NIH Clinical Center
Posted on by Dr. Francis Collins
Recently, CBS’s “60 Minutes” highlighted the story of Jennelle Stephenson, a brave young woman with sickle cell disease (SCD). Jennelle now appears potentially cured of this devastating condition, thanks to an experimental gene therapy being tested at the NIH Clinical Center in Bethesda, MD. As groundbreaking as this research may be, it’s among a variety of innovative strategies now being tried to cure SCD and other genetic diseases that have long seemed out of reach.
One particularly exciting approach involves using gene editing to increase levels of fetal hemoglobin (HbF) in the red blood cells of people with SCD. Shortly after birth, babies usually stop producing HbF, and switch over to the adult form of hemoglobin. But rare individuals continue to make high levels of HbF throughout their lives. This is referred to as hereditary persistence of fetal hemoglobin (HPFH). (My own postdoctoral research in the early 1980s discovered some of the naturally occurring DNA mutations that lead to this condition.)
Individuals with HPFH are entirely healthy. Strikingly, rare individuals with SCD who also have HPFH have an extremely mild version of sickle cell disease—essentially the presence of significant quantities of HbF provides protection against sickling. So, researchers have been exploring ways to boost HbF in everyone with SCD—and gene editing may provide an effective, long-lasting way to do this.
Clinical trials of this approach are already underway. And new findings reported in Nature Medicine show it may be possible to make the desired edits even more efficiently, raising the possibility that a single infusion of gene-edited cells might be able to cure SCD .
Sickle cell disease is caused by a specific point mutation in a gene that codes for the beta chain of hemoglobin. People with just one copy of this mutation have sickle cell trait and are generally healthy. But those who inherit two mutant copies of this gene suffer lifelong consequences of the presence of this abnormal protein. Their red blood cells—normally flexible and donut-shaped—assume the sickled shape that gives SCD its name. The sickled cells clump together and stick in small blood vessels, resulting in severe pain, anemia, stroke, pulmonary hypertension, organ failure, and far too often, early death.
Eleven years ago, a team led by Vijay Sankaran and Stuart Orkin at Boston Children’s Hospital and the Dana-Farber Cancer Institute discovered that a protein called BCL11A seemed to determine HbF levels . Subsequent work showed the protein actually works as a master mediator of the switch from fetal to adult hemoglobin, which normally occurs shortly after birth.
Five years ago, Orkin and Daniel Bauer identified a specific enhancer of BCL11A expression that could be an attractive target for gene editing . They could knock out the enhancer in the bone marrow, and BCL11A would not be produced, allowing HbF to stay switched on.
Because the BCL11A protein is required to turn off production of HbF in red cells. the researchers had another idea. They thought it might be possible to keep HbF on permanently by disrupting BCL11A in blood-forming hematopoietic stem cells (HSCs). The hope was that such a treatment might offer people with SCD a permanent supply of healthy red blood cells.
Fast-forward to the present, and researchers are now testing the ability of gene editing tools to cure the disease. A favorite editing system is CRISPR, which I’ve highlighted on my blog.
CRISPR is a highly precise gene-editing tool that relies on guide RNA molecules to direct a scissor-like Cas9 enzyme to just the right spot in the genome to correct the misspelling. The gene-editing treatment involves removing bone marrow from a patient, modifying the HSCs outside the body using CRISPR gene-editing tools, and then returning them back to the patient. Preclinical studies had shown that CRISPR can be effective in editing BCL11A to boost HbF production.
But questions lingered about the editing efficiency in HSCs versus more common, shorter-lived progenitor cells found in bone marrow samples. The efficiency greatly influences how long the edited cells might benefit patients. Bauer’s team saw room for improvement and, as the new study shows, they were right.
To produce lasting HbF production, it’s important to edit as many HSCs as possible. But it turns out that HSCs are more resistant to editing than other types of cells in bone marrow. With a series of adjustments to the gene-editing protocol, including use of an optimized version of the Cas9 protein, the researchers showed they could push the number of edited genes from about 80 percent to about 95 percent.
Their studies show that the most frequent Cas9 edits in HSCs are tiny insertions of a single DNA “letter.” With that slight edit to the BCL11A gene, HSCs reprogram themselves in a way that ensures long-term HbF production.
