharm.D., will retire on February 8 from a position he held for the past 25 years, providing visionary leadership in rare diseases research and bringing hope and progress to patients across the globe. On February 28, NIH will celebrate Rare Disease Day, an annual event established to raise public awareness about rare diseases and celebrate advances in the field.

What Is a Rare Disease?
In the United States, a rare disease is generally considered to be a disease that affects fewer than 200,000 people. Rare diseases are sometimes called orphan diseases.

Steve has championed rare diseases research throughout his career, which began in the late 1960s at a small-town Pennsylvania pharmacy. His early work helping patients understand their conditions and medications spurred a lifelong focus and tireless efforts to forge relationships with members of the rare diseases community. When Steve began working at the Food and Drug Administration (FDA), rare disease patients faced an even tougher battle than they do today. Thanks in part to a crucial law Steve supported — the Orphan Drug Act of 1983 — R&D for so-called “orphan products” is now more cost-effective for pharmaceutical companies. The law’s passage marked a renewed focus on rare diseases and a coordinated approach among industry, government, scientists, patients and families, and patient advocacy groups.

Since 1983, the FDA has approved more than 450 orphan products to treat rare diseases. NCATS aims to ensure that number continues to rise as new research advances are made. The expanded role of patient advocacy groups as research partners, the Internet and social media as avenues for communication, publicity about genetic testing and gene therapies, and the global marketplace have cleared new pathways for scientific progress.

Steve and his colleagues have greatly fostered this atmosphere and laid the groundwork enabling many new discoveries. Now, instead of focusing on one rare disease at a time, we take a comprehensive approach to studying these diseases and their common characteristics. 

On February 28, Rare Disease Day at NIH will shed light on the latest research through feature talks, NIH Clinical Center tours, posters and exhibits from NCATS and other NIH Institutes and Centers; the FDA Office of Orphan Product Development, which Steve established in 1982; other federal agencies; and advocacy organizations. Support for Rare Disease Day is just one of the many ways that NCATS will remain committed to honoring and strengthening Steve’s legacy in this critical area of research, speeding advances that ultimately lead to improved health for patients counting on us to succeed.

Christopher P. Austin, M.D.
Director
National Center for Advancing Translational Sciences


March 14, 2014: NCATS Technology Is Transforming the Search for Combination Drug Treatments

For many diseases, there is no single “magic bullet” therapy. Instead, combining two or more drugs is the standard of care for diseases such as cancer, tuberculosis and HIV/AIDS. Combinations of drugs can work better than a single therapy, providing patients with a more effective treatment while also making it more difficult for diseased cells and microbes to develop resistance. In 2013, the U.S. Food and Drug Administration released guidance for the co-development of investigational drugs used in combination, further encouraging advancement of this promising therapeutic strategy.

Still, a major problem remains: How can researchers best determine which drug combinations show enough promise to move forward into clinical trials? Almost all of the multidrug therapeutics used currently in the clinic resulted from years of trial and error. For example, a combination of drugs known as R-CHOP is the standard of care for several types of lymphoma, a cancer of the white blood cells. It took decades for clinicians to assemble this five-drug treatment, yet despite these efforts, it is an ineffective therapy for many people battling lymphoma. Unfortunately, this example is not an isolated one. As patients await new advances in treatment, and with limited research dollars, we have insufficient time and resources to continue developing combination therapies using the traditional iterative process.

Thanks to the work of NCATS biologists, chemists, engineers, informaticians and other experts, we now have an efficient way forward: a high-throughput technology platform for screening novel two-drug combinations in diseased cells. Because this system can quickly narrow down a long list of potential drug combinations to identify those with the most potential to help patients, it could shave years off the process of developing effective multidrug treatments.

