This microscope photo provided by the Centers for Disease Control and Prevention shows crescent-shaped red blood cells from a sickle cell disease patient.
| Photo Credit: AP

India is getting closer to developing a gene therapy for sickle cell disease, a genetic blood disorder with a high prevalence rate among the Scheduled Tribes, officials of the Union Tribal Affairs Ministry said on June 19.

Vibhu Nayyar, Secretary, of the Tribal Affairs Ministry, said the government was expecting to hear “good news” by January 2025 on the laboratory tests that are being run. M. Srinivas, Director of the All India Institute of Medical Sciences (AIIMS), said researchers were working to develop a gene therapy using CRISPR-Cas9, a gene-editing tool.

“We want that in the next six months to one year, we will be able to go forward with using this method for treating SCD — making India one of the first countries to do so,” Mr. Srinivas said.

He was speaking at the National Conclave on Generating Awareness on Sickle Cell Disease, organised by the Tribal Affairs Ministry in collaboration with the Birsa Munda Centre at the AIIMS.

Union Tribal Affairs Minister Jual Oram, addressing the opening of the conclave, lauded the efforts but said it was important to involve and coordinate with ground-level healthcare workers such as ASHAs and Anganwadi workers for these plans to be implemented properly.

“They will be the ones doing the heavy lifting on the ground,” Mr. Oram said.

Officials of the Tribal Affairs Ministry told The Hindu that the “good news” Mr. Nayyar was referring to was related to the tests that are currently being run by the Council of Scientific and Industrial Research–Institute of Genomics and Integrative Biology (CSIR-IGIB).

“Following this, the tests will proceed to the next phase and eventually move on to being tested on patients,” a senior official said.

This comes months after the U.S. Food and Drug Administration approved the CRISPR-Cas9 technology for a cell-based gene therapy to treat sickle cell disease in December 2023.

Officials of the Tribal Affairs Ministry said one of the main challenges for India was to find a way to make this therapy cost-effective.

Developing a gene therapy using CRISPR has been part of India’s mission to eradicate sickle cell disease by 2047. A government dossier on the mission, which was launched by Prime Minister Narendra Modi in July 2023, said the technology had “the potential to be a single dose cure for blood disorders like sickle cell anaemia”.

Part of this mission is to also conduct over seven crore screenings among vulnerable tribal populations across 17 States and Union Territories, of which three crore screenings have been achieved so far, Ministry officials said.

The CRISPR-Cas9 system consists of an enzyme that behaves like molecular scissors which can be directed to cut a piece of DNA at a precise location. This will then allow a guide RNA to insert a changed genetic code at the sites of the incision. While there are a few ways to effect such changes, the CRISPR system is believed to be fast and the most versatile of all.

Addressing the gathering of doctors, experts, and healthcare professionals, Mr. Oram said the Union government was committed to working on the sickle cell disease eradication mission and called for officials from across Ministries and departments to ensure that grassroots workers were roped in for the implementation process and that they should themselves engage with them.

Following the addresses by senior officials and the Minister, a series of technical panel discussions were also held on recognising and screening for sickle cell disease, managing the disease, and other issues. Officials said district centres at nearly 350 districts across the country were taking part in the conclave virtually.

Apart from the gene therapy being developed by India, the sickle cell disease eradication mission also includes developing two coded formulations — AYUSH-RP and AYUSH-SC3 — for managing the disease through a systemic drug development process, for which continued testing will be undertaken by the Central Council for Research in Ayurvedic Sciences in collaboration with the Indian Council of Medical Research.

Hearing loss is one of the most prevalent disorders and it is estimated that over one billion people suffer from hearing loss and approximately one-two children in every 1,000 births are born with congenital hearing loss. It is not therefore surprising that screening for newborns is an essential component of newborn screening programmes.

Hearing loss is a complex condition that can result from a variety of environmental and genetic factors including ear infections. Often, hearing loss serves as symptoms indicating defects or pathologies in the ear’s process that converts sound into electrical signals sent to the brain. It is widely estimated that a significant majority, amounting to approximately 50-60% of congenital hearing loss cases, are attributed to genetic causes. Among the various populations, genetic variants play a significant role. For example, mutations in the GJB2 gene are the most common genetic cause of hearing loss in Caucasian, Asian and Hispanic populations. In Africa, the MYO15A and ATP6V1B1 genes are more frequently implicated. In total, over two dozen genes have been linked to genetic causes of hearing loss. Besides genomic mutations, mitochondrial genetic defects can also lead to hearing impairment. Genetic variants could also play a role in the complex interplay with other factors, like medications. For instance, a prevalent genetic defect in the mitochondrial MTRNR1 gene can predispose individuals to hearing loss when administered with the aminoglycoside antibiotics, widely used in treatment of TB.

