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Enduring severe anemia and excruciating pain attacks since childhood, Saritee Sanodiya finally had a diagnosis at 21 years of age.
Credit: Alisha Vasudev
Sanodiya has sickle cell disease. Despite India having one of the highest prevalences of sickle cell disease in the world, cases like Sanodiya’s can go undiagnosed or remain misdiagnosed for years.
Credit: Alisha Vasudev
She remains plagued by the disease's symptoms; now her government is investing in developing new treatments, in addition to raising awareness about the disease and screening more people.
India has one of the highest prevalences of sickle cell disease in the world, and many of those affected are people from tribal communities and other historically disadvantaged groups. Recently approved gene therapies for sickle cell disease are an exciting new treatment option, but their price tags mean they are out of reach for health-care systems and individuals in lower- and middle-income countries. Researchers in India are now trying to develop similar gene therapies locally to serve people with severe sickle cell disease.
Saritee Sanodiya, 26, has spent countless days wondering if she’ll ever live a “normal” life. Growing up, Sanodiya often missed school, frequenting the hospital for sudden, life-threatening drops in her hemoglobin levels and excruciating pain in her joints. High fever, severe headache, extreme fatigue, and difficulty breathing often accompanied these crises, which lasted days—occasionally weeks. “It would come out of nowhere,” she says. “The pain is hard to describe, but it’s unbearable. Sometimes you lose the desire to live.”
In hospitals, doctors would treat the anemia with blood transfusions and prescribe painkillers to relieve the acute body aches. The symptoms would subside, but within months, they would come roaring back.
In the hope that someone could find and fix the problem, Sanodiya’s mother took her to different doctors in and around their village of Jamuniya in the central Indian state of Madhya Pradesh, to no avail. The crises continued into Sanodiya’s adolescence, and they were often preceded by jaundice—a condition easily recognized by the yellowing of the skin and whites of the eyes.
Finally, in 2018, an answer came. The anemia and medical history prompted an obstetrician to order a blood test for sickle cell disease during Sanodiya’s first pregnancy checkup. The test turned up positive, meaning a genetic mutation was causing her body to produce several crescent-shaped red blood cells in addition to the normal, round ones. But the disease was a surprise to Sanodiya. “I’d never heard of it,” she says.
The pain is hard to describe, but it’s unbearable. Sometimes you lose the desire to live.
Saritee Sanodiya, a 26-year-old who has severe sickle cell disease
The deformed cells in sickle cell disease are stiff and sticky and can clog tiny arteries and veins. They block the flow of blood—and thus oxygen—to various parts of the body, causing debilitating pain and progressive damage to organs including the brain, liver, kidneys, heart, lungs, and joints. And unlike normal blood cells, which have a lifespan of about 120 days, sickle cells die within 10–20 days.
When fewer blood cells circulate, anemia prevails. Meanwhile, the liver’s blood filtration capabilities struggle to keep pace with the volume of dying sickle cells. A breakdown by-product—bilirubin—begins to build up and cause jaundice.
Normal red blood cells flow freely within blood vessel
Normal hemoglobin
Abnormal hemoglobin forms strands that cause sickle shape
Sickle cells block blood flow
Normal hemoglobin
These blood cells contain healthy hemoglobin that carries oxygen to various parts of the body.
The birth of C-shaped cells
In patients with sickle cell disease—a genetic blood disorder—round blood cells turn into crescent shaped ones.
Abnormal hemoglobin
A mutation allows for the production of abnormal (sickle) hemoglobin in blood cells causing them to become deformed. These sickle cells are stiff and sticky and can clog tiny arteries and veins.
In 2023, US and UK regulators approved two gene therapies for treating sickle cell disease—the first of their kind for this disorder. While they have side effects and potential risks, the outcomes seem promising so far, says Alexis Thompson, the chief of the Division of Hematology at the Children’s Hospital of Philadelphia. But a price tag of as much as $3 million per patient makes these treatments unaffordable for most people or health-care systems in the world.