To showcase this advance in light of the Center’s “3Ds”:

  • A multidisciplinary NCATS team first developed the screening system to address the obstacle of finding potential drug combinations quickly and efficiently.
  • To test the system, the team engaged partners throughout NIH, including clinical experts working on cancers and infectious diseases. The team, in collaboration with researchers from the National Cancer Institute, first publically demonstrated the power of the platform using a common, aggressive form of lymphoma.
  • When the study was complete, team members disseminated the data and the NCATS-designed software to the larger research community.

This is just one example of how NCATS works to overcome roadblocks that hinder the translation of a basic science discovery into a new health intervention. Along with other efforts, such as our RNAi screening and data-sharing initiatives that I highlighted in January, NCATS’ work is generating great interest in the broader translational research community. I’m thrilled to be able to share these examples of game-changing new approaches and technologies from NCATS scientists and collaborators.

Christopher P. Austin, M.D.
Director
National Center for Advancing Translational Sciences


April 17, 2014: 3-D Disease Models May Better Predict Therapeutic Success

In order for a new drug to be approved by the FDA for use in patients, it must be shown to be effective in clinical trials. Currently, more than 80 percent of new drugs tested in clinical trials fail, preventing therapies from reaching the medicine cabinet and causing enormous loss of time and expense. To address this translational roadblock, NCATS is developing new technologies to better predict which drugs will be safe and effective in clinical trials.

Once a molecule or compound has been shown to have an effect that is relevant to a disease, researchers try to predict if it will work in people by testing it in isolated cells and animal models that mimic some of the characteristics of the human disease. Unfortunately, current cell and animal models often are poor predictors of how people will react to a drug. This probably is because in the body, cells are never isolated, and animals frequently respond differently to drugs than people do.

Remarkable advances in tissue engineering, stem cells and biosensor technologies now make it possible to combine the best of cellular and animal models to create better testing systems for new drugs. These models use human cells, usually taken from patients with the disease under study, that are placed in 3-D clumps made of multiple cell types in a cellular environment that more closely resembles the complex and interactive systems in the human body.

NCATS is fostering the development of these technologies via collaborations with academia, industry and small businesses. For example, the Tissue Chip for Drug Screening initiative is an interagency collaboration among NIH, the Defense Advanced Research Projects Agency and the Food and Drug Administration to develop 3-D human tissue chips that model the structure and function of human organs, such as the lung, liver and heart. Once they are developed, researchers can use these models to predict whether a candidate drug, vaccine or biologic agent is safe and effective in humans.

Earlier this year, NCATS partnered with the bioprinting company Organovo and the National Eye Institute (NEI) to develop a more clinically predictive tissue model for eye diseases. NCATS now houses Organovo’s NovoGene MMX Bioprinter, where researchers from NCATS and NEI are creating 3-D, architecturally accurate eye tissue to test the safety and effectiveness of candidate drugs. NCATS researchers are also working with Organovo to develop 3-D skin and other tissue models.

Another new NCATS partnership — with biotechnology company InSphero — is allowing NCATS scientists to develop and test the effects of potential anti-cancer drugs in 3-D, pancreatic and ovarian tumor models. Both the InSphero and Organovo platforms will enable researchers to test more candidate drugs in much less time than would be possible in animal models, producing results that promise to be more predictive of therapeutic success in human patients.

Our focus on 3-D disease models exemplifies the NCATS approach: developing, demonstrating and disseminating transformational technologies to overcome critical translational roadblocks via team-science based collaboration, ultimately catalyzing the delivery of more therapies to more people more quickly.

Christopher P. Austin, M.D.
Director
National Center for Advancing Translational Sciences


May 19, 2014: NCATS Advisory Council Provides Expertise and Guidance in Translational Science

NCATS’ work to develop, demonstrate and disseminate innovative tools and research approaches already is enabling great strides in advancing translational science. Our achievements to date would not have been possible without the diligent work of the diverse group of individuals serving on the NCATS Advisory Council. Comprised of experts from academia, industry, patient advocacy groups and government, our Council provides second-level reviews of scientific grant applications as well as invaluable guidance, consultation and recommendations on Center initiatives, policies and programs.

