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Single-Cell Study Offers New Clue into Causes of Cystic Fibrosis

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Healthy airways (left) show well-defined layers of ciliated cells (green) and basal stem cells (red). In airways affected by cystic fibrosis (right), the layers are disrupted, and a transitioning cell type (red and green in the same cell).
Credit: Carraro G, Nature, 2021

More than 30 years ago, I co-led the Michigan-Toronto team that discovered that cystic fibrosis (CF) is caused by an inherited misspelling in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [1]. The CFTR protein’s normal function on the surface of epithelial cells is to serve as a gated channel for chloride ions to pass in and out of the cell. But this function is lost in individuals for whom both copies of CFTR are misspelled. As a consequence, water and salt get out of balance, leading to the production of the thick mucus that leaves people with CF prone to life-threatening lung infections.

It took three decades, but that CFTR gene discovery has now led to the development of a precise triple drug therapy that activates the dysfunctional CFTR protein and provides major benefit to most children and adults with CF. But about 10 percent of individuals with CF have mutations that result in the production of virtually no CFTR protein, which means there is nothing for current triple therapy to correct or activate.

That’s why more basic research is needed to tease out other factors that contribute to CF and, if treatable, could help even more people control the condition and live longer lives with less chronic illness. A recent NIH-supported study, published in the journal Nature Medicine [2], offers an interesting basic clue, and it’s visible in the image above.

The healthy lung tissue (left) shows a well-defined and orderly layer of ciliated cells (green), which use hair-like extensions to clear away mucus and debris. Running closely alongside it is a layer of basal cells (outlined in red), which includes stem cells that are essential for repairing and regenerating upper airway tissue. (DNA indicating the position of cell is stained in blue).

In the CF-affected airways (right), those same cell types are present. However, compared to the healthy lung tissue, they appear to be in a state of disarray. Upon closer inspection, there’s something else that’s unusual if you look carefully: large numbers of a third, transitional cell subtype (outlined in red with green in the nucleus) that combines properties of both basal stem cells and ciliated cells, which is suggestive of cells in transition. The image below more clearly shows these cells (yellow arrows).

Photomicroscopy showing red basal cells below green ciliated cells, with transitional cells between showing green centers and red outlines
Credit: Carraro G, Nature, 2021

The increased number of cells with transitional characteristics suggests an unsuccessful attempt by the lungs to produce more cells capable of clearing the mucus buildup that occurs in airways of people with CF. The data offer an important foundation and reference for continued study.

These findings come from a team led by Kathrin Plath and Brigitte Gomperts, University of California, Los Angeles; John Mahoney, Cystic Fibrosis Foundation, Lexington, MA; and Barry Stripp, Cedars-Sinai, Los Angeles. Together with their lab members, they’re part of a larger research team assembled through the Cystic Fibrosis Foundation’s Epithelial Stem Cell Consortium, which seeks to learn how the disease changes the lung’s cellular makeup and use that new knowledge to make treatment advances.

In this study, researchers analyzed the lungs of 19 people with CF and another 19 individuals with no evidence of lung disease. Those with CF had donated their lungs for research in the process of receiving a lung transplant. Those with healthy lungs were organ donors who died of other causes.

The researchers analyzed, one by one, many thousands of cells from the airway and classified them into subtypes based on their distinctive RNA patterns. Those patterns indicate which genes are switched on or off in each cell, as well as the degree to which they are activated. Using a sophisticated computer-based approach to sift through and compare data, the team created a comprehensive catalog of cell types and subtypes present in healthy airways and in those affected by CF.

The new catalogs also revealed that the airways of people with CF had alterations in the types and proportions of basal cells. Those differences included a relative overabundance of cells that appeared to be transitioning from basal stem cells into the specialized ciliated cells, which are so essential for clearing mucus from the lungs.

We are not yet at our journey’s end when it comes to realizing the full dream of defeating CF. For the 10 percent of CF patients who don’t benefit from the triple-drug therapy, the continuing work to find other treatment strategies should be encouraging news. Keep daring to dream of breathing free. Through continued research, we can make the story of CF into history!

