rare disease
Unraveling the Role of the Skin Microbiome in Health and Disease
Posted on by Lindsey A. Criswell, M.D., M.P.H., D.Sc., National Institute of Arthritis and Musculoskeletal and Skin Diseases
Human skin is home to diverse ecosystems including bacteria, viruses, and fungi. These microbial communities comprise hundreds of species and are collectively known as the skin microbiome. The skin microbiome is thought to play a vital role in fending off disease-causing microorganisms (pathogens), boosting barrier protection, and aiding immune defenses.
Maintaining a balanced skin microbiome involves a complex and dynamic interplay among microorganisms, immune cells, skin cells, and other factors. In general, bacteria far outnumber viral, fungal, or other microbial species on the skin. Bacterial communities, which are strongly influenced by conditions such as skin moisture, temperature, and pH, vary widely across the body. For example, facial cheek skin hosts mostly Cutibacterium along with a bit of the skin fungus Malassezia. The heel is colonized by different types of bacteria including Staphylococcus and Corynebacteria.
In some diseases, such as acne and eczema, the skin microbiome is altered. Typically, this means an increase in pathogenic microorganisms and a decrease in beneficial ones. An altered skin microbiome can also be associated with inflammation, severe disease symptoms, and changes in the human immune system.
Heidi H. Kong is working to understand the role of the skin microbiome in health and disease. She is a senior investigator in the Intramural Research Program at NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and an adjunct investigator at NIH’s National Cancer Institute (NCI).
More than a decade ago, Kong and Julie A. Segre, an intramural researcher at NIH’s National Human Genome Research Institute, analyzed the microbial makeup of healthy individuals. Kong swabbed the skin of these healthy volunteers in 20 different sites, from the forehead to the toenail. The study revealed that the surface of the human body provides various environmental niches, depending on whether the skin is moist, dry, or sebaceous (oily). Different bacterial species predominate in each niche. Kong and Segre were particularly interested in body areas that have predilections for disease. For example, psoriasis is often found on the outside of elbows and knees, and the back of the scalp.
Earlier this year, Kong and Segre published another broad analysis of the human skin microbiome [1] in collaboration with scientists at the European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), United Kingdom. This new catalog, called the Skin Microbial Genome Collection, is thought to identify about 85 percent of the microorganisms present on healthy skin from 19 body sites. It documents more than 600 bacterial species—including 174 that were discovered during the study—as well as more than 6,900 viruses and some fungi, including three newly discovered species.
Kong’s work has provided compelling evidence that the human immune system plays a role in shaping the skin microbiome. In 2018, she, Segre, and colleagues from the intramural programs of NCI and NIH’s National Institute of Allergy and Infectious Diseases analyzed skin from eight different sites on 27 people with a rare primary immunodeficiency disease known as DOCK8 deficiency [2].
People with the condition have recurrent infections in the skin, sinuses, and airways, and are susceptible to different cancers. Kong and colleagues found that the skin of people with DOCK8 deficiency contains significantly more DNA viruses (90 percent of the skin microbiome on average) than people without the condition (6 or 7 percent of the skin microbiome).
Other researchers are hoping to leverage features of the microbiome to develop targeted therapies for skin diseases. Richard L. Gallo, a NIAMS grantee at the University of California, San Diego, is currently focused on acne and eczema (also called atopic dermatitis). Acne is associated with certain strains of Cutibacterium acnes (C. acnes, formerly called Propionibacterium acnes or P. acnes). Eczema is often associated with Staphylococcus aureus (S. aureus).
Severe cases of acne and eczema are commonly treated with broad-spectrum antibiotics, which wipe out most of the bacteria, including beneficial species. The goal of microbiome-targeted therapy is to kill only the disease-associated bacteria and avoid increasing the risk that some strains will develop antibiotic resistance.