Correction of the gene defect underlies the genetic cause of hearing loss, and therefore gene therapy and genome editing have been touted as one of the possible emerging therapies for hereditary or genetic causes of deafness. Gene therapy typically involves replacing or supplementing a dysfunctional gene with normal or functional genes. There are a number of molecular approaches that have been widely used for such replacement or supplementation.

In addition to viral vectors, advanced non-viral methods are revolutionising gene therapy for genetic hearing loss. Lipid nanoparticles (LNPs) facilitate gene delivery by encapsulating nucleic acids and fusing with cell membranes, enabling efficient and targeted gene transfer. Electroporation employs controlled electrical pulses to transiently permeabilize the cell membrane, allowing direct uptake of genetic material. Cutting-edge genome editing technologies, such as CRISPR-Cas9, enable precise modification of specific DNA sequences through RNA-guided endonuclease activity, allowing targeted gene disruption or correction. These methodologies collectively enhance the potential for precise, efficient, and lasting correction of genetic defects underlying hearing loss. One of the widely used approaches involves viral vectors, which can package large pieces of genetic material required to be delivered inside the cell (referred to as cargo). Adeno-associated virus (AAV) is one of the most well-studied and widely used vectors for this purpose. AAV offers several advantages: it is a safe vector, as it does not cause human diseases, and it can infect both dividing and non-dividing cells, thus having a broad spectrum of cells it can target for genetic editing.

In a recent report published in Nature Medicine, Chinese researchers provide early promise towards using gene therapy for at least one genetic hearing loss. Researchers at the Fudan University, in collaboration with a number of research and clinical centres in China, proposed that gene therapy could effectively treat a form of genetic deafness involving the OTOF gene, known as hereditary deafness 9. Mutations in the OTOF gene account for approximately 2-8% of all genetic hearing loss cases. In this clinical trial, researchers employed Adeno-associated virus vectors with the intention of inserting a healthy OTOF gene into patients’ ears using a harmless virus. All patients experienced improved hearing in both ears. Initially performed on one ear, the study was expanded to test bilateral (both ears) therapy in five paediatric patients.

The researchers in the report suggest that no severe side effects were observed, while among the recorded 36-odd minor side effects, the most common were increased lymphocyte counts and cholesterol levels apart from an increase in lactate dehydrogenase levels, which is a marker for tissue damage in the body. Hearing tests showed significant improvement in all patients reported and all patients regained the ability to understand speech and locate sound sources. The promising results indicate that AAV gene therapy is safe and effective for treating hereditary deafness.

While the initial results are encouraging, Adeno-associated virus vectors come with their own set of caveats. The foremost being that our immune system can recognise and eliminate the virus making it less effective in individuals who are immunised, and also limits the re-administration of the gene therapy vector, since the primary administration would produce antibodies against the virus. Previous studies have suggested that approximately one-fifth to one-third of the patients have neutralising antibodies against AAV.

The present report is limited by the small number of patients studied and reported over a short follow-up period. However, it is encouraging that the clinical trial is ongoing and longer-term follow-up data of the patients would be available soon. While the results are encouraging and provide immense hope, we are not yet on a firm ground to assert that gene therapy for hearing loss is paving the way towards a sound future.

(Vinod Scaria is a consultant at Vishwanath Cancer Care Foundation, and Rahul Bhoyar is a senior scientist at Karkinos Healthcare. Opinions are personal)

Pfizer’s gene therapy trial for Duchenne muscular dystrophy resulted in a young patient’s death. File
| Photo Credit: Reuters

A young patient died due to cardiac arrest after receiving Pfizer’s experimental gene therapy being tested in a mid-stage trial for a muscle-wasting disorder called Duchenne muscular dystrophy(DMD), the drugmaker told Reuters on May 7.

“A fatal serious adverse event was reported as cardiac arrest for a participant in the Phase 2 DAYLIGHT study,” a company spokesperson told Reuters in an emailed response.