References:

[1] Identification of the cystic fibrosis gene: chromosome walking and jumping. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N, et al. Science.1989 Sep 8;245(4922):1059-65.

[2] Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition. Carraro G, Langerman J, Sabri S, Lorenzana Z, Purkayastha A, Zhang G, Konda B, Aros CJ, Calvert BA, Szymaniak A, Wilson E, Mulligan M, Bhatt P, Lu J, Vijayaraj P, Yao C, Shia DW, Lund AJ, Israely E, Rickabaugh TM, Ernst J, Mense M, Randell SH, Vladar EK, Ryan AL, Plath K, Mahoney JE, Stripp BR, Gomperts BN. Nat Med. 2021 May;27(5):806-814.

Links:

Cystic Fibrosis (National Heart, Lung, and Blood Institute/NIH)

Kathrin Plath (University of California, Los Angeles)

Brigitte Gomperts (UCLA)

Stripp Lab (Cedars-Sinai, Los Angeles)

Cystic Fibrosis Foundation (Lexington, MA)

Epithelial Stem Cell Consortium (Cystic Fibrosis Foundation, Lexington, MA)

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


DNA Base Editing May Treat Progeria, Study in Mice Shows

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Sam Berns with personalized snare drum carrier
Credit: Progeria Research Foundation

My good friend Sam Berns was born with a rare genetic condition that causes rapid premature aging. Though Sam passed away in his teens from complications of this condition, called Hutchinson-Gilford progeria syndrome, he’s remembered today for his truly positive outlook on life. Sam expressed it, in part, by his willingness to make adjustments that allowed him, in his words, to put things that he always wanted to do in the “can do” category.

In this same spirit on behalf of the several hundred kids worldwide with progeria and their families, a research collaboration, including my NIH lab, has now achieved a key technical advance to move non-heritable gene editing another step closer to the “can do” category to treat progeria. As published in the journal Nature, our team took advantage of new gene-editing tools to correct for the first time a single genetic misspelling responsible for progeria in a mouse model, with dramatically beneficial effects [1, 2]. This work also has implications for correcting similar single-base typos that cause other inherited genetic disorders.

The outcome of this work is incredibly gratifying for me. In 2003, my NIH lab discovered the DNA mutation that causes progeria. One seemingly small glitch—swapping a “T” in place of a “C” in a gene called lamin A (LMNA)—leads to the production of a toxic protein now known as progerin. Without treatment, children with progeria develop normally intellectually but age at an exceedingly rapid pace, usually dying prematurely from heart attacks or strokes in their early teens.

The discovery raised the possibility that correcting this single-letter typo might one day help or even cure children with progeria. But back then, we lacked the needed tools to edit DNA safely and precisely. To be honest, I didn’t think that would be possible in my lifetime. Now, thanks to advances in basic genomic research, including work that led to the 2020 Nobel Prize in Chemistry, that’s changed. In fact, there’s been substantial progress toward using gene-editing technologies, such as the CRISPR editing system, for treating or even curing a wide range of devastating genetic conditions, such as sickle cell disease and muscular dystrophy

It turns out that the original CRISPR system, as powerful as it is, works better at knocking out genes than correcting them. That’s what makes some more recently developed DNA editing agents and approaches so important. One of them, which was developed by David R. Liu, Broad Institute of MIT and Harvard, Cambridge, MA, and his lab members, is key to these latest findings on progeria, reported by a team including my lab in NIH’s National Human Genome Research Institute and Jonathan Brown, Vanderbilt University Medical Center, Nashville, TN.

The relatively new gene-editing system moves beyond knock-outs to knock-ins [3,4]. Here’s how it works: Instead of cutting DNA as CRISPR does, base editors directly convert one DNA letter to another by enzymatically changing one DNA base to become a different base. The result is much like the find-and-replace function used to fix a typo in a word processor. What’s more, the gene editor does this without cutting the DNA.