As a first test of their CRISPR-edited human HSCs, the researchers carried out the editing on HSCs derived from patients with SCD. Then they transferred the editing cells into immune-compromised mice. Four months later, the mice continued to produce red blood cells that produced high levels of HbF and resisted sickling. Bauer says they’re already taking steps to begin testing cells edited with their optimized protocol in a clinical trial.
What’s truly exciting is that the first U.S. human clinical trials of such a gene-editing approach for SCD are already underway, led by CRISPR Therapeutics/Vertex Pharmaceuticals and Sangamo Therapeutics/Sanofi. In January, CRISPR Therapeutics/Vertex Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) had granted Fast Track Designation for their CRISPR-based treatment called CTX001 .
In that recent “60 Minutes” segment, I dared to suggest that we now have what looks like a cure for SCD. As shown by this new work and the clinical trials underway, we in fact may soon have multiple different strategies to provide cures for this devastating disease. And if this can work for sickle cell, a similar strategy might work for other genetic conditions that currently lack any effective treatment.
 Highly efficient therapeutic gene editing of human hematopoietic stem cells. Wu Y, Zeng J, Roscoe BP, Liu P, Yao Q, Lazzarotto CR, Clement K, Cole MA, Luk K, Baricordi C, Shen AH, Ren C, Esrick EB, Manis JP, Dorfman DM, Williams DA, Biffi A, Brugnara C, Biasco L, Brendel C, Pinello L, Tsai SQ, Wolfe SA, Bauer DE. Nat Med. 2019 Mar 25.
 Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Sankaran VG, Menne TF, Xu J, Akie TE, Lettre G, Van Handel B, Mikkola HK, Hirschhorn JN, Cantor AB, Orkin SH.Science. 2008 Dec 19;322(5909):1839-1842.
 An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Bauer DE, Kamran SC, Lessard S, Xu J, Fujiwara Y, Lin C, Shao Z, Canver MC, Smith EC, Pinello L, Sabo PJ, Vierstra J, Voit RA, Yuan GC, Porteus MH, Stamatoyannopoulos JA, Lettre G, Orkin SH. Science. 2013 Oct 11;342(6155):253-257.
 CRISPR Therapeutics and Vertex Announce FDA Fast Track Designation for CTX001 for the Treatment of Sickle Cell Disease, CRISPR Therapeutics News Release, Jan. 4, 2019.
Sickle Cell Disease (National Heart, Lung, and Blood Institute/NIH)
Cure Sickle Cell Initiative (NHLBI)
What are Genome Editing and CRISPR-Cas9? (National Library of Medicine/NIH)
Could Gene Therapy Cure Sickle Cell Anemia? (CBS News)
Daniel Bauer (Dana-Farber Cancer Institute, Boston)
Somatic Cell Genome Editing Program (Common Fund/NIH)
NIH Support: National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences; National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases
Posted on by Dr. Francis Collins
There are nearly 7,000 rare diseases, some of which affect just a few dozen people. Yet, if one considers all these conditions together, about 30 million people in the United States have rare diseases. On this Rare Disease Day, I’d like to challenge each of you to think about how we can raise the visibility of individuals living with rare diseases, as well as the researchers working hard to help them.
I’d like to introduce you to Harper Spero, who is using her rare gift of storytelling to share the experiences of people with a wide variety of conditions that she likes to call “invisible illnesses.” Through her podcast series, called Made Visible, this 34-year-old New York City native is among the many people helping to spread the word that rare diseases are not rare.
Spero knows what it’s like to live with a rare disease. Shortly after she was born, it became clear that she was unusually prone to infections. But doctors had a hard time figuring out what exactly was wrong with this little girl. Finally, at the age of 10, Spero was diagnosed with Hyper-Immunoglobulin E Syndrome (HIES), also known as Job’s syndrome. There currently is no cure for this rare genetic disease, which impairs the immune system and affects multiple parts of the body. But Spero is determined to live a normal life despite her chronic “invisible illness.”
