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NCATS

A Rare Public Health Challenge

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child's drawing of houses labeled Scleroderma, Sjogren's, CRMO, Vasculitis, Autoimmune Encephalitis, Cystic Fibrosis
Caption: More than 10,000 rare diseases affect nearly 400 million people across the globe. Credit: Christina Loccke, Lindsey Bergstrom and Sarah Theos

Most public health challenges may seem obvious. The COVID-19 pandemic, for example, swept the globe and in some way touched the lives of everyone. But not all public health challenges are as readily apparent.

Rare diseases are a case in point. While individually each disease is rare, collectively rare diseases are common: More than 10,000 rare diseases affect nearly 400 million people worldwide. In the United States, the prevalence of rare diseases (over 30 million people) rivals or exceeds that of common diseases such as diabetes (37.3 million people), Alzheimer’s disease (6.5 million people), and heart failure (6.2 million people).

Shouldering the Burden of Rare Diseases

As with common diseases, the personal and economic burdens of rare diseases are immense. People who live with rare diseases often struggle for years before they receive an accurate diagnosis, with some remaining undiagnosed for a decade or longer. The diagnostic odyssey includes countless doctor visits, unnecessary tests and procedures, and wrong diagnoses. For people in rural and low-income communities, lack of access to care is an additional barrier to an accurate diagnosis. And a diagnosis often doesn’t lead to better health—only about 5 percent of rare diseases have U.S. Food and Drug Administration–approved treatments.

Collectively, the personal burdens of those with rare diseases impose a significant economic cost on the nation. When quantifying the health care expenses for people with rare diseases, we found that they have three to five times greater costs than those without rare diseases [1]. In the United States, the total direct medical costs for those with rare diseases is approximately $400 billion annually, a figure validated independently by the EveryLife Foundation for Rare Diseases. The EveryLife study also included indirect and non-medical costs, resulting in a higher total economic burden of nearly $1 trillion annually [2].

What’s even starker is that the true scope and impact of rare diseases actually may be greater because rare diseases aren’t easily visible in our health care system. Many of the diseases are too rare to have a code that identifies them in the electronic health record (EHR).

Speeding Up the Search for Solutions

Each and every day, NIH’s National Center for Advancing Translational Sciences (NCATS) works with patients, advocates, clinicians, and researchers to meet the public health challenge of rare diseases. Driving those conversations are three overarching goals to help people living with rare diseases get the high-quality care they need, faster:

1. Shorten the duration of the diagnostic odyssey by more than half. The diagnostic odyssey for someone with a rare disease takes on average seven years, and there are several ways we can speed the journey. For example, we are designing computational tools to detect rare genetic disorders from EHR data. This work is part of a broader research effort focused on using genetic analysis and machine learning to make it easier for health care providers to diagnose people with rare diseases correctly. Also, connecting patients more quickly with each other and the research community can hasten the search for answers. Check out the resources below to learn about rare diseases, find patient support organizations, and get involved in research efforts.

2. Develop treatments for more than one rare disease at a time. A key strategy is leveraging what rare diseases have in common. Some of our efforts build upon the fact that 80–85 percent of rare diseases are genetic. We can use this knowledge to develop genetic and molecular interventions for groups of rare diseases. Two programs—the Platform Vector Gene Therapy pilot project and the Bespoke Gene Therapy Consortium, which is part of the public-private Accelerating Medicines Partnership®—are streamlining the gene therapy development process. Their ultimate goal is to make gene therapies more accessible to many people with rare diseases. We also have joined in to advance the clinical application of genome editing for rare genetic diseases.

The NCATS-led Rare Diseases Clinical Research Network, which is supported across NIH, brings scientists together with rare disease organizations and patient advocacy groups to better understand common characteristics, which also might speed clinical research. With this in mind, we are adapting a clinical trial strategy used in cancer research to test a single therapy on multiple rare diseases.

3. Make it easier and more efficient for scientists to discover and develop treatments for rare diseases. NCATS develops ways for new treatments to reach people more quickly. Repurposing drugs, for example, is revealing already-approved drugs that may work for rare diseases. Programs such as Therapeutics for Rare and Neglected Diseases and Bridging Interventional Development Gaps move basic research discoveries in the lab closer to becoming new drugs. Ambitious initiatives, such as the Biomedical Data Translator, unite data from biomedical research, clinical trials, and EHRs to find treatments for rare diseases faster.