Members of the NCATS Advisory Council also serve on our Cures Acceleration Network (CAN) Review Board. CAN was established to find ways to reduce significant barriers to successful translation, accelerate the development of high-need cures and provide flexibility in funding some projects. Board members provide advice and recommendations for carrying out the CAN mission.

Both the NCATS Advisory Council and CAN Review Board last met on Friday, May 16, 2014. At the meeting, members heard from the Advisory Council Working Group on the IOM Report: The CTSA Program at NIH, a group tasked with responding to the June 2013 Institute of Medicine (IOM) report on the Clinical and Translational Science Awards (CTSA) program. I am grateful for the hard work and thoughtful consideration that went into developing the Working Group’s report (PDF - 414KB), with findings that clearly indicate the members’ investment in the best interests of NCATS, the CTSA program and translational science in general.

At the meeting, I joined Advisory Council and CAN Review Board members in welcoming the latest addition to the NCATS leadership team, Petra Kaufmann, M.D., M.Sc., who became director of the NCATS Division of Clinical Innovation earlier this month. Her new role includes overseeing the CTSA program, and I look forward to working with her to review and evaluate the Working Group findings and develop the next steps for this important program.

Another key milestone highlighted at the meeting was the release of four new funding opportunities for NCATS’ Discovering New Therapeutic Uses for Existing Molecules program. For these, NCATS collaborated with AstraZeneca, Janssen Research & Development, L.L.C., Pfizer Inc. and Sanofi to make 26 therapeutic candidates — referred to as “assets” — available to researchers to crowdsource ideas for new uses. For the first time, included are assets that are suitable for exploring pediatric indications. By working together with our industry partners to address the common problem of failure in therapeutic development, we are advancing our goal of speeding treatments to patients in need.

Translation is a team sport, from the research level to the leadership level, and this teamwork and collaboration among external experts, the broader scientific and patient communities and NCATS leadership drives the translational science successes that ultimately will benefit patients and improve human health.

Christopher P. Austin, M.D.
Director
National Center for Advancing Translational Sciences


June 26, 2014: From Chemical Probes to Potential Therapeutics: This LOX Is No Fish Story

For basic research scientists, defining the role of a particular protein in health and disease — an early translational hurdle called “target qualification” — often is easier said than done. A chemical “probe” that can increase or decrease the activity of the target protein can be invaluable for target qualification. The problem is that creating these probes requires expertise in high-throughput (large-scale) screening and chemistry that most disease biologists lack. In these situations, collaboration across scientific disciplines is essential to moving research forward.

To meet this critical need, the NIH Chemical Genomics Center (NCGC), which is now part of NCATS, was established in 2004. NCGC was the first center in a network of small molecule screening and medicinal chemistry optimization sites that produced small molecule chemical probes as part of the NIH Common Fund’s Molecular Libraries Program.

Over the past decade, NCGC scientists have partnered with academic, nonprofit and biotech researchers on more than 300 probe development projects in virtually every area of biology and disease. NCGC is organized much like a biotechnology firm, including a collaborative project team structure and leading-edge tools and technologies. But NCGC scientists focus on the large universe of unexplored targets, thus leading to new approaches and complementing the work of private-sector partners.

NCGC staff work collaboratively with disease experts to develop research plans and produce biological assays (or tests), which are screened against hundreds of thousands of compounds using our state-of-the-art, high-throughput screening robots. In this way, investigators with a promising idea about important new biology or a novel way to reverse a disease state can access the scientific expertise, tools and resources required to test that idea. Innovative translational solutions like this one help speed the development of new treatments for patients and are at the core of NCATS’ mission.

Here’s a recent example of how our problem-solving potential can become a reality and exemplify the “NCATS 3Ds”: Three molecular probes developed in collaboration with our experts spurred work by multiple academic scientists that led to insights about the biology of several diseases. The probes act as inhibitors of various lipoxygenase (LOX) enzymes, which help the body break down fatty acids. The team, comprised of NCATS researchers and their collaborators, then demonstrated that these three small molecule LOX inhibitors have the potential to treat diabetes, stroke and thrombosis (a clot-forming condition). The scientists now have disseminated their findings through multiple publications and invited conference presentations, which has fueled renewed interest by the broader research community in the role LOX enzymes may play in numerous diseases.