Our three labs (Liu, Brown, and Collins) first teamed up with the Progeria Research Foundation, Peabody, MA, to obtain skin cells from kids with progeria. In lab studies, we found that base editors, targeted by an appropriate RNA guide, could successfully correct the LMNA gene in those connective tissue cells. The treatment converted the mutation back to the normal gene sequence in an impressive 90 percent of the cells.

But would it work in a living animal? To get the answer, we delivered a single injection of the DNA-editing apparatus into nearly a dozen mice either three or 14 days after birth, which corresponds in maturation level roughly to a 1-year-old or 5-year-old human. To ensure the findings in mice would be as relevant as possible to a future treatment for use in humans, we took advantage of a mouse model of progeria developed in my NIH lab in which the mice carry two copies of the human LMNA gene variant that causes the condition. Those mice develop nearly all of the features of the human illness

In the live mice, the base-editing treatment successfully edited in the gene’s healthy DNA sequence in 20 to 60 percent of cells across many organs. Many cell types maintained the corrected DNA sequence for at least six months—in fact, the most vulnerable cells in large arteries actually showed an almost 100 percent correction at 6 months, apparently because the corrected cells had compensated for the uncorrected cells that had died out. What’s more, the lifespan of the treated animals increased from seven to almost 18 months. In healthy mice, that’s approximately the beginning of old age.

This is the second notable advance in therapeutics for progeria in just three months. Last November, based on preclinical work from my lab and clinical trials conducted by the Progeria Research Foundation in Boston, the Food and Drug Administration (FDA) approved the first treatment for the condition. It is a drug called Zokinvy, and works by reducing the accumulation of progerin [5]. With long-term treatment, the drug is capable of extending the life of kids with progeria by 2.5 years and sometimes more. But it is not a cure.

We are hopeful this gene editing work might eventually lead to a cure for progeria. But mice certainly aren’t humans, and there are still important steps that need to be completed before such a gene-editing treatment could be tried safely in people. In the meantime, base editors and other gene editing approaches keep getting better—with potential application to thousands of genetic diseases where we know the exact gene misspelling. As we look ahead to 2021, the dream envisioned all those years ago about fixing the tiny DNA typo responsible for progeria is now within our grasp and getting closer to landing in the “can do” category.

References:

[1] In vivo base editing rescues Hutchinson-Gilford Progeria Syndrome in mice. Koblan LW et al. Nature. 2021 Jan 6.

[2] Base editor repairs mutation found in the premature-ageing syndrome progeria. Vermeij WP, Hoeijmakers JHJ. Nature. 6 Jan 2021.

[3] Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Nature. 2016 May 19;533(7603):420-424.

[4] Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, Liu DR. Nature. 2017 Nov 23;551(7681):464-471.

[5] FDA approves first treatment for Hutchinson-Gilford progeria syndrome and some progeroid laminopathies. Food and Drug Administration. 2020 Nov 20.

Links:

Progeria (Genetic and Rare Diseases Information Center/NIH)

What are Genome Editing and CRISPR-Cas9? (National Library of Medicine/NIH)

Somatic Cell Genome Editing Program (Common Fund/NIH)

David R. Liu (Harvard University, Cambridge, MA)

Collins Group (National Human Genome Research Institute/NIH)

Jonathan Brown (Vanderbilt University Medical Center, Nashville, TN)

NIH Support: National Human Genome Research Institute; National Center for Advancing Translational Sciences; National Institute of Biomedical Imaging and Bioengineering; National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences; Common Fund


Encouraging News for Kids with Neurofibromatosis Type 1

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Dr. Collins with NF1 Patient
Caption: This photo goes back a few years. I’m talking to a child with neurofibromatosis type 1 during the search for the NF1 gene, which was discovered in 1990. Credit: University of Michigan Bio Med Photo Department, Ann Arbor

Amid all the headlines and uncertainty surrounding the current COVID-19 pandemic, it’s easy to overlook the important progress that biomedical research is making against other diseases. So, today, I’m pleased to share word of what promises to be the first effective treatment to help young people suffering from the consequences of a painful, often debilitating genetic disorder called neurofibromatosis type 1 (NF1).