In 2020, Gallo and colleagues identified a strain of Staphylococcus capitis from healthy human skin (S. capitis E12) that selectively inhibits the growth of C. acnes without negatively impacting other bacteria or human skin cells [3]. S. capitis E12 produces four different toxins that act together to target C. acnes. The research team created an extract of the four toxins and tested it using animal models. In most cases, the extract was more potent at killing C. acnes—including acne-associated strains—than several commonly prescribed antibiotics (erythromycin, tetracycline, and clindamycin). And, unlike antibiotics, the extract does not appear to promote drug-resistance, at least for the 20 generations observed by the researchers.
Eczema is a chronic, relapsing disease characterized by skin that is dry, itchy, inflamed, and prone to infection, including by pathogens such as S. aureus and herpes virus. Although the cause of eczema is unknown, the condition is associated with human genetic mutations, disruption of the skin’s barrier, inflammation-triggering allergens, and imbalances in the skin microbiome.
In 2017, Gallo’s research team discovered that, in healthy human skin, certain strains of Staphylococcus hominis and Staphylococcus epidermis produce potent antimicrobial molecules known as lantibiotics [4]. These beneficial strains are far less common on the skin of people with eczema. The lantibiotics work synergistically with LL-37, an antimicrobial molecule produced by the human immune system, to selectively kill S. aureus, including methicillin-resistant strains (MRSA).
Gallo and his colleagues then examined the safety and therapeutic potential of these beneficial strains isolated from the human skin microbiome. In animal tests, strains of S. hominis and S. epidermis that produce lantibiotics killed S. aureus and blocked production of its toxin.
Gallo’s group has now expanded their work to early studies in humans. In 2021, two independent phase 1 clinical trials [5,6] conducted by Gallo and his colleagues investigated the effects of these strains on people with eczema. These double-blind, placebo-controlled trials involved one-week of topical application of beneficial bacteria to the forearm of adults with S. aureus-positive eczema. The results demonstrated that the treatment was safe, showed a significant decrease in S. aureus, and improved eczema symptoms in most patients. This is encouraging news for those hoping to develop microbiome-targeted therapy for inflammatory skin diseases.
As research on the skin microbiome advances on different fronts, it will provide deeper insight into the multi-faceted microbial communities that are so critical to health and disease. One day, we may even be able to harness the microbiome as a source of therapeutics to alleviate inflammation, promote wound healing, or suppress certain skin cancers.
References:
[1] Integrating cultivation and metagenomics for a multi-kingdom view of skin microbiome diversity and functions. Saheb Kashaf S, Proctor DM, Deming C, Saary P, Hölzer M; NISC Comparative Sequencing Program, Taylor ME, Kong HH, Segre JA, Almeida A, Finn RD. Nat Microbiol. 2022 Jan;7(1):169-179.
[2] Expanded skin virome in DOCK8-deficient patients. Tirosh O, Conlan S, Deming C, Lee-Lin SQ, Huang X; NISC Comparative Sequencing Program, Su HC, Freeman AF, Segre JA, Kong HH. Nat Med. 2018 Dec;24(12):1815-1821.
[3] Identification of a human skin commensal bacterium that selectively kills Cutibacterium acnes. O’Neill AM, Nakatsuji T, Hayachi A, Williams MR, Mills RH, Gonzalez DJ, Gallo RL. J Invest Dermatol. 2020 Aug;140(8):1619-1628.e2.
[4] Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Nakatsuji T, Chen TH, Narala S, Chun KA, Two AM, Yun T, Shafiq F, Kotol PF, Bouslimani A, Melnik AV, Latif H, Kim JN, Lockhart A, Artis K, David G, Taylor P, Streib J, Dorrestein PC, Grier A, Gill SR, Zengler K, Hata TR, Leung DY, Gallo RL. Sci Transl Med. 2017 Feb 22;9(378):eaah4680.