This work already has improved our understanding of how this enzyme family functions in health and disease and could potentially lead to the development of new therapies for a variety of conditions. These are exactly the kinds of outcomes we strive for at NCATS in our quest to improve the process of transforming basic science knowledge into treatments for disease and improved human health.

Christopher P. Austin, M.D.
Director
National Center for Advancing Translational Sciences


July 9, 2014: NCATS Collaboration Translates into Potential Treatment for Sickle Cell Disease

I often cite the essential components of translational science — collaboration, public-private partnerships, innovative research models — as common denominators of all NCATS initiatives. One of the most exciting parts of our work is when research teams demonstrate that these elements can produce breakthroughs in translation.

Our latest accomplishment is truly a historic one, producing two “firsts”: For the first time, efforts of researchers from NCATS’ Therapeutics for Rare and Neglected Diseases (TRND) program have culminated in the acquisition of a drug candidate by a biopharmaceutical company, Baxter International, to complete clinical development. And also for the first time, a drug targeting the underlying cause of sickle cell disease — the first genetic condition ever defined at the molecular level — has advanced into late-stage clinical development.

The project began in 2010, when TRND researchers signed a collaborative agreement with a small biotechnology company, AesRx, LLC — which Baxter recently acquired — to develop Aes-103 as a potential treatment for sickle cell disease. The project team included researchers from our TRND program; AesRx; and the National Heart, Lung, and Blood Institute. Prior to the collaboration, AesRx had been unable to secure private financing, essentially stalling the project. Without TRND, it is unlikely Aes-103 would have made it to patients in clinical trials.

TRND researchers are experts in pre-clinical drug development, and they focus solely on innovative approaches to advancing potential treatments for rare and neglected diseases to first-in-human trials, an approach known as “de-risking.” The aim is to scientifically and medically validate new drug candidates like Aes-103, which makes them more attractive to external partners who then invest in completing development, manufacturing and marketing.

The AesRx/NIH team worked together to develop Aes-103 through a successful Phase II clinical trial to evaluate safety and effectiveness. Baxter then acquired AesRx, including its Aes-103 development program, and the company will now perform the clinical development activities required for regulatory approval and commercialization.

People with sickle cell disease have defective hemoglobin (the protein in red blood cells that carries oxygen), causing cells to become rigid and crescent-shaped and leading to clots and blocked blood vessels. Despite knowing the genetic basis of sickle cell disease and having a molecular target for 65 years, no approved drugs directly target the defect. Aes-103, which binds directly to the defective hemoglobin, is the first compound specifically developed to address the underlying molecular mechanism of the disease.

This project could not be more important to NCATS, and more broadly to NIH, for a multitude of reasons, including that it:

  • Is the first TRND project to reach the ultimate goal of de-risking a drug candidate to the point of attracting commercial interest, an outcome that validates the program’s model.
  • Involved a close collaboration between NIH and industry, demonstrating that public-private partnerships like this one can move mountains.
  • Provides a potential therapeutic for a rare and neglected disease of paramount importance to U.S. public health and elimination of health disparities. (Sickle cell disease disproportionately affects African-Americans.)
  • Offers a compound that targets the molecular defect of the disease, alleviating the common failure to translate basic knowledge of a disease’s molecular mechanism into a treatment that specifically targets that mechanism.

This success vividly illustrates the compelling need and enormous promise of the NCATS approach we have developed. Now that we’ve demonstrated it works, we look forward to continuing to applying our model to the thousands of rare and neglected diseases that are currently untreatable and disseminating that approach to the research community.