The COVID-19 pandemic showed us the power of working together to solve public health challenges. Let’s now come together to address the public health challenge of rare diseases. If you want to get involved, please join us at Rare Disease Day at NIH 2023 on February 28. You’ll hear personal stories, learn about the latest research, and discover helpful resources. I hope to see you there!

References:

[1] The IDeaS initiative: pilot study to assess the impact of rare diseases on patients and healthcare systems. Tisdale A, Cutillo CM, Nathan R, Russo P, Laraway B, Haendel M, Nowak D, Hasche C, Chan CH, Griese E, Dawkins H, Shukla O, Pearce DA, Rutter JL, Pariser AR. Orphanet Journal of Rare Diseases. 2021 Oct 22; ;16(1):429.

[2] The national economic burden of rare disease in the United States in 2019. Yang G, Cintina I, Pariser A, Oehrlein E, Sullivan J, Kennedy A. Orphanet Journal of Rare Diseases. 2022 Apr 12;17(1):163.

Links:

Rare Disease Day at NIH 2023 (National Center for Advancing Translational Sciences/NIH)

Genetic and Rare Diseases Information Center (NCATS)

Toolkit for Patient-Focused Therapy Development (NCATS)

Rare Diseases Registry Program (NCATS)

Rare Diseases Research and Resources (NCATS)

Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 23rd in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.


Chipping Away at the Causes of Polycystic Kidney Disease

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Organoid on a chip. Glucose fills a space behind the lumen of the tubule.
Caption: Image depicts formation of cyst (surrounded by white arrows) within kidney organoid on a chip. As cyst absorbs glucose passing through the tubule, it grows larger.

It’s often said that two is better than one. That’s true whether driving across the country, renovating a kitchen, or looking for a misplaced set of car keys. But a recent study shows this old saying also applies for modeling a kidney disease with two very complementary, cutting-edge technologies: an organoid, a living miniaturized organ grown in a laboratory dish; and an “organ-on-a-chip,” silicon chips specially engineered to mimic the 3D tissue structure and basic biology of a human body organ.

Using this one-two approach at the lab bench, the researchers modeled in just a few weeks different aspects of the fluid-filled cysts that form in polycystic kidney disease (PKD), a common cause of kidney failure. This is impossible to do in real-time in humans for a variety of technical reasons.

These powerful technologies revealed that blood glucose plays a role in causing the cysts. They also showed the cysts form via a different biological mechanism than previously thought. These new leads, if confirmed, offer a whole new way of thinking about PKD cysts, and more exciting, how to prevent or slow the disease in millions of people worldwide.

These latest findings, published in the journal Nature Communications, come from Benjamin Freedman and colleagues at the University of Washington School of Medicine, Seattle [1]. While much is known about the genetic causes of PKD, Freedman and team realized there’s much still much to learn about the basics of how cysts form in the kidney’s tiny tubes, or tubules, that help to filter toxins out of the bloodstream.

Each human kidney has millions of tubules, and in people with PKD, some of them expand gradually and abnormally to form sacs of fluid that researchers liken to water balloons. These sacs, or cysts, crowd out healthy tissue, leading over time to reduced kidney function and, in some instances, complete kidney failure.

To understand cyst formation better, Freedman’s team and others have invented methods to grow human kidney organoids, complete with a system of internal tubules. Impressively, organoids made from cells carrying mutations known to cause PKD develop cysts, just as people with these same mutations do. When suspended in fluid, the organoids also develop telltale signs of PKD even more dramatically, showing they are sensitive to changes in their environments.

At any given moment, about a quarter of all the fluids in the body pass through the kidneys, and this constant flow was missing from the organoid. That’s when Freedman and colleagues turned to their other modeling tool: a kidney-on-a-chip.

These more complex 3D models, containing living kidney cells, aim to mimic more fully the kidney and its environment. They also contain a network of microfluidic channels to replicate the natural flow of fluids in a living kidney. Combining PKD organoids with kidney-on-a-chip technology provided the best of both worlds.