[5] Development of a human skin commensal microbe for bacteriotherapy of atopic dermatitis and use in a phase 1 randomized clinical trial. Nakatsuji T, Hata TR, Tong Y, Cheng JY, Shafiq F, Butcher AM, Salem SS, Brinton SL, Rudman Spergel AK, Johnson K, Jepson B, Calatroni A, David G, Ramirez-Gama M, Taylor P, Leung DYM, Gallo RL. Nat Med. 2021 Apr;27(4):700-709.
[6] Use of autologous bacteriotherapy to treat Staphylococcus aureus in patients with atopic dermatitis: A randomized double-blind clinical trial. Nakatsuji T, Gallo RL, Shafiq F, Tong Y, Chun K, Butcher AM, Cheng JY, Hata TR. JAMA Dermatol. 2021 Jun 16;157(8):978-82.
Links:
Acne (National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH)
Atopic Dermatitis (NIAMS)
Cutaneous Microbiome and Inflammation Laboratory, Heidi Kong (NIAMS)
Julie Segre (National Human Genome Research Institute/NIH)
Gallo Lab (University of California, San Diego)
[Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the cool science that they support and conduct. This is the fifth in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.]
NCI Support for Basic Science Paves Way for Kidney Cancer Drug Belzutifan
Posted on by Norman "Ned" Sharpless, M.D., National Cancer Institute
There’s exciting news for people with von Hippel-Lindau (VHL) disease, a rare genetic disorder that can lead to cancerous and non-cancerous tumors in multiple organs, including the brain, spinal cord, kidney, and pancreas. In August 2021, the U.S. Food and Drug Administration (FDA) approved belzutifan (Welireg), a new drug that has been shown in a clinical trial led by National Cancer Institute (NCI) researchers to shrink some tumors associated with VHL disease [1], which is caused by inherited mutations in the VHL tumor suppressor gene.
As exciting as this news is, relatively few people have this rare disease. The greater public health implication of this advancement is for people with sporadic, or non-inherited, clear cell kidney cancer, which is by far the most common subtype of kidney cancer, with more than 70,000 cases and about 14,000 deaths per year. Most cases of sporadic clear cell kidney cancer are caused by spontaneous mutations in the VHL gene.
This advancement is also a great story of how decades of support for basic science through NCI’s scientists in the NIH Intramural Research Program and its grantees through extramural research funding has led to direct patient benefit. And it’s a reminder that we never know where basic science discoveries might lead.
Belzutifan works by disrupting the process by which the loss of VHL in a tumor turns on a series of molecular processes. These processes involve the hypoxia-inducible factor (HIF) transcription factor and one of its subunits, HIF-2α, that lead to tumor formation.
The unraveling of the complex relationship among VHL, the HIF pathway, and cancer progression began in 1984, when Bert Zbar, Laboratory of Immunobiology, NCI-Frederick; and Marston Linehan, NCI’s Urologic Oncology Branch, set out to find the gene responsible for clear cell kidney cancer. At the time, there were no effective treatments for advanced kidney cancer, and 80 percent of patients died within two years.
Zbar and Linehan started by studying patients with sporadic clear cell kidney cancer, but then turned their focus to investigations of people affected with VHL disease, which predisposes a person to developing clear cell kidney cancer. By studying the patients and the genetic patterns of tumors collected from these patients, the researchers hypothesized that they could find genes responsible for kidney cancer.
Linehan established a clinical program at NIH to study and manage VHL patients, which facilitated the genetic studies. It took nearly a decade, but, in 1993, Linehan, Zbar, and Michael Lerman, NCI-Frederick, identified the VHL gene, which is mutated in people with VHL disease. They soon discovered that tumors from patients with sporadic clear cell kidney cancer also have mutations in this gene.
Subsequently, with NCI support, William G. Kaelin Jr., Dana-Farber Cancer Institute, Boston, discovered that VHL is a tumor suppressor gene that, when inactivated, leads to the accumulation of HIF.