This news is particularly meaningful to me because, 30 years ago, I led a team that discovered the gene that underlies NF1. About 1 in 3,000 babies are born with NF1. In about half of those affected, a type of tumor called a plexiform neurofibroma arises along nerves in the skin, face, and other parts of the body. While plexiform neurofibromas are not cancerous, they grow steadily and can lead to severe pain and a range of other health problems, including vision and hearing loss, hypertension, and mobility issues.

The good news is the results of a phase II clinical trial involving NF1, just published in the New England Journal of Medicine. The trial was led by Brigitte Widemann and Andrea Gross, researchers in the Center for Cancer Research at NIH’s National Cancer Institute.

The trial’s results confirm that a drug originally developed to treat cancer, called selumetinib, can shrink inoperable tumors in many children with NF1. They also establish that the drug can help affected kids make significant improvements in strength, range of motion, and quality of life. While selumetinib is not a cure, and further studies are still needed to see how well the treatment works in the long term, these results suggest that the first effective treatment for NF1 is at last within our reach.

Selumetinib blocks a protein in human cells called MEK. This protein is involved in a major cellular pathway known as RAS that can become dysregulated and give rise to various cancers. By blocking the MEK protein in animal studies and putting the brakes on the RAS pathway when it malfunctions, selumetinib showed great initial promise as a cancer drug.

Selumetinib was first tested several years ago in people with a variety of other cancers, including ovarian and non-small cell lung cancers. The clinical research looked good at first but eventually stalled, and so did much of the initial enthusiasm for selumetinib.

But the enthusiasm picked up when researchers considered repurposing the drug to treat NF1. The neurofibromas associated with the condition were known to arise from a RAS-activating loss of the NF1 gene. It made sense that blocking the MEK protein might blunt the overactive RAS signal and help to shrink these often-inoperable tumors.

An earlier phase 1 safety trial looked promising, showing for the first time that the drug could, in some cases, shrink large NF1 tumors [2]. This fueled further research, and the latest study now adds significantly to that evidence.

In the study, Widemann and colleagues enrolled 50 children with NF1, ranging in age from 3 to 17. Their tumor-related symptoms greatly affected their wellbeing and ability to thrive, including disfigurement, limited strength and motion, and pain. Children received selumetinib alone orally twice a day and went in for assessments at least every four months.

As of March 2019, 35 of the 50 children in the ongoing study had a confirmed partial response, meaning that their tumors had shrunk by more than 20 percent. Most had maintained that response for a year or more. More importantly, the kids also felt less pain and were more able to enjoy life.

It’s important to note that the treatment didn’t work for everyone. Five children stopped taking the drug due to side effects. Six others progressed while on the drug, though five of them had to reduce their dose because of side effects before progressing. Nevertheless, for kids with NF1 and their families, this is a big step forward.

Drug developer AstraZeneca, working together with the researchers, has submitted a New Drug Application to the Food and Drug Administration (FDA). While they’re eagerly awaiting the FDA’s decision, the work continues.

The researchers want to learn much more about how the drug affects the health and wellbeing of kids who take it over the long term. They’re also curious whether it could help to prevent the growth of large tumors in kids who begin taking it earlier in the course of the disease, and whether it might benefit other features of the disorder. They will continue to look ahead to other potentially promising treatments or treatment combinations that may further help, and perhaps one day even cure, kids with NF1. So, even while we cope with the COVID-19 pandemic, there are reasons to feel encouraged and grateful for continued progress made throughout biomedical research.

References:

[1] Selumitinib in children with inoperable plexiform neurofibromas. New England Journal of Medicine. Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC. 18 March 2020. N Engl J Med. 2020 Mar 18. [Epub ahead of publication.]

[2] Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P1, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC. N Engl J Med. 2016 Dec 29;375(26):2550-2560.