Their studies found that exposing PKD organoid-on-a-chip models to a solution including water, glucose, amino acids, and other nutrients caused cysts to expand more quickly than they otherwise would. However, the cysts don’t develop from fluids that the kidneys outwardly secrete, as long thought. The new findings reveal just the opposite. The PKD cysts arise and grow as the kidney tissue works to retain most of the fluids that constantly pass through them.

They also found out why: the cysts were absorbing glucose and taking in water from the fluid passing over them, causing the cysts to expand. Although scientists had known that kidneys absorb glucose, they’d never connected this process to the formation of cysts in PKD.

In further studies, the scientists gave fluorescently labeled glucose to mice with PKD and could see that kidney cysts in the animals also took up glucose. The researchers think that the tubules are taking in fluid in the mice just as they do in the organoids.

Understanding the mechanisms of PKD can point to new ways to treat it. Indeed, the research team showed adding compounds that block the transport of glucose also prevented cyst growth. Freedman notes that glucose transport inhibitors (flozins), a class of oral drugs now used to treat diabetes, are in development for other types of kidney disease. He said the new findings suggest glucose transport inhibitors might have benefits for treating PKD, too.

There’s much more work to do. But the hope is that these new insights into PKD biology will lead to promising ways to prevent or treat this genetic condition that now threatens the lives of far too many loved ones in so many families.

This two-is-better-than-one approach is just an example of the ways in which NIH-supported efforts in tissue chips are evolving to better model human disease. That includes NIH’s National Center for Advancing Translational Science’s Tissue Chip for Drug Screening program, which is enabling promising new approaches to study human diseases affecting organ systems throughout the body.

Reference:

[1] Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease. Li SR, Gulieva RE, Helms L, Cruz NM, Vincent T, Fu H, Himmelfarb J, Freedman BS. Nat Commun. 2022 Dec 23;13(1):7918.

Links:

Polycystic Kidney Disease (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Your Kidneys & How They Work (NIDDK)

Freedman Lab (University of Washington, Seattle)

Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)

NIH Support: National Center for Advancing Translational Sciences; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute


Exploring Drug Repurposing for COVID-19 Treatment

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Drug screening-High throughput robot
Caption: Robotic technology screening existing drugs for new purposes. Credit: Scripps Research

It usually takes more than a decade to develop a safe, effective anti-viral therapy. But, when it comes to coronavirus disease 2019 (COVID-19), we don’t have that kind of time. One way to speed the process may be to put some old drugs to work against this new disease threat. This is generally referred to as “drug repurposing.”

NIH has been doing everything possible to encourage screens of existing drugs that have been shown safe for human use. In a recent NIH-funded study in the journal Nature, researchers screened a chemical “library” that contained nearly 12,000 existing drug compounds for their potential activity against SARS-CoV-2, the novel coronavirus that causes COVID-19 [1]. The results? In tests in both non-human primate and human cell lines grown in laboratory conditions, 21 of these existing drugs showed potential for repurposing to thwart the novel coronavirus—13 of them at doses that likely could be safely given to people. The majority of these drugs have been tested in clinical trials for use in HIV, autoimmune diseases, osteoporosis, and other conditions.

These latest findings come from an international team led by Sumit Chanda, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA. The researchers took advantage of a small-molecule drug library called ReFRAME [2], which was created in 2018 by Calibr, a non-profit drug discovery division of Scripps Research, La Jolla, CA.

In collaboration with Yuen Kwok-Yung’s team at the University of Hong Kong, the researchers first developed a high-throughput method that enabled them to screen rapidly each of the 11,987 drug compounds in the ReFRAME library for their potential to block SARS-CoV-2 in cells grown in the lab. The first round of testing narrowed the list of possible COVID-19 drugs to about 300. Next, using lower concentrations of the drugs in cells exposed to a second strain of SARS-CoV-2, they further narrowed the list to 100 compounds that could reliably limit growth of the coronavirus by at least 40 percent.

Generally speaking, an effective anti-viral drug is expected to show greater activity as its concentration is increased. So, Chanda’s team then tested those 100 drugs for evidence of such a dose-response relationship. Twenty-one of them passed this test. This group included remdesivir, a drug originally developed for Ebola virus disease and recently authorized by the U.S. Food and Drug Administration (FDA) for emergency use in the treatment of COVID-19. Remdesivir could now be considered a positive control.