Another NCI grantee, Gregg L. Semenza, Johns Hopkins School of Medicine, Baltimore, identified HIF as a transcription factor. And Peter Ratcliffe, University of Oxford, United Kingdom, discovered that HIF plays a role in blood vessel development and tumor growth.
Kaelin and Ratcliffe simultaneously showed that the VHL protein tags a subunit of HIF for destruction when oxygen levels are high. These results collectively answered a very old question in cell biology: How do cells sense the intracellular level of oxygen?
Subsequent studies by Kaelin, with NCI’s Richard Klausner and Linehan, revealed the critical role of HIF in promoting the growth of clear cell kidney cancer. This work ultimately focused on one member of the HIF family, the HIF-2α subunit, as the key mediator of clear cell kidney cancer growth.
The fundamental work of Kaelin, Semenza, and Ratcliffe earned them the 2019 Nobel Prize in Physiology or Medicine. It also paved the way for drug discovery efforts that target numerous points in the pathway leading to clear cell kidney cancer, including directly targeting the transcriptional activity of HIF-2α with belzutifan.
Clinical trials of belzutifan, including several supported by NCI, demonstrated potent anti-cancer activity in VHL-associated kidney cancer, as well as other VHL-associated tumors, leading to the aforementioned recent FDA approval. This is an important development for patients with VHL disease, providing a first-in-class therapy that is effective and well-tolerated.
We believe this is only the beginning for belzutifan’s use in patients with cancer. A number of trials are now studying the effectiveness of belzutifan for sporadic clear cell kidney cancer. A phase 3 trial is ongoing, for example, to look at the effectiveness of belzutifan in treating people with advanced kidney cancer. And promising results from a phase 2 study show that belzutifan, in combination with cabozantinib, a widely used agent to treat kidney cancer, shrinks tumors in patients previously treated for metastatic clear cell kidney cancer [2].
This is a great scientific story. It shows how studies of familial cancer and basic cell biology lead to effective new therapies that can directly benefit patients. I’m proud that NCI’s support for basic science, both intramurally and extramurally, is making possible many of the discoveries leading to more effective treatments for people with cancer.
References:
[1] Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, Oudard S, Else T, Maranchie JK, Welsh SJ, Thamake S, Park EK, Perini RF, Linehan WM, Srinivasan R; MK-6482-004 Investigators. N Engl J Med. 2021 Nov 25;385(22):2036-2046.
[2] Phase 2 study of the oral hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC). Choueiri TK et al. J Clin Oncol. 2021 Feb 20;39(6_suppl): 272-272.
Links:
Von Hippel-Lindau Disease (Genetic and Rare Diseases Information Center/National Center for Advancing Translational Sciences/NIH)
Clear Cell Renal Cell Carcinoma (National Cancer Institute/NIH)
Belzutifan Approved to Treat Tumors Linked to Inherited Disorder VHL, Cancer Currents Blog, National Cancer Institute, September 21, 2021.
The Long Road to Understanding Kidney Cancer (Intramural Research Program/NIH)
[Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s institutes and centers to contribute occasional guest posts to the blog as a way to highlight some of the cool science that they support and conduct. This is the first in the series of NIH institute and center guest posts that will run until a new permanent NIH director is in place.]
Biomedical Research Leads Science’s 2021 Breakthroughs
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Hi everyone, I’m Larry Tabak. I’ve served as NIH’s Principal Deputy Director for over 11 years, and I will be the acting NIH director until a new permanent director is named. In my new role, my day-to-day responsibilities will certainly increase, but I promise to carve out time to blog about some of the latest research progress on COVID-19 and any other areas of science that catch my eye.
I’ve also invited the directors of NIH’s Institutes and Centers (ICs) to join me in the blogosphere and write about some of the cool science in their research portfolios. I will publish a couple of posts to start, then turn the blog over to our first IC director. From there, I envision alternating between posts from me and from various IC directors. That way, we’ll cover a broad array of NIH science and the tremendous opportunities now being pursued in biomedical research.