Christopher P. Austin, M.D.
Director
National Center for Advancing Translational Sciences


Sept. 12, 2014: New Opportunity for Evolving Clinical and Translational Science

Understanding the characteristics and course of diseases in people, investigating the effectiveness and safety of new treatments, and devising ways to get treatments to all the people who need them are just some of the issues addressed in the clinical phase of the translational process. Like the pre-clinical phase I discussed in previous Director’s Messages in April and June, clinical translation is inefficient and poorly understood, leading to many lost opportunities for health improvement.

Through the Clinical and Translational Science Awards (CTSA) program, NCATS is tackling the system-wide issues that limit efficiency in clinical translation. The CTSA program supports a national network of more than 60 medical research institutions (called “hubs”) that work together to transform the translational science process to bring more treatments to more patients more quickly. With the dramatic increase in fundamental scientific understanding in the past decade have come unmatched opportunities for clinical translation of discoveries into improved health. To realize this promise, we must transform clinical translational technologies, operations and efficiency.

Over the past two years, NCATS has consulted widely about how to evolve the CTSA program to drive this transformation. We have been fortunate to receive diverse and insightful input from the Institute of Medicine, a working group of the NCATS Advisory Council, CTSA investigators, patient groups, and the broader clinical and translational research community. I am extremely grateful to the hundreds of individuals and groups who have provided thoughtful suggestions about the accomplishments of the CTSA program to date and strategies to build on this foundation to meet the needs and opportunities now before us.

I am thrilled about the exciting new vision for the CTSA program that resulted, and today we take the first step toward its implementation. NCATS has released a new funding opportunity for the CTSA program, which emphasizes:

  • Greater alignment between the CTSA program and the NCATS mission of understanding and improving the translational process;
  • Continued strength of individual hubs while creating a whole that is greater than the sum of the parts: a collaborative national network that will lead the transformation of clinical and translational science across the country;
  • New initiatives to train a new generation of scientists with the special skills and knowledge required for clinical translation, including team science; and
  • Accountability with evaluation using defined criteria for measurement, deliverables and metrics.

The CTSA program is a unique national resource that has evolved continually since its inception to leverage and lead new developments in science and medicine. Now the program is evolving again to meet the enormous new opportunities — and enormous needs — in translational science and create a dramatically accelerated and more efficient translational engine.

As a catalyst, integrator and collaborator, NCATS continues to listen and respond to the needs of the translational community, which includes researchers, clinicians, regulators, patient and community groups, and industry. As a data-driven organization, NCATS will continue to evolve this and all its programs in response to results and your continued input. Together, we will make the NCATS vision a reality for the benefit of science, medicine and patients.

Christopher P. Austin, M.D.
Director
National Center for Advancing Translational Sciences


Oct. 8, 2014: Integration Expands Opportunities to Understand and Treat Rare Diseases

I often talk about how NCATS’ mission and programs are different from other organizations in the research ecosystem. One of these differences is that NCATS is “disease-agnostic”: rather than focusing on a single type of condition or biological system, we look for what is common among diseases and the translational process. This approach acknowledges that seemingly different conditions can share underlying molecular causes, and it has the potential to greatly accelerate the development of health-improving interventions, including those that treat more than one disease.

This systematic approach is especially important for investigating rare diseases, which number in the thousands; only a few hundred have treatments approved by the Food and Drug Administration. Although rare diseases by definition affect relatively small numbers of people (defined as fewer than 200,000 people in the U.S.), together these diseases affect an estimated 25 million Americans and are the source of enormous suffering, premature death and lost economic activity. Mutations in single genes cause most rare diseases, but these mutations typically affect many different organ systems simultaneously. The large number of currently untreatable rare diseases and their effects on multiple organs make the typical one-disease-at-a-time, one-organ-at-a-time translational model untenable.