These findings raised another intriguing question: Could any of the other drugs with a dose-response relationship work well in combination with remdesivir to block SARS-CoV-2 infection? Indeed, the researchers found that four of them could.

Further study showed that some of the most promising drugs on the list reduced the number of SARS-CoV-2 infected cells by 65 to 85 percent. The most potent of these was apilimod, a drug that has been evaluated in clinical trials for treating Crohn’s disease, rheumatoid arthritis, and other autoimmune conditions. Apilimod is now being evaluated in the clinic for its ability to prevent the progression of COVID-19. Another potential antiviral to emerge from the study is clofazimine, a 70-year old FDA-approved drug that is on the World Health Organization’s list of essential medicines for the treatment of leprosy.

Overall, the findings suggest that there may be quite a few existing drugs and/or experimental drugs fairly far along in the development pipeline that have potential to be repurposed for treating COVID-19. What’s more, some of them might also work well in combination with remdesivir, or perhaps other drugs, as treatment “cocktails,” such as those used to successfully treat HIV and hepatitis C.

This is just one of a wide variety of drug screening efforts that are underway, using different libraries and different assays to detect activity against SARS-CoV-2. The NIH’s National Center for Advancing Translational Sciences has established an open data portal to collect all of these data as quickly and openly as possible. As NIH continues its efforts to use the power of science to end the COVID-19 pandemic, it is critically important that we explore as many avenues as possible for developing diagnostics, treatments, and vaccines.

References:

[1] Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Riva L, Yuan S, Yin X, et al. Nature. 2020 Jul 24 [published online ahead of print]

[2] The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis. Janes J, Young ME, Chen E, et al. Proc Natl Acad Sci USA. 2018;115(42):10750-10755.

Links:

Coronavirus (COVID-19) (NIH)

ReFRAMEdb (Scripps Research, La Jolla, CA)

The Chanda Lab (Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA)

Yuen Kwok-Yung (University of Hong Kong)

OpenData|Covid-19 (National Center for Advancing Translational Sciences/NIH)

NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences


Repurposing an “Old” Drug for Alzheimer’s Disease

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Senator Mikulski during her tour of NCATS

Caption: Here I am with Senator Barbara Mikulski (center) and NCATS Director Chris Austin (right). Credit: NIH

Alzheimer’s disease research is among the many areas of biomedical science that Senator Barbara Mikulski has championed during her nearly 40 years on Capitol Hill. And it’s easy to understand why the Senator is concerned: an estimated 5 million Americans age 65 and older have Alzheimer’s disease, and those numbers are expected to rise exponentially as the U.S. population continues to age.

So, I was thrilled to have some encouraging progress to report last week when Senator Mikulski (D-MD) paid a visit to NIH’s National Center for Advancing Translational Sciences (NCATS) in Gaithersburg, MD. After a whirlwind tour of the cutting-edge robotics facility for high throughput screening of small molecules, she joined me and NCATS Director Dr. Chris Austin in announcing that, thanks to an innovative public-private partnership, an experimental drug originally developed to fight cancer is now showing promise against Alzheimer’s disease.


siRNAs: Small Molecules that Pack a Big Punch

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Photo of parkin protein (green) that tags damaged mitochondria (red)

Caption: NIH scientists used RNA interference to find genes that interact with the parkin protein (green), which tags damaged mitochondria (red). Mutations in the parkin gene are linked to Parkinson’s disease and other mitochondrial disorders.
Credit: Richard J. Youle Laboratory, NINDS, NIH

It would be terrific if we could turn off human genes in the laboratory, one at a time, to figure out their exact functions and learn more about how our health is affected when those functions are disrupted. Today, I’m excited to announce the availability of new data that will empower researchers to do just that on a genome-wide scale. As part of a public-private collaboration between the NIH’s National Center for Advancing Translational Sciences (NCATS) and Life Technologies Corporation, researchers now have access to a wealth of information about small interfering RNAs (siRNAs), which are snippets of ribonucleic acid (RNA) with the power to turn off a gene, or reduce its activity—in much the same way that we use a dimmer switch to modulate a light.


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