Since I’m up first, let’s start where the NIH Director’s Blog usually begins each year: by taking a look back at Science’s Breakthroughs of 2021. The breakthroughs were formally announced in December near the height of the holiday bustle. In case you missed the announcement, the biomedical sciences accounted for six of the journal Science’s 10 breakthroughs. Here, I’ll focus on four biomedical breakthroughs, the ones that NIH has played some role in advancing, starting with Science’s editorial and People’s Choice top-prize winner:
Breakthrough of the Year: AI-Powered Predictions of Protein Structure
The biochemist Christian Anfinsen, who had a distinguished career at NIH, shared the 1972 Nobel Prize in Chemistry, for work suggesting that the biochemical interactions among the amino acid building blocks of proteins were responsible for pulling them into the final shapes that are essential to their functions. In his Nobel acceptance speech, Anfinsen also made a bold prediction: one day it would be possible to determine the three-dimensional structure of any protein based on its amino acid sequence alone. Now, with advances in applying artificial intelligence to solve biological problems—Anfinsen’s bold prediction has been realized.
But getting there wasn’t easy. Every two years since 1994, research teams from around the world have gathered to compete against each other in developing computational methods for predicting protein structures from sequences alone. A score of 90 or above means that a predicted structure is extremely close to what’s known from more time-consuming work in the lab. In the early days, teams more often finished under 60.
In 2020, a London-based company called DeepMind made a leap with their entry called AlphaFold. Their deep learning approach—which took advantage of 170,000 proteins with known structures—most often scored above 90, meaning it could solve most protein structures about as well as more time-consuming and costly experimental protein-mapping techniques. (AlphaFold was one of Science’s runner-up breakthroughs last year.)
This year, the NIH-funded lab of David Baker and Minkyung Baek, University of Washington, Seattle, Institute for Protein Design, published that their artificial intelligence approach, dubbed RoseTTAFold, could accurately predict 3D protein structures from amino acid sequences with only a fraction of the computational processing power and time that AlphaFold required [1]. They immediately applied it to solve hundreds of new protein structures, including many poorly known human proteins with important implications for human health.
The DeepMind and RoseTTAFold scientists continue to solve more and more proteins [1,2], both alone and in complex with other proteins. The code is now freely available for use by researchers anywhere in the world. In one timely example, AlphaFold helped to predict the structural changes in spike proteins of SARS-CoV-2 variants Delta and Omicron [3]. This ability to predict protein structures, first envisioned all those years ago, now promises to speed fundamental new discoveries and the development of new ways to treat and prevent any number of diseases, making it this year’s Breakthrough of the Year.
Anti-Viral Pills for COVID-19
The development of the first vaccines to protect against COVID-19 topped Science’s 2020 breakthroughs. This year, we’ve also seen important progress in treating COVID-19, including the development of anti-viral pills.
First, there was the announcement in October of interim data from Merck, Kenilworth, NJ, and Ridgeback Biotherapeutics, Miami, FL, of a significant reduction in hospitalizations for those taking the anti-viral drug molnupiravir [4] (originally developed with an NIH grant to Emory University, Atlanta). Soon after came reports of a Pfizer anti-viral pill that might target SARS-CoV-2, the novel coronavirus that causes COVID-19, even more effectively. Trial results show that, when taken within three days of developing COVID-19 symptoms, the pill reduced the risk of hospitalization or death in adults at high risk of progressing to severe illness by 89 percent [5].
On December 22, the Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for Pfizer’s Paxlovid to treat mild-to-moderate COVID-19 in people age 12 and up at high risk for progressing to severe illness, making it the first available pill to treat COVID-19 [6]. The following day, the FDA granted an EUA for Merck’s molnupiravir to treat mild-to-moderate COVID-19 in unvaccinated, high-risk adults for whom other treatment options aren’t accessible or recommended, based on a final analysis showing a 30 percent reduction in hospitalization or death [7].