Enter the Rare Diseases Clinical Research Network (RDCRN), an NCATS-led initiative with an aim to address many of the unique challenges in developing rare disease therapies, including difficulties in diagnosis, widely dispersed patients and scientific experts, and a perceived high risk and cost for developing such treatments. Established in 2003, the RDCRN supports consortia of medical research centers that work together to investigate groups of related rare diseases, including performing long-term natural history studies and clinical trials of new medications. The RDCRN develops robust data on more than 200 rare conditions, enabling scientists to better understand and learn from the common features among diseases.

I am pleased to announce that on Oct. 8, 2014, NIH announced nearly $29 million in awards to expand the RDCRN to support 22 consortia and a Data Management and Coordinating Center (DMCC). The network is a distinctive clinical research entity that exemplifies fundamentals of the NCATS mission:

  • Collaboration: Multidisciplinary scientists from 240 institutions work together to conduct multisite studies, of which 91 are currently active and enrolling patients.
  • Patient and community engagement: Nearly 100 patient advocacy groups have partnered with consortia to assist in patient recruitment, study design, information dissemination and young scientist training.
  • Training: Young scientists receive mentoring and guidance in conducting research on rare diseases.
  • Central data collection and storage: A DMCC provides the resources to pool data from RDCRN studies in a single location so that researchers can access information more easily and find links among diseases.

A recent success from the RDCRN-supported Urea Cycle Disorders Consortium illustrates the kind of outcomes these consortia can produce. Urea cycle disorders (UCDs) are caused by genetic defects that render the body unable to remove ammonia from the blood. Ammonia is toxic and can damage organs, including the brain. Scientists have discovered a number of UCDs, all caused by defects in different genes but related by the biochemical pathway they affect and the symptoms they cause. By tackling UCDs as a group rather than individually, the UCD Consortium team catalyzed the development and approval of three drugs to treat UCDs, giving patients treatments for these life-threatening conditions.

You can follow the RDCRN’s successes on the NCATS website, where you also can learn more about the critical role of patients in each of the consortia. The RDCRN showcases an integrated approach to disease translation that also promises to provide insights into optimal translational methods as well as causes and treatments of rare and common diseases. In my “3 D’s” parlance, the RDCRN developed innovative approaches and demonstrated their success in individual rare diseases, and now NCATS is actively disseminating those approaches to the research community to advance our goal of delivering more treatments to more patients more quickly.

Christopher P. Austin, M.D.
Director
National Center for Advancing Translational Sciences


Nov. 25, 2014: Partnerships with Patient Groups Accelerate Therapeutic Development

Developing interventions for better human health differs from developing other consumer goods in a fundamental way: Interventions to improve health generally are developed without direct input from the people they are meant to benefit. I believe this odd fact of history is responsible for much of the inefficiency and ineffectiveness of translational science. Imagine for a moment that developers of a new snack food locked themselves away in a lab where the criteria for success were novelty and appeal to fellow developers, but they did not consult any consumers. The result could be an innovative snack food that would delight the developers but taste terrible; no one would buy it. This kind of scenario happens often in intervention development.

Patients — or more broadly, people, because most of us are or eventually will be patients — bring data, insights, connections, priorities and urgency to translational research projects. These cannot all come from professionally trained scientists. (I say “professionally trained” because many patients and families become experts in the diseases affecting them.) To make the most of the enormous value patients can offer, I have challenged NCATS scientists to involve patients from the beginning in every project we do, as full members of the team. The NCATS-supported Rare Diseases Clinical Research Network is a leader in this approach; stay tuned for more in a future message. This month, I want to tell you of remarkable success in the pre-clinical arena at NCATS enabled by a partnership with patients.

Charcot-Marie-Tooth disease (CMT) is the most commonly inherited disorder of the peripheral nervous system, affecting more than 2.6 million people worldwide. This incurable disease slowly damages the nerve cells leading to the arms, hands, legs and feet and results in pain as well as loss of muscle and sensation. A common form of CMT is caused by abnormally high production of a gene called PMP22; blocking this gene’s over-expression could potentially lead to new treatments. But researchers had never identified a small molecule drug with this sort of activity.