Links:

Neurofibromatosis Fact Sheet (National Institute of Neurological Disorders and Stroke/NIH)

Brigitte Widemann (National Cancer Institute/NIH)

Andrea Gross (National Cancer Institute/NIH)

NIH Support: National Cancer Institute


Seven Questions for a Rare Disease Warrior

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Francis Collins with David Fajgenbaum
Caption: David Fajgenbaum (right) and I pose for a photo a few years ago in Philadelphia.
Credit: National Disease Research Interchange, Philadelphia

Tomorrow is Rare Disease Day at NIH, marking the 12th year that this annual event has been held on the NIH campus. Similar gatherings have been organized independently around the world this week, all to raise awareness for the nearly 7,000 rare diseases, some affecting just a few dozen people. But, collectively, rare diseases are hardly rare. One in 10 Americans has a rare disease (defined as affecting 200,000 or fewer individuals in the US), and about half are children. Without needed treatments, about 30 percent of these children will die by age 5.

To join everyone in raising awareness, I wanted to feature on my blog a unique perspective about rare diseases, and David Fajgenbaum certainly has one. Fajgenbaum is an immunologist and NIH grantee at the Perelman School of Medicine, University of Pennsylvania, Philadelphia. When Fajgenbaum isn’t running studies or clinical trials, he must remain vigilant of his own health. Fajgenbaum has a rare disease called idiopathic multicentric Castleman disease (iMCD), and this devastating condition, which emerged while he was in medical school, nearly claimed his life several times.

Now 34 years old and in a long remission, Fajgenbaum can discuss rare diseases as a doctor, as a patient, as a researcher, and as an advocate. His personal journey, published in his recent book Chasing My Cure, is a gripping read. Fajgenbaum was kind enough to answer a few of my questions on rare diseases and share some of his lessons learned.

The last time that I saw you, David, you looked great. How long have you been in remission?

I have been in remission for 73.83 months. I say 73.83, because I know that I can’t round up—I may relapse tomorrow. But I also refuse to round down because so many colleagues and I have worked so hard for every day of remission for me and other patients with my disease.

For me, every day is particularly special, because I never thought that I would be alive this long. As you know, I became deathly ill during medical school in 2010 and even had my last rites read to me when my doctors didn’t think I would survive. I was eventually diagnosed with idiopathic multicentric Castleman disease (iMCD), which is like a deadly cross between cancer and autoimmunity. Chemotherapy saved my life, but I would go on to have four near-death relapses.

After one of those relapses, I got out of the hospital and dedicated my life to conducting iMCD research and co-founded the Castleman Disease Collaborative Network (CDCN). Later, I identified a particular cellular pathway called mTOR that was highly active in my samples. I began testing on myself an mTOR inhibitor [sirolimus]—developed 30 years before and approved for kidney transplantation but never considered for iMCD. It’s this drug that has kept me in remission for the last 73.83 months and helped other people. During this time, I’ve been able to marry my wife, have a daughter, help launch a new center at Penn specializing in rare diseases, and write a book to share my personal journey with others.

As a physician-scientist and as a person with a rare disease, what have you learned about the biomedical research process?

I’ve learned so much, but I’d like to highlight three lessons in particular. First, we must leverage all perspectives to prioritize research and give us the best chance of translating research into meaningful breakthroughs. The traditional approach to rare disease research involves a subset of researchers within a rare disease field submitting their best ideas for funding and a panel selecting the best applicant.

Through the CDCN, we’ve spearheaded a new approach called the Collaborative Network Approach, where we crowdsource research questions from the entire community of patients, physicians, and researchers (not just a subset of researchers) and then recruit the best researchers in the world (not just from within the Castleman disease field) to perform the prioritized studies. We’re now working to improve and spread this approach to other diseases.

Second, collaboration between all players is critical. Patient advocacy groups are uniquely positioned to serve as the glue between all stakeholders. Researchers and physicians need to share ideas, data, and samples with one another. Patients need to be actively involved in research question prioritization and study design. Biopharma and the Food and Drug Administration (FDA) need to be engaged early in the process of research discoveries and drug development.

