Am I Going To Live? Genetic Diseases Leave 70 Million Indians At God's Mercy

In the front office of a laboratory in Bangalore, colour-coded tubes that have just arrived are being sorted and sent away—a journey into deep, searching questions. Merely looking at the assortment of machines they will pass through won’t give a full sense of the intricate steps involved because these are automated. The samples in the tube contain DNA—those knowledgeable little molecules must be extracted first. Then, the strings of DNA are cut and made into libraries, small enough for the machine to read. Think of it—millions of unknown strands stacked up, copied, sequenced. A mind-boggling scrabble game with the four alphabets—ATGC—that make up the building blocks of DNA. In a few hours, the code that defines a human being somewhere in the country is ready. Then, an intense search begins: the hunt for spelling errors in that vast bibliotheca which has thrown that person into a debilitating descent.

That’s where the story starts, for some. Since actual numbers are hard to come by in India, we have to fall back on estimates of global incidence rates. About 70 million Indians are likely to be suffering from rare genetic diseases, most of them with no cure yet. Usually, the road to a dia­gnosis is long and brooding, strewn with red herrings along the way till a clinical geneticist actually connects their ailment to a genetic mutation, that spelling error. It’s taken years in many cases, some even up to a couple of decades for a correct diagnosis. Yes, costs of ­genome sequencing are plummeting. Most times you don’t need to sequence the entire gen­ome with all its hereditary information to locate the gene mutations that caused a genetic disorder. Sequencing only the exome, the gen­ome’s portions with the protein-coding genes, would be enough. That cost around Rs 80,000 five years ago. Today, it’s about Rs 30,000, the price of a mid-range smartphone. But after the diagnosis, a question haunts several thousand families in the country. Now what?

Genetic diseases, however, refer to a large collection of disorders. Some are exceptionally rare—where the odds are one in 10 million—and each with a small set of silent sufferers. But, as genome sequencing got more accessible, it turns out that many diseases once thought rare weren’t actually so rare after all.

Take both ends of the spectrum: Shilpi Bhattacharya, 36, a law professor in Delhi, learnt Bharatanatyam as a kid. Back then, parents Alok and Sudha Bhattacharya noticed that her gait was different and that she couldn’t walk fast. At first, it looked like she was being lazy. In college, after a dance recital for an annual day event, friends even joked that she was the girl who could dance but not walk. But, as a young adult, the symptoms began showing—after many years and several doctors, the family finally found out that Shilpi had GNE myopathy, a rarest-of-rare genetic disorder caused by gene mutations that lead to muscle wasting. “We never dreamed that it was something in her genes,” says Sudha, a molecular biologist. There’s no cure for GNE myopathy, no treatment either. As Sudha puts it, there’s a diagnosis, but no doctor to treat it.

Now look at Duchenne muscular dystrophy (DMD), another muscle-related disorder caused by a gene mutation that alters the body’s ability to produce the protein dystrophin. Since the dystrophin gene sits on the X chromosome, it mostly affects only boys. “We assume India has the largest number in the world,” says Bangalore-based Ravdeep Singh Anand, whose struggle with DMD started in 2003 when his son Karanveer, 18, was diagnosed. Again, he’s going by worldwide statistics: DMD affects one in 3,500 boys. But Anand is an even rarer ­parent—in his despair, with no treatment in sight, he started a lab to develop a drug that could help his son to live with the disease.

Other genetic diseases, especially blood-­related disorders such as haemophilia and thalassaemia, are common. The good news is that research initiatives into gene therapy are ­showing promise—for instance, several clinical trials of gene therapy for haemophilia are at an advanced stage globally, with an approved product likely in the next year or two. A gene therapy product for thalassaemia has recently been approved in Europe. In India, a programme has been initiated to develop gene therapy for both haemophilia and thalassaemia at the Centre for Stem Cell Research (CSCR)—a unit of the Bangalore-based research institute inStem at the Christian Medical College in Vellore. A clinical trial has been proposed for haemophilia A, a first in the country, and is awaiting regulatory approval. Other clinical trials will follow as product development progresses.