Credit: Alisha Vasudev
Molecular biologist Debojyoti Chakraborty is codeveloping a gene therapy for people with severe sickle cell disease.
In a quest to make such revolutionary therapies accessible to people with sickle cell disease in India, research teams in the country are trying to develop the technology locally. They want to serve a population that experiences one of the highest prevalences of this disease in the world but that wasn’t represented in the clinical trials for the recently approved gene therapies. The teams also hope to make these treatments available at much lower costs.
“We’re still far from it,” says Debojyoti Chakraborty, a molecular biologist at the Institute of Genomics and Integrative Biology in Delhi, who coleads a team developing a gene therapy for sickle cell disease. “But things are moving in the right direction.”
What’s at stake
Every day since Sanodiya’s diagnosis, aside from the months she was pregnant with her two kids, she has been taking hydroxyurea pills, the most widely used oral drug for treating sickle cell disease. It helps keep red blood cells round and flexible, reducing the number of sickle-shaped cells in the bloodstream.
Although not curative, a daily use of hydroxyurea can decrease pain episodes and minimize the need for blood transfusions and hospital visits. While many patients benefit from using the drug, “not every patient responds equivalently,” says Vijay Sankaran, a physician and scientist who studies the genetic underpinnings of blood disorders at Boston Children’s Hospital and Harvard Medical School.
Sanodiya, for instance, remains plagued by the disease’s harrowing symptoms. In April, while sitting in her family’s one-bedroom home in Bhilai—an industrial city in central India—her eyes were visibly yellow. In her hands was a stack of medical records including discharge summaries from recent hospitalizations for pain attacks, chest X-rays that tracked her lung health, blood reports indicating anemia and liver dysfunction, and medication prescriptions. “Only another sickle cell patient can possibly relate to this plight,” she says.
While doctors are cautiously trying to increase Sanodiya’s hydroxyurea dose, a curative option for patients with severe sickle cell disease is a bone marrow transplant. The procedure involves replacing abnormal stem cells residing in the patient’s bone marrow with healthy ones from a matched donor—typically siblings. But a well-matched donor is very hard to find, says Dibyendu De, a hematologist at the Balco Medical Center in Raipur, India. Also, most people can’t afford this treatment without financial help or government subsidies. That’s certainly true for Sanodiya, whose family is now in debt because of expenses incurred for urgent care at a private hospital.
In search of a better cure
For years, researchers looking for better treatments for sickle cell disease and another inherited blood disorder, β thalassemia, have focused on increasing fetal hemoglobin (HbF) levels. These are high at birth but decrease as children grow up, and adult hemoglobin largely replaces the fetal form. But the bone marrow in people with sickle cell disease typically produces an abnormal form of hemoglobin instead of normal adult hemoglobin. Increasing the amount of HbF helps stop the polymerization of this sickle hemoglobin, resulting in less-severe disease symptoms and a longer life.
To safely target BCL11A for sickle cell disease, the team members identified a region within the gene that’s crucial for BCL11A expression specifically in red blood cells. They used CRISPR gene-editing tools to introduce a cut in this region and disrupt the DNA sequence, thus dialing down the expression of BCL11A and so enhancing HbF production.
It’s a roundabout approach, says Stuart Orkin, a physician and stem cell biologist at Boston Children’s Hospital and Harvard Medical School whose laboratory led the BCL11A research. But it resulted in one of the first approved gene therapies for sickle cell disease.
Called Casgevy, the treatment was developed by CRISPR Therapeutics and Vertex Pharmaceuticals. It involves removing blood-producing stem cells from the bone marrow, cutting both DNA strands at the precise location in the BCL11A gene, and infusing these edited cells back into the patient. The therapy raises HbF levels in adult red blood cells to about 30–40%. Clinical trials showed that 29 out of 30 people who underwent the treatment did not have severe crisis episodes for at least 12 months, and none required hospitalization.