Third, we must leverage all 1,500-plus, existing FDA-approved drugs to help as many patients without any options as quickly as possible. As you know, less than 5 percent of the nearly 7,000 rare diseases have an FDA-approved therapy, but many diseases share similar cellular and genetic defects that could make them susceptible to the same drugs. I’m literally alive today thanks to a drug developed for another disease. How many of the drugs approved for one disease may be effective for many of the 7,000 diseases without any? I don’t know the answer, but I hope we can begin to address this important question and incentivize repurposing.

In your experience, how can people with rare diseases help to advance progress for their conditions?

There is so much work to be done for so many rare diseases. Sometimes it can feel so overwhelming and like “what can I really do?”

But I’ve learned that there are so many ways that we can each contribute and so many incredible examples of advocates who have made a difference for themselves and those that they love. Cystic fibrosis and chordoma are just two of many examples where patient-advocates have been critical partners in transforming their diseases.

People with rare diseases can raise funds for research. Every dollar truly counts. We can work with existing organizations for our disease to ensure that those funds are distributed as efficiently and effectively as possible. If there are major gaps within our rare disease fields that aren’t being addressed by existing organizations, we can start new rare disease organizations (but we should try to avoid this whenever possible). We can contribute samples and data towards research, participate in clinical trials, and share with other patients about our experiences. We can advocate for new drug development and repurposing already-FDA approved drugs for our diseases.

What would you tell other researchers who are studying rare diseases?

I would tell other rare disease researchers that you are doing such important work. You give us hope that a treatment can be identified that will change our lives. It’s an incredible responsibility and incredibly stressful. There are unfortunately far too many scientific questions and diseases with major unmet need for any of us to compete over the use of samples and data. We have to share these within our fields. And we must also work together across rare diseases. We can’t continue to reinvent the wheel; we must share learnings with one another

I enjoyed doing the CastleMan Warrior Flex with you. Tell us more about what it represents?

Doing the CastleMan Warrior Flex with you is one of my favorite pictures. In fact, it’s hanging up in my office.

Castleman disease was named after Dr. Benjamin Castleman, who first described our disease in 1954. We have repurposed the “Castleman” name to be a “CastleMan Warrior” (below is our cartoon mascot). We do the “CastleMan Warrior” Flex to raise awareness for Castleman disease and rare diseases generally—we’re all warriors in the rare disease space.

CastleMan Warrior Flex
Credit: David Fejgenbaum/National Disease Research Interchange, Philadelphia

What are your future plans as a rare disease advocate and as a researcher?

We’ve made a lot of progress for Castleman disease: we’ve advanced our findings about mTOR towards a clinical trial, gained approval for the treatment siltuximab for iMCD, developed diagnostic criteria and treatment guidelines, and invested about $1.5 million into Castleman disease research, which has led to over $7 million in additional funding from other sources.

But we still have important work ahead of us. The treatments sirolimus and siltuximab work for only a portion of all iMCD patients. We need to identify more effective treatments for all forms of Castleman disease.

I will continue to study Castleman disease and other diseases at the intersection of autoimmunity and oncology to gain insights into how the immune system works in myriad diseases. In parallel, I will continue to advocate for the adoption of the “Collaborative Network Approach” to crowdsource all stakeholder perspectives as well as for new models for drug repurposing.

Any other issues that you’d like to address?

I feel a responsibility to share with the world the lessons that I’ve learned about life from nearly dying five times. This is a major reason that I wrote my book.

One lesson that I think about a lot is related to my growing up playing football. Some of my games were extended into an overtime period to decide the outcome. In overtime, every second counts and you’re totally focused on what’s important. I’ve lived with that exact same feeling ever since I had my last rites read to me.

I’ve also learned that humor can be incredibly powerful. You may think that a good laugh may be the last thing that you’d want to do when you’re dying in the ICU. But laughing with the people that I love actually helped me feel like I could transcend my illness, and it helped to connect us.