Additional promising anti-viral pills for COVID-19 are currently in development. For example, a recent NIH-funded preclinical study suggests that a drug related to molnupiravir, known as 4’-fluorouridine, might serve as a broad spectrum anti-viral with potential to treat infections with SARS-CoV-2 as well as respiratory syncytial virus (RSV) [8].
Artificial Antibody Therapies
Before anti-viral pills came on the scene, there’d been progress in treating COVID-19, including the development of monoclonal antibody infusions. Three monoclonal antibodies now have received an EUA for treating mild-to-moderate COVID-19, though not all are effective against the Omicron variant [9]. This is also an area in which NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership has made big contributions.
Monoclonal antibodies are artificially produced versions of the most powerful antibodies found in animal or human immune systems, made in large quantities for therapeutic use in the lab. Until recently, this approach had primarily been put to work in the fight against conditions including cancer, asthma, and autoimmune diseases. That changed in 2021 with success using monoclonal antibodies against infections with SARS-CoV-2 as well as respiratory syncytial virus (RSV), human immunodeficiency virus (HIV), and other infectious diseases. This earned them a prominent spot among Science’s breakthroughs of 2021.
Monoclonal antibodies delivered via intravenous infusions continue to play an important role in saving lives during the pandemic. But, there’s still room for improvement, including new formulations highlighted on the blog last year that might be much easier to deliver.
CRISPR Fixes Genes Inside the Body
One of the most promising areas of research in recent years has been gene editing, including CRISPR/Cas9, for fixing misspellings in genes to treat or even cure many conditions. This year has certainly been no exception.
CRISPR is a highly precise gene-editing system that uses guide RNA molecules to direct a scissor-like Cas9 enzyme to just the right spot in the genome to cut out or correct disease-causing misspellings. Science highlights a small study reported in The New England Journal of Medicine by researchers at Intellia Therapeutics, Cambridge, MA, and Regeneron Pharmaceuticals, Tarrytown, NY, in which six people with hereditary transthyretin (TTR) amyloidosis, a condition in which TTR proteins build up and damage the heart and nerves, received an infusion of guide RNA and CRISPR RNA encased in tiny balls of fat [10]. The goal was for the liver to take them up, allowing Cas9 to cut and disable the TTR gene. Four weeks later, blood levels of TTR had dropped by at least half.
In another study not yet published, researchers at Editas Medicine, Cambridge, MA, injected a benign virus carrying a CRISPR gene-editing system into the eyes of six people with an inherited vision disorder called Leber congenital amaurosis 10. The goal was to remove extra DNA responsible for disrupting a critical gene expressed in the eye. A few months later, two of the six patients could sense more light, enabling one of them to navigate a dimly lit obstacle course [11]. This work builds on earlier gene transfer studies begun more than a decade ago at NIH’s National Eye Institute.
Last year, in a research collaboration that included former NIH Director Francis Collins’s lab at the National Human Genome Research Institute (NHGRI), we also saw encouraging early evidence in mice that another type of gene editing, called DNA base editing, might one day correct Hutchinson-Gilford Progeria Syndrome, a rare genetic condition that causes rapid premature aging. Preclinical work has even suggested that gene-editing tools might help deliver long-lasting pain relief. The technology keeps getting better, too. This isn’t the first time that gene-editing advances have landed on Science’s annual Breakthrough of the Year list, and it surely won’t be the last.
The year 2021 was a difficult one as the pandemic continued in the U.S. and across the globe, taking far too many lives far too soon. But through it all, science has been relentless in seeking and finding life-saving answers, from the rapid development of highly effective COVID-19 vaccines to the breakthroughs highlighted above.