Several years ago, patients in the CMT Association (CMTA) proposed to NCATS a partnership to develop testing systems that would help identify chemical compounds to transform into potential drugs to treat CMT. As part of the partnership, NCATS developed a new assay technique to screen for compounds that lower PMP22 expression. Because translation is a team sport, NCATS scientists accomplished this rapid work by collaborating with researchers at the National Human Genome Research Institute, the University of Wisconsin and Sangamo BioSciences. To create the assay, the scientists used a new technique called genome editing to insert biological tools known as reporter genes into the DNA sequence of PMP22 in cells grown in culture. This technique is more specific than past methods, which inserted reporter genes at random locations into the cell’s DNA. The increased specificity led to discovery of an expanded number of potential treatment targets.

CMTA is only one patient-driven group that has worked closely with NCATS; Center experts have formed collaborative relationships with many other rare disease foundations, including those for Niemann-Pick type C, myotonic dystrophy and chordoma. Hannah’s Hope Fund and Alpha-1 Foundation currently support postdoctoral researchers at NCATS seeking potential treatments for giant axonal neuropathy and alpha-1 antitrypsin deficiency, respectively. And the Michael J. Fox Foundation for Parkinson’s Research is supporting screening with NCATS’ chemical libraries to identify potential treatment compounds.

These collaborative relationships are truly synergistic: The patient groups bring funding, expertise in disease biology and advice on meaningful intervention approaches, and NCATS brings expertise in therapeutic development. The result is a more patient-relevant and efficient route to new treatments — true translational innovation.

Christopher P. Austin, M.D.
Director
National Center for Advancing Translational Sciences


Dec. 18, 2014: NCATS Collaborating with Pfizer’s Centers for Therapeutic Innovation Network

In recent decades, scientists have made rapid progress both in understanding countless diseases and in generating technologies that offer unprecedented potential to advance the translation of basic science discoveries into new medical treatments. However, most diseases have little or no treatment approved by the Food and Drug Administration (FDA), and the process of developing new therapeutics is fraught with uncertainty and failure. For every 10,000 promising compounds that enter the development pipeline, only a few currently make it into the nation’s medicine chest.

NCATS works to make translation more efficient and effective through new collaborative structures, innovation in technology and methods, and a relentless focus on deliverables that are useful to patients. Today, I’m pleased to announce NCATS’ latest success, which embodies all of these approaches: The National Institutes of Health (NIH) is joining the Centers for Therapeutic Innovation (CTI) network of Pfizer, Inc.

Created in 2010, the Pfizer CTI is an entrepreneurial research unit that pairs leading researchers with Pfizer resources to pursue scientific and medical advances through joint therapeutic development. In addition to NIH, the network includes 25 academic institutions and four patient foundations. The goal of this new collaboration is to identify biologic compounds with activity in a pathway or target of interest to an NIH intramural researcher and to Pfizer, then attempt to move these compounds into the clinic rapidly to test them.

The CTI structure is designed to bridge the gap between early scientific discovery and clinical application through public-private resource sharing. The partnership will combine NIH intramural scientists’ knowledge of disease mechanisms with Pfizer’s expertise in drug development.

NIH intramural researchers selected for CTI projects will have identified disease-related pathways or mechanisms as potential therapeutic targets and will have access to Pfizer’s drug development resources. These include Pfizer’s proprietary pre-clinical drug discovery tools and technologies, pre-clinical study and regulatory expertise, and support for investigational new drug applications to the FDA to move potential treatments into human clinical trials. A joint NIH-Pfizer steering committee will govern the partnership and be responsible for selecting and making decisions about the progress of each research program.

This new NIH-Pfizer collaboration will enable NIH scientists to move novel disease targets into therapeutic development using industry-standard translational tools and expertise. Most importantly, this agreement provides more hope for patients, who will benefit from two of the world’s largest research organizations working together to develop more treatments faster. And that is what NCATS is all about.

Christopher P. Austin, M.D.
Director
National Center for Advancing Translational Sciences

Last updated: 08-22-2017
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