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.