As this list also attests, the search for answers has progressed impressively in other research areas during these difficult times. These groundbreaking discoveries are something in which we can all take pride—even as they encourage us to look forward to even bigger breakthroughs in 2022. Happy New Year!
References:
[1] Accurate prediction of protein structures and interactions using a three-track neural network. Baek M, DiMaio F, Anishchenko I, Dauparas J, Grishin NV, Adams PD, Read RJ, Baker D., et al. Science. 2021 Jul 15:eabj8754.
[2] Highly accurate protein structure prediction with AlphaFold. Jumper J, Evans R, Pritzel A, Green T, Senior AW, Kavukcuoglu K, Kohli P, Hassabis D. et al. Nature. 2021 Jul 15.
[3] Structural insights of SARS-CoV-2 spike protein from Delta and Omicron variants. Sadek A, Zaha D, Ahmed MS. preprint bioRxiv. 2021 Dec 9.
[5] Pfizer’s novel COVID-19 oral antiviral treatment candidate reduced risk of hospitalization or death by 89% in interim analysis of phase 2/3 EPIC-HR Study. Pfizer. 5 November 52021.
[6] Coronavirus (COVID-19) Update: FDA authorizes first oral antiviral for treatment of COVID-19. Food and Drug Administration. 22 Dec 2021.
[7] Coronavirus (COVID-19) Update: FDA authorizes additional oral antiviral for treatment of COVID-19 in certain adults. Food and Drug Administration. 23 Dec 2021.
[8] 4′-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replication. Sourimant J, Lieber CM, Aggarwal M, Cox RM, Wolf JD, Yoon JJ, Toots M, Ye C, Sticher Z, Kolykhalov AA, Martinez-Sobrido L, Bluemling GR, Natchus MG, Painter GR, Plemper RK. Science. 2021 Dec 2.
[9] Anti-SARS-CoV-2 monoclonal antibodies. NIH COVID-19 Treatment Guidelines. 16 Dec 2021.
[10] CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. Gillmore JD, Gane E, Taubel J, Kao J, Fontana M, Maitland ML, Seitzer J, O’Connell D, Walsh KR, Wood K, Phillips J, Xu Y, Amaral A, Boyd AP, Cehelsky JE, McKee MD, Schiermeier A, Harari O, Murphy A, Kyratsous CA, Zambrowicz B, Soltys R, Gutstein DE, Leonard J, Sepp-Lorenzino L, Lebwohl D. N Engl J Med. 2021 Aug 5;385(6):493-502.
[11] Editas Medicine announces positive initial clinical data from ongoing phase 1/2 BRILLIANCE clinical trial of EDIT-101 For LCA10. Editas Medicine. 29 Sept 2021.
Links:
Structural Biology (National Institute of General Medical Sciences/NIH)
The Structures of Life (NIGMS)
COVID-19 Research (NIH)
2021 Science Breakthrough of the Year (American Association for the Advancement of Science, Washington, D.C)
Encouraging News on Gene Therapy for Hemophilia A
Posted on by Dr. Francis Collins
About 20,000 people in the U.S. live with hemophilia A. It’s a rare X-linked genetic disorder that affects predominantly males and causes their blood to clot poorly when healing wounds. For some, routine daily activities can turn into painful medical emergencies to stop internal bleeding, all because of changes in a single gene that disables an essential clotting protein.
Now, results of an early-stage clinical trial, published recently in the New England Journal of Medicine, demonstrate that gene therapy is within reach to produce the essential clotting factor in people with hemophilia A. The results show that, in most of the 18 adult participants, a refined gene therapy strategy produced lasting expression of factor VIII (FVIII), the missing clotting factor in hemophilia A [1]. In fact, gene therapy helped most participants reduce—or, in some cases, completely eliminate—bleeding events.
Currently, the most-common treatment option for males with hemophilia A is intravenous infusion of FVIII concentrate. Though infused FVIII becomes immediately available in the bloodstream, these treatments aren’t a cure and must be repeated, often weekly or every other day, to prevent or control bleeding.