My greatest regrets on my deathbed were not things that I had done or said. I regretted what I didn’t do or didn’t say and that I would no longer be able to do. I now follow the motto: “Think It, Do It.” In other words, we should reflect on what we’re hoping for and then turn our hopes into action.

Finally, I’ve learned that it really takes a strong team to make a difference in the world, especially against diseases. If it was just me on my own, we would have made less than 1 percent of the progress that’s been achieved. I hope that all rare disease warriors will join together into strong teams, armies even, and make a difference in the world.

Links:

Multicentric Castleman Disease (Genetic and Rare Diseases Information Center/NIH)

Castleman Disease Collaborative Network (Paso Robles, CA)

His Doctors Were Stumped. Then He Took Over (New York Times, February 4, 2017)

Video: Chasing My Cure: Dr. David Fajgenbaum’s Lessons From His Rare Disease And On Finding Cures For Others (Exponential Medicine, November 4, 2019)

Rare Disease Day at NIH 2020 (National Center for Advancing Translational Sciences/NIH)


Tackling Fibrosis with Synthetic Materials

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April Kloxin
April Kloxin/Credit: Evan Krape, University of Delaware, Newark

When injury strikes a limb or an organ, our bodies usually heal quickly and correctly. But for some people, the healing process doesn’t shut down properly, leading to excess fibrous tissue, scarring, and potentially life-threatening organ damage.

This permanent scarring, known as fibrosis, can occur in almost every tissue of the body, including the heart and lungs. With support from a 2019 NIH Director’s New Innovator Award, April Kloxin is applying her expertise in materials science and bioengineering to build sophisticated fibrosis-in-a-dish models for unraveling this complex process in her lab at the University of Delaware, Newark.

Though Kloxin is interested in all forms of fibrosis, she’s focusing first on the incurable and often-fatal lung condition called idiopathic pulmonary fibrosis (IPF). This condition, characterized by largely unexplained thickening and stiffening of lung tissue, is diagnosed in about 50,000 people each year in the United States.

IPF remains poorly understood, in part because it often is diagnosed when the disease is already well advanced. Kloxin hopes to turn back the clock and start to understand the disease at an earlier stage, when interventions might be more successful. The key is to develop a model that better recapitulates the complexity and irreversibility of the disease process in people.

Building that better model starts with simulating the meshwork of collagen and other proteins in the extracellular matrix (ECM) that undergird every tissue and organ in the body. The ECM’s interactions with our cells are essential in wound healing and, when things go wrong, also in causing fibrosis.

Kloxin will build three-dimensional hydrogels, crosslinked sponge-like networks of polymers, peptides, and proteins, with structures that more accurately capture the biological complexities of human tissues, including the ECMs within fibrous collagen-rich microenvironments. Her synthetic matrices can be triggered with light to lock in place and stiffen. The matrices also will make it possible to culture the lung’s epithelium, or outermost layer of cells, and connective tissue that surrounds it, to study cellular responses as the model shifts from a healthy and flexible to a stiffened, disease-like state.

Kloxin and her team will also integrate into their model system lung cells that have been engineered to fluoresce or light up under a microscope when the wound-healing program activates. Such fluorescent reporters will allow her team to watch for the first time how different cells and their nearby microenvironment respond as the composition of the ECM changes and stiffens. With this system, she’ll also be able to search for small molecules with the ability to turn off excessive wound healing.

The hope is that what’s learned with her New Innovator Award will lead to fresh insights and ultimately new treatments for this mysterious, hard-to-treat condition. But the benefits could be even more wide-ranging. Kloxin thinks that her findings will have implications for the prevention and treatment of other fibrotic diseases as well.

Links:

Idiopathic Pulmonary Fibrosis (National Heart, Lung, and Blood Institute/NIH)

April Kloxin Group (University of Delaware, Newark)

Kloxin Project Information (NIH RePORTER)

NIH Director’s New Innovator Award (Common Fund)

NIH Support: Common Fund; National Heart, Lung, and Blood Institute


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