How patients will fare in the long term remains to be seen. “But the therapy isn’t benign,” Sankaran says. Patients must undergo intensive chemotherapy to clear native stem cells and make room for the corrected ones. This process, called conditioning, can cause infertility. Patients also have a small but increased risk of developing blood cancer.
In 2023 and 2024, regulatory agencies in Bahrain, Europe, Saudi Arabia, the US, and the UK approved at least one of these therapies for people aged 12 years and older with severe sickle cell disease. But the therapies are expensive and take a long time to manufacture and administer. The course of treatment can last up to a year.
“We’ll be lucky if we treat 20-50 sickle cell disease patients in 2025 in the US using gene therapy,” says Akshay Sharma, a pediatric hematologist at St. Jude Children’s Research Hospital who has conducted clinical trials for sickle cell disease treatments, including Casgevy.
And the approved gene therapies are unlikely to reach patients in lower- or middle-income countries, where the disease is most prevalent. “These companies are not interested in running trials in Africa, India, or Brazil,” Sharma says. “They’re not going to be able to charge $2–$3 million there; they’re not going to make a profit out of it, and so they don’t want to do it.” Bringing gene therapies to those regions means “it’ll have to come from individuals who are working in those countries,” he says.
And it’s not just the costs. “If we don’t start to understand how they [gene therapies] are going to interface with the biology of cells and genetics in different populations, we’re killing time thinking that we’ve got something that’s going to be a one shot fits all,” says Jennifer Adair, co-founder of the Global Gene Therapy Initiative.
Neglect no more
The mutation for sickle cell disease evolved to help humans in malaria hot spots survive the infection. Scientists have shown that sickle cells aren’t conducive for the growth of the parasite that causes malaria. Estimates suggest that more than half of the world’s sickle cell disease population lives in three countries—Nigeria, the Democratic Republic of the Congo, and India. As in many other parts of the world, the disease remained neglected in India for decades.
Health-care providers’ lack of awareness means that individuals can go undiagnosed or be misdiagnosed for years, says Dipty Jain, a sickle cell disease expert at the Shalinitai Meghe Medical College in Nagpur, India. That lack of awareness also makes it difficult to measure the true burden of sickle cell disease in India. Some estimates suggest that more than 1 million people may be affected—many of whom are people from tribal communities and other historically disadvantaged groups known as “scheduled castes” and “other backward classes.”
That pattern may be because malaria was rampant in areas where some of these communities resided, and hence they carry the mutation. Also, India’s age-old practice of marrying within one’s own community or caste—a system historically rooted in maintaining social hierarchies and segregation—creates more opportunities for two people who are carriers of the sickle cell mutation to give birth to a child who has sickle cell disease. But this disease doesn’t just occur in tribal or other marginalized groups, Jain says. Another challenge was limited attention from the global health community, which considered sickle cell disease in India to be mainly mild, says Frédéric Piel, an epidemiologist at Imperial College London studying the health burden of sickle cell disease. But Jain, for example, has observed severe symptoms among many patients in central India. “That perception has changed,” Jain says, “but it took a long time to convince the [global] health community.”
On the ground, however, “there’s still a lack of seriousness among some doctors when it comes to this disease,” says Gautam Dongre, secretary of the nonprofit National Alliance of Sickle Cell Organizations in India. Because people with sickle cell disease show up frequently to health-care centers for their recurring pain attacks, doctors and nurses may minimize their pain and not prioritize them for emergency care. “The trouble is that the crisis is unfolding internally and affecting the whole body, but it isn’t [always] visible on the outside,” Dongre says.
What makes the disease even more invisible is how it pushes people to withdraw from society. For Jitendra Kumar Sahu, quitting high school was his only choice, despite his desire to study. Sahu was often sick from the sickle cell attacks, so he barely made it to school a few months every year. He rarely participated in sports or other extracurricular activities that were physically demanding, and the disease’s damage to his hip was so grave that he needed a hip replacement.