The trial is testing boys two to three years of age with Duchenne muscular dystrophy (DMD), a genetic muscle wasting disorder in which most patients lack the protein dystrophin which keeps muscles intact. The disorder affects an estimated one-in-3,500 male births worldwide.

“The patient received the investigational gene therapy, fordadistrogene movaparvovec, in early 2023,” as per a statement from a community letter attributed to the drugmaker’s DMD gene therapy team and posted by a nonprofit advocacy group.

Pfizer did not immediately respond to a Reuters request seeking confirmation on the community letter attributed to the company.

All participants will be followed in the study, for five years after treatment with gene therapy, initiated in August 2022 and estimated to complete in early 2029, as per information updated by the company on a registry of clinical trials.

The company said, together with the independent external data monitoring committee, it is in the process of reviewing the data to understand the potential cause.

The gene therapy candidate is also being tested in the another late-stage DMD study, called CIFFREO, in patients in boys 4 to less than 8 years of age, as per pipeline updates on the drugmaker’s website.

There is not an impact to our expectation of having late-stage results, the company told Reuters in its email.

“We anticipate potentially beginning the primary analysis of the Phase 3 CIFFREO trial of fordadistrogene movaparvovec at the end of this month and sharing top-line results relatively soon,” it added.

“We will each write a ghost story”, said Lord Byron; and his proposition was acceded to. And so on a cold and rainy supposedly summer night in 1816, four friends inspired by German ghost stories, gathered to write one. Among them, a young Mary Shelley, consumed by the idea of creating a story that would “curdle the blood” of her readers, ended up with a novel titled Frankenstein.

With Frankenstein 200 years in the past, the possibility of creating such life is a reality. With the first gene editing technology securing approval for the treatment of sickle cell anemia and beta-thalassemia, we transcend into a new revolutionary phase. The possibilities are endless.

(For top health news of the day, subscribe to our newsletter Health Matters)

Casgevy and Lyfgenia, the two cell-based gene therapies approved by the Food and Drug Administration (FDA) for sickle cell anemia treatment and beta-thalassemia utilise the Nobel-winning CRISPR/Cas 9 genome editing technology.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), a feature of the bacterial immune system, forms the basis for this technology. In a nutshell, the system in bacteria serves as a warehouse for past infections by storing a part of the viral genetic material and incorporating it into its own, so the next time it is attacked, the bacteria is capable of recognising the virus and destroying it. The bacteria, in short, is immunised when it employs the CRISPR system. The CRISPR-Cas system is effective and easy to manipulate. Researchers have adapted it as a tool to cut, delete, or add DNA sequences at precise locations, opening different windows to treat genetic disorders, develop drought-resistant plants, modify food crops, or experiment with de-extinction projects involving the woolly mammoth and the dodo.

Sickle-cell anemia (SCA) is an inherited disorder where red blood cells contort to a sickle or crescent shape because of defective hemoglobin, restricting its ability to carry oxygen. According to an article published in the Indian Journal of Medical Research over 20 million people live with SCA in India and it is predominantly seen in the scheduled tribes (ST) and scheduled caste (SC) populations where the majority are economically backward.

Also Read: Explained | How is India addressing sickle cell anaemia? 

Casgevy costs 2.2 million US$ per patient to treat sickle-cell anemia. Indian researchers are working on indigenous treatment involving CRISPR genome editing to reduce the cost. “For India, the issue of pricing is a very important consideration, since it impacts equitable distribution. It is little early to determine now, if production costs can be reduced, or there can be alternative pricing models, or coverage through healthcare, insurance, negotiations with pharma sector, policies around commercialisation for sustainable and affordable solutions”, explained Roli Mathur, Head, Bioethics Unit, Indian Council of Medical Research (ICMR) over mail.

For many people living with the disease accessing even hydroxyurea, a medicine used as a first-line therapy for SCD, is a challenge in India. While researchers are doing their best to find a cost-effective treatment, there are chances of it still being beyond reach for most of them. “When you have such a blockbuster therapy, you also have to think about how you can make it accessible and many people around the world including us are working along those lines”, said Debojyoti Chakraborty, Principal Scientist at CSIR Institute of Genomics and Integrative Biology (IGIB).