“I think we are on the edge of possibilities for genetic disorders that didn’t exist till recently,” says Vijay Chandru, co-founder of Strand Life Sciences, a genomic profiling company. But the story of genetic diseases threads tog­ether several chapters—the plight of sufferers, the world’s most expensive drugs, government policy and the hope of new therapies. “There are many battles here to be fought,” says Chandru.

On a recent weekday morning, five patients visited the rare diseases ward at Bangalore’s government-run Indira Gandhi Institute of Child Health for their periodic infusions, all of them aged below 18. The ward—a day care set up by the Organisation of Rare Diseases India (ORDI), Centre for Human Genetics in Bangalore, and the Karnataka government—carries out 112 infusions on an average every month. The IV drip takes four to five hours. The kids usually watch cartoons on TV or are glued to a movie on their phones. The infusions—once a week or fortnight—help them to live normally.

Among the regular visitors here are about 25 patients with Lysosomal storage disorders. This is a group of about 50 disorders, of which about seven or eight have treatments. These patients afford the treatment through different routes. Some come under a charitable access programme by the drug manufacturer. The others are government-funded or get compensated through the Employees State Insurance Corporation. Karnataka was among the first states to commit money ­towards the treatment of some rare diseases, but often this still comes via court cases. It’s a classic conundrum on perennial loop—how do we save patients who need lifelong infusions that cost lakhs every month?

Of these, Gaucher disease may actually be well-known in India. Not because it is easily recognisable; it presents just like maybe malaria would­—distended spleen, big stomach and anaemia—so only an expert eye can suspect Gaucher at first look. But rather, for its treatment—a vial costs upwards of Rs 1 lakh and patients need regular infusions running into lakhs of rupees annually, lifelong. The disease framed the context of a landmark 2014 Delhi High Court judgment by Justice Manmohan on a plea by rickshaw-puller Mohammed Sirajuddin to save his son, Mohammed Ahmed. Invoking Martin Luther King Jr—“of all forms of inequality, inj­ustice in healthcare is the most shocking and inhumane”—the judge directed the Delhi government to provide the boy with free enzyme replacement therapy as and when required. On the court’s prodding, the Union health ministry came up with the National Policy on Treatment of Rare Diseases 2017, only to make a U-turn and withdraw it this February. The ministry has sought time to frame a fresh policy.

“Something was better than nothing,” says Prasanna Shirol, co-founder of the Organi­sation of Rare Diseases India, an association of parents. “It’s a setback because applications from patients seeking help are piling up. Now, they say there was no Rs 100 crore budget. They say the policy was not good enough.”

Shirol doesn’t buy the argument that the states weren’t on board. “Our argument is, the states didn’t agree for GST or Ayushman Bharat, yet they found a way to implement it. I don’t see any effort was made to implement the policy in true spirit. It was eyewash,” he says.

Since insurance companies won’t cover gen­etic diseases, things naturally fall back on ­government guidelines for treatment. “The problem will continue as long as we don’t have a right to public health,” says Ashok Agarwal, a Delhi-based lawyer who has argued cases for several patients over the years. “Every step of managing these diseases presents a challenge,” says Shirol, whose daughter Nidhi, 20, is among India’s first recognised patients of Pompe disease—a degenerative neuromuscular condition where muscles get damaged and progressively weaken because of an enzyme deficiency. She’s been on a portable ventilator since age eight ­because her breathing muscles too were weak. She went to school and then college on a wheelchair with the ventilator by her side. Fortu­nately, Shirol was able to enroll her in a charitable access programme by drugmakers Sanofi-Genzyme for the treatment that, for a girl of her weight, 30kg, costs about Rs 1.2 crore annually. She needs an infusion every fortnight.

There are also many genetic conditions about which something can be done a bit more easily. “Something effective, not necessarily cures,” says Dr Meenakshi Bhat of the Centre for Human Genetics in Bangalore. A child with beta thalassaemia, which would require a monthly blood transfusion for life, can be treated with a matched stem cell transplant. Inborn errors of metabolism—large family of disorders where enzymes that do key digestive tasks are missing—often turn up in infants with the first feed and rapidly progress. But over a dozen such fatal metabolic disorders can be managed with special diets, some of which are now