Gene therapy, however, represents a possible cure for hemophilia A. Earlier clinical trials reported some success using benign adeno-associated viruses (AAVs) as the vector to deliver the therapeutic FVIII gene to cells in the liver, where the clotting protein is made. But after a year, those trial participants had a marked decline in FVIII expression. Follow-up studies then found that the decline continued over time, thought to be at least in part because of an immune response to the AAV vector.
In the new study, an NIH-funded team led by Lindsey George and Katherine High of the Children’s Hospital of Philadelphia and the University of Pennsylvania, tested their refined delivery system. High is also currently with Asklepios BioPharmaceutical, Inc., Chapel Hill, NC. (Back in the 1970s, she and I were medical students in the same class at the University of North Carolina.) The study was also supported by Spark Therapeutics, Philadelphia.
Trial participants received a single infusion of the novel recombinant AAV-based gene therapy called SPK-8011. It is specifically designed to produce FVIII expression in the liver. In this phase 1/2 clinical trial, which evaluates the safety and initial efficacy of a treatment, participants received one of four different doses of SPK-8011. Most also received steroids to prevent or treat the presumed counterproductive immune response to the therapy.
The researchers followed participants for a year after the experimental treatment, and all enrolled in a follow-up trial for continued observation. During this time, researchers detected no major safety concerns, though several patients had increases in blood levels of a liver enzyme.
The great news is all participants produced the missing FVIII after gene therapy. Twelve of the 16 participants were followed for more than two years and had no apparent decrease in clotting factor activity. This is especially noteworthy because it offers the first demonstration of multiyear stable and durable FVIII expression in individuals with hemophilia A following gene transfer.
Even more encouraging, the men in the trial had more than a 92 percent reduction in bleeding episodes on average. Before treatment, most of the men had 8.5 bleeding episodes per year. After treatment, those events dropped to an average of less than one per year. However, two study participants lost FVIII expression within a year of treatment, presumably due to an immune response to the therapeutic AAV. This finding shows that, while steroids help, they don’t always prevent loss of a therapeutic gene’s expression.
Overall, the findings suggest that AAV-based gene therapy can lead to the durable production of FVIII over several years and significantly reduce bleeding events. The researchers are now exploring possibly more effective ways to control the immune response to AAV in expansion of this phase 1/2 investigation before pursuing a larger phase 3 trial. They’re continuing to monitor participants closely to establish safety and efficacy in the months and years to come.
On a related note, the recently announced Bespoke Gene Therapy Consortium (BGTC), a partnership between NIH and industry, will expand the refined gene therapy approach demonstrated here to more rare and ultrarare diseases. That should make these latest findings extremely encouraging news for the millions of people born with other rare genetic conditions caused by known alterations to a single gene.
Reference:
[1] Multiyear Factor VIII expression after AAV Gene transfer for Hemophilia A. George LA, Monahan PE, Eyster ME, Sullivan SK, Ragni MV, Croteau SE, Rasko JEJ, Recht M, Samelson-Jones BJ, MacDougall A, Jaworski K, Noble R, Curran M, Kuranda K, Mingozzi F, Chang T, Reape KZ, Anguela XM, High KA. N Engl J Med. 2021 Nov 18;385(21):1961-1973.
Links:
Hemophilia A (National Center for Advancing Translational Sciences/NIH)
FAQ About Rare Diseases (National Center for Advancing Translational Sciences/NIH)
Bespoke Gene Therapy Consortium (BGTC) (NIH)
Accelerating Medicines Partnership® (AMP®) (NIH)
Lindsey George (University of Pennsylvania, Philadelphia)
Katherine High (University of Pennsylvania)
NIH Support: National Heart, Lung, and Blood Institute
Single-Cell Study Offers New Clue into Causes of Cystic Fibrosis
Posted on by Dr. Francis Collins
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).
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
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