In April, the 21-year-old had just had that surgery and was recuperating. “I feel sad,” he says about needing a hip replacement at such a young age. Sometimes, Sahu says, he also feels disheartened about the future, as he may not be able to work. He worries about how his family—which is currently in debt because of his medical expenses—will cope financially.
Credit: Alisha Vasudev
Twenty-one-year-old Jitendra Kumar Sahu recently underwent hip replacement surgery because sickle cell disease caused severe damage to his hip joint.
The disease also carries social stigma. Parents of many young adults—especially women—worry that marriage prospects may be hard to come by for their children with sickle cell disease. For some families, that fear could cause them to not disclose the disease status or avoid conversation about what it’s like to live with the symptoms.
In some other cases, stigma comes from believing that sickle cell disease occurs only among people from socially disadvantaged groups. If a person outside that community is diagnosed with the disease, “they feel embarrassed, scared, and either don’t acknowledge it or don’t seek treatment,” Dongre says.
The disease’s mental health burden is an ongoing challenge. The struggle to cope with a lifelong illness, the lack of support socially and in health-care settings, and the financial woes can all contribute to people feeling frustrated, anxious, and depressed. Two of Dongre’s colleagues who had sickle cell disease recently died by suicide, he says. For Dongre, there’s much more that needs to be done to support patients and their families.
In July 2023, the Indian government launched a mission to curb sickle cell disease’s passage to next generations and mostly eliminate its prevalence by 2047. One of the mission’s goals is to increase awareness and, by 2026, screen 70 million people in 17 states where sickle cell disease is prevalent.
India’s all-female, million-plus group of community health workers called accredited social health activists, or ASHAs (a Hindi word meaning “hope”) is key for spreading awareness and meeting these screening targets, particularly in rural India. In Julum, a village in the central Indian state of Chhattisgarh, for example, ASHA workers have been conducting sickle cell testing nearly weekly for the past 3–4 months. Lata Verma, an ASHA worker since 2002, says many people in the village are carriers of the trait, meaning they have one copy of the sickle cell gene and are symptom-free. A small percentage have two copies of the gene and experience disease symptoms.
Credit: Alisha Vasudev
India’s community health-care workers are key to ensuring 70 million people in 17 states are screened for sickle cell disease by 2026—a goal the country’s government set.
Credit: Alisha Vasudev
In India’s Julum village, residents gather to get tested for sickle cell disease.
Credit: Alisha Vasudev
Community health-care workers use a rapid test to detect the presence of abnormal (sickle) hemoglobin. If that test is positive, they conduct a lateral flow test to check if the blood sample indicates a sickle cell carrier or a person with sickle cell disease.
Credit: Alisha Vasudev
In the (rapid) solubility test, presence of sickle cells will make the prepared solution–a mixture of an individual's blood sample and a buffer–turn cloudy. But false negatives occur in severe anemia cases or in people with high HbF levels.
Credit: Alisha Vasudev
Indu Sahu trains community health-care workers to conduct sickle cell blood tests in Julum, India, and nearby towns.
Going forward, premarital or prenatal screening will be key, says Jain, who is a nodal officer in the national sickle cell elimination mission. The government wants to make genetic counseling readily available to help prospective partners and parents understand the compatibility of their genes and chances of passing on sickle cell disease. Another aim is to ensure treatments and quality care, including hydroxyurea and blood transfusions, are accessible and affordable for patients. These treatment options aren’t within easy reach for many people—especially those living in rural parts of the country.
Thaneshwar Kumar Sahu’s wife and two young kids have sickle cell disease, and the family lives in Pond-Paduka village in Chhattisgarh. Sahu travels to Raipur, a city that’s about 2 h away, to get 1 month’s worth of hydroxyurea for his family. Sometimes a pharmacist he knows in Raipur will ship the medication to his hometown. “It would make things much easier if the medicine was available locally,” he says.
Credit: Alisha Vasudev
Thaneshwar Kumar Sahu must travel about 2 h each way to get hydroxyurea—the most widely used oral drug for treating sickle cell disease—for his wife and two young children.