The tribal population which is affected the most has limited healthcare access for various reasons: one being that they live in remote areas where there is a scarcity of healthcare professionals. “There is a need to provide primary care to deal with this debilitating disease that the community is suffering from. If you don’t do primary care then how are you going to do tertiary care?” asked Amar Jesani, a medical doctor, independent researcher, and teacher of bioethics and public health.

The Sickle Cell Anemia Elimination Mission launched in India on 1^st July 2023 aims to strengthen the existing healthcare system and improve primary, secondary, and tertiary healthcare teams. “Equitability is a factor which has to be accessed both at the local and global level. The government has a lot of power and we have seen how they can actually make things accessible to everyone like they did for vaccines. A similar modality would have to be put into place where you have partners from scientists, governments, and industries come together to see how you can get these kinds of therapies out”, said Dr. Chakraborty.

Indian regulation

The decision-making process for CRISPR research is governed by the existing legal and regulatory framework. The New Drugs and Clinical Trials Rules (2019) classify Gene Therapy Products (GTPs), including those developed through CRISPR, as new drugs, subjecting them to a thorough approval process by the Central Drugs Standard Control Organization (CDSCO). Additional requirements will be determined following the ICMR-DBT National guidelines for GTPs and oversight by bodies such as the Review Committee on Genetic Manipulation (RCGM) and the Genetic Engineering Approval Committee (GEAC) as applicable. Moreover, all biomedical and health research in India must adhere to the ICMR National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, 2017.

Germline editing and CRISPR

Apart from the health equity and disparities associated with CRISPR, one of the biggest controversies has been about germline editing. Most of the scientific community supports the use of CRISPR to treat monogenic diseases. Germline editing is heritable and more complex and begs the question if it is even moral to subject an individual to heritable changes, even if it is to treat debilitating genetic conditions.

As of now, genome editing is restricted to somatic cells and there is a moratorium on germline editing. But when the advantages surpass the drawbacks, where will science draw the line with genome editing?

Chinese scientist He Jiankui took the scientific world by storm when he announced that he had edited healthy embryos in an attempt to minimise girls’ predisposition to HIV infection. This was in 2018 despite having guidelines against germline editing and at a time when studies had no clear-cut answers to the outcome of such an intervention. We still fully do not understand the long-term effects of CRISPR editing.

“It’s not a technology which is absolutely 100% full-fledgedly understood. [Germline editing] can come slowly, progressively once we have totally understood the pros and cons of the gene editing technology”, explained Dr. Chakraborty.

Guidelines, laws, and dialogues around ethical, societal, and safety issues need to evolve parallelly as technology evolves. “Most countries including India have forbidden genome editing in human embryos through legal instruments or through guidelines. In India every Institution involved in biomedical research is required to follow ICMR National Ethical Guidelines and register with the ethics committee which monitors research (including around gene editing)”, said Dr. Mathur.

The gene editing technology has also raised concerns regarding it becoming a commodity that wealthy parents will exploit to improve the fate of their children not only for therapeutic purposes but for genetic enhancement. “There is a chance that if we do not have a way to distribute these therapies to different parts of the world where it is needed through whatever mechanism, then you would have a division in the world because the therapy is there but the affordability isn’t there”, Dr. Chakraborty added.

Public engagement

Also given our incomplete knowledge about the long-term effects of CRISPR, researchers and policy-makers are considering real-world implications in the long run. The method is here to stay and the media and public need to engage in open dialogues to prevent the spread of misinformation. “Institutions undertaking cutting-edge research must also come up with best practices in community engagement, education, and timely and truthful communication to build trust among all stakeholders with a special focus on communities”, according to Dr. Mathur.

Written in an era before DNA was discovered, Frankenstein became an inspiration for science fiction and was one of the first novels to question the outcome of interfering with nature. It served as a reminder for scientists to proceed with caution and explore the moral consequences of scientific innovation. We have come a long way since then. Unlike the scientist in the novel, scientists today are aware of the power they hold with a technology that can change the genetic code and the societal implications for it, while also holding accountability for violating guidelines as seen in 2018.

At the end of the day, CRISPR is a tool whose endgame is determined by how humans utilise it. “Unless ethics is at the fore, even if there is scientific success, societal acceptance cannot be guaranteed. There needs to be enough commitment to integrate ethics in research work for the technology to have a positive impact”, explained Dr. Mathur.

(The author is a freelance content provider based in Hyderabad. )