Spero also knows what it’s like to take part in biomedical research. Seven years ago, she came to the NIH Clinical Center here in Bethesda, MD, seeking help for a large cyst in her right lung. It marked the beginning of a positive partnership with a Job’s syndrome research team led by two of NIH’s many dedicated physician-scientists, Alexandra Freeman and Steven Holland. Not only did the NIH researchers work with Spero to figure out the best ways of managing her symptoms, they are using what they’ve learned from her and about 175 other Job’s syndrome patients to develop approaches for earlier diagnosis and interventions. Spero, who visits the Clinical Center annually and communicates with the NIH team on a weekly basis, has been so inspired by the experience that she even chose to feature Dr. Freeman in one of her recent podcasts.
Unlike Spero, I don’t have a podcast—at least not yet. But I do have a blog, and Spero was kind enough to respond to a few of my questions on rare diseases and medical research. So, I’m sharing her thoughts below—I hope you are inspired by them as much as I was!
Why do you feel it is important for people with rare diseases to take part in medical research?
Without research, we can’t make any improvements, changes or find cures. Participating in medical research allows researchers and doctors to learn about the trends (or lack of) between patients, and determine what’s working and what’s not.
What have your own experiences been with the health-care system and medical research?
When I was younger, I really didn’t want to be a specimen. I was going through so much trying to find answers and treatments for myself that it was hard to think about how it would help other patients down the road to be sharing my experiences. I didn’t want to add another doctor’s visit to my schedule. After coming to NIH in 2012, I recognized the importance of being part of the research because it could essentially help me, other patients and for early detection of rare diseases. I recognize that the medical researchers are often much more compassionate than many doctors who simply treat symptoms. Researchers are curious and genuinely care to understand you and your story.
Your podcast is fantastic. How has it affected you to hear and share the stories of so many people affected by rare diseases?
I was definitely aware how many people were living with rare diseases, but I was surprised by how many people were willing to share their stories on my show and how many people wanted to listen to these stories. I hadn’t heard stories being shared in this way around this topic and I wanted to be the one who brought them to life. Many of my guests haven’t publicly (let alone with friends or family) shared their stories so I’m honored that they’re willing to do it with me. They see how important it is to have these conversations and to educate people on what it’s like to have an invisible illness.
What would you tell someone who’s just learned he or she has a rare disease?
You don’t have to do this alone! Find a team of medical professionals you trust to support you. I spent most of my life without a team of doctors that I loved and truly understood me, and now I can’t imagine my life without my team at NIH. Also, talk to your loved ones—let them know what you’re feeling and discuss how they can support you. This is likely new for them too and there’s no right way of navigating and managing a rare disease.
What would you tell a young person who’s considering becoming a rare disease researcher?
Thank you for your interest in doing this! We need more compassionate, curious and passionate people doing this work and investing their time to learn more and help find answers for rare diseases. Please treat us with respect and care.
If you could change one thing in the medical care/research of rare disease, what would it be? And what about in society in general?
There’s a way to do your job without treating patients like guinea pigs. We’re humans too, and we’re humans who have likely been through the wringer in the medical world. Be kind to us. Treat us the way you’d like to be treated. Compassion seems to be a word I’m using a lot. I think society can be more compassionate towards one another especially around rare disease. You can never fully understand what someone is going through so ask questions, show you care and treat people with kindness.
What are your hopes for the future?
I’d love there to be more answers and solutions for navigating a rare disease. A lot of the treatments I do are based on trial-and-error. What works for one patient definitely doesn’t always work for me. So, we’re constantly trying to navigate what works best for me. I’d love to see a cure to be found for Hyper IgE/Job’s Syndrome, as well as other rare diseases.
Podcast Series: Made Visible
NIH Patient Shares Stories of ‘Invisible Illness,’ The NIH Record, February 8, 2019
Hyper-Immunoglobulin E Syndrome (HIES) (National Institute of Allergy and Infectious Diseases/NIH)
Rare Disease Day at NIH 2019 (National Center for Advancing Translational Sciences/NIH)
Video: Rare Disease Patient Profiles (NCATS)
Undiagnosed Diseases Network (Common Fund/NIH)
Video: One in a Million (Undiagnosed Diseases Network, University of Utah Health, Salt Lake City)