As part of the mission, the government plans to identify and upgrade some tertiary care centers in the 17 states to make bone marrow transplant services available to eligible patients. But some officials are hoping for a more effective solution: an Indian-developed gene therapy to treat sickle cell disease.
Targeting the mutation
In April, in a corner room on the second floor of the Chandulal Chandrakar Memorial Government Medical College in Durg, Chhattisgarh, about 25 people with sickle cell disease were seated with their families. Some lived in the vicinity, while others traveled 2–4 h to get there.
They had gathered to meet with Chakraborty and Souvik Maiti, a chemist at the Institute of Genomics and Integrative Biology who coleads one of the CRISPR-based gene-editing projects in India. The pair were there to keep the attendees abreast of the therapy they’re developing in the laboratory and testing in mice. If all goes well, the team hopes to start a human clinical trial in 2025 and recruit three to five people from Chhattisgarh for the first phase of the study.
“We’re trying to cure this disease you’re grappling with by targeting its root cause,” Chakraborty told the crowd. “That’s our goal.”
Credit: Alisha Vasudev
Scientists Debojyoti Chakraborty (center) and Souvik Maiti (not pictured) met with people who have sickle cell disease to acquaint them and their families with the gene therapy the duo are developing.
“If you correct the sickle cell mutation, you convert that [person] into a sickle cell carrier,” he says. That change would make people with sickle cell disease who receive these edited cells asymptomatic.
For its CRISPR editor, the team has created an engineered form of FnCas9 rather than opting for the more commonly used SpCas9 protein. In a 2019 study, the researchers reported the superior specificity with which FnCas9—in its untweaked form—can bind to a region of the DNA that needs to be edited. But the protein lacked efficiency. So the team engineered this protein to retain its specificity and increase its efficiency.
As proof of concept, the researchers used the engineered protein to correct a mutation for a rare genetic eye disorder in the laboratory in human cells. The researchers also used the engineered FnCas9-based therapy to correct the mutation for sickle cell disease in mice, and the results are encouraging, Maiti says. These results are yet to be published.
The team has patented the engineered FnCas9 in the US. “The patent now allows us to license this CRISPR system,” Chakraborty says, which he believes could motivate Indian biotechnology companies to one day bring this therapy to market. The researchers hope that the treatment could be made available for about $60,000, which is a lot less than existing gene therapies but still unaffordable for many people in India. Chakraborty reckons that government-sponsored schemes for treating rare diseases could largely cover those costs.
Similar to the currently approved therapies, the treatment process would entail the use of a mobilizing drug to draw stem cells out of a patient’s bone marrow into their blood, which clinicians would collect and send to the researchers to modify while the patient underwent chemotherapy to kill remaining bone marrow stem cells.
At the session in Durg, Chakraborty told patients about the benefits that people with severe sickle cell disease experienced after being treated with Casgevy or Lyfgenia. He also informed them about fertility problems that can arise from undergoing chemotherapy. “You’ll have to make this decision very thoughtfully,” he said: “whether to be disease-free or to plan a family.” (Patients will have access to fertility preservation options before receiving this therapy in a clinical trial.)
Chakraborty also pointed out that these gene therapies are new, so it’s hard to know whether people continue to feel well and if they’re fully cured. He mentioned Victoria Gray, the first patient to receive a gene therapy for sickle cell disease, in 2018, as part of the Casgevy trial.
More than 5 years on, Gray remains free of severe pain episodes and hasn’t had to be admitted to the hospital. “I haven’t had a blood transfusion, I haven’t had a crisis, and I’m not attached to a medicine basket,” she says. “I feel free and not just existing in this life anymore. I’m thriving and actually enjoying my life now.”
Eighteen-year-old Deepak Kumar Sahu hopes to live a life free from severe pain too one day. After attending the session in Durg, he and his father left feeling somewhat optimistic. “The difficulties our son has faced, we as parents have faced, we don’t want any other family to experience that,” says Hemlal Sahu, Deepak’s father. “We must come forward to support such research.”
Credit: Alisha Vasudev
Hemlal Sahu (left) and his son Deepak Kumar Sahu (right), who has sickle cell disease, attend the gene therapy information session in Durg, India.
The team led by Chakraborty and Maiti isn’t the only one developing a gene therapy for sickle cell disease in India. Scientists at the Christian Medical College, Vellore, have been collaborating with Emory University to test a gene addition approach similar to Lyfgenia’s by delivering the correct genes to express healthy adult hemoglobin or fetal hemoglobin. These therapies seem to alleviate symptoms of the disease in mice. The researchers are also developing a CRISPR-based gene-editing technology.
“There are now companies [in India] that we’re talking to and others that are interested in actually making the gene therapeutic products, but it’s not there yet,” says Trent Spencer, director of the Cell and Gene Therapy Program at the Emory University School of Medicine.
Meanwhile, in February, the German biotechnology company Miltenyi Biotec announced that it is setting up a center in India for cell and gene therapies. The company wants to help Indian researchers by providing hands-on training, access to expertise, and manufacturing help. It is also collaborating with the Translational Health Science and Technology Institute to develop gene therapies with a particular focus on cancer and sickle cell disease.
Hope for a less costly future
In the US, researchers are now conducting clinical trials to test if Casgevy and Lyfgenia work just as well in children younger than 12 years old. These studies are particularly important given that sickle cell disease is the 12th leading cause of death in kids less than 5 years old globally.
Many scientists in different parts of the world who are focused on gene therapies are also trying to find better targets than BCL11A to increase HbF levels. Similar to what Chakraborty and Maiti are doing, they’re also working toward correcting the underlying mutation that causes sickle cell disease. And to make treatments safer, researchers are seeking ways to bypass chemotherapy. Still, any gene therapy will be hard to scale. “If the objective is to get the burden of the disease down, you really need in vivo therapies, or you need a better pill,” Orkin of Boston Children’s Hospital says.
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An in vivo gene therapy would entail getting corrected genes to the right cells in the body directly, without having to take the cells out, edit the DNA, and put them back. In a recent proof-of-concept study, researchers at the Children’s Hospital of Philadelphia and University of Pennsylvania used lipid nanoparticles studded with antibodies capable of recognizing specific cell receptors to transport gene-editing tools to blood stem cells in mice. The team found that its one-and-done approach, which didn’t require chemotherapy or stem cell transplantation, hugely increased the production of healthy hemoglobin, and almost no new sickle cells formed in the blood.
“It’s very exciting, but it’s still very preliminary,” says Thompson, the chief of the Division of Hematology at the Children’s Hospital of Philadelphia. “It could be the approach that might level the playing field and make these therapies available to more people.”
But Spencer warns that the in vivo approach is a very challenging one. “It’s hard enough just changing genetics when you take cells out of a person; selectively engineering cells when they’re still in the person is still really, really complicated,” he says. “But 10 years from now, who knows what it’s going to look like.”
Sankaran, on the other hand, argues that focusing heavily on gene therapies to treat sickle cell disease could take away from developing oral drugs that are better than hydroxyurea. Small-molecule drugs are a lot more cost effective and accessible than gene therapies, he says.
Since 2017, the US Food and Drug Administration has approved a monoclonal antibody injection called crizanlizumab and two new oral drugs, voxelotor and L-glutamine, to treat sickle cell disease. Like hydroxyurea, these aren’t curative, and they aren’t readily accessible globally.
“We still think of hydroxyurea as probably being the most effective medication that we have,” Sankaran says.
Meanwhile, for many people with sickle cell disease in India, the work done by researchers like Chakraborty and Maiti offers a glimmer of hope. “That our scientists are trying to develop a cure in itself is a huge thing for patients like me and for future generations,” Sanodiya says.
Editor's note: Priyanka Runwal conducted interviews for this story in English, Hindi, and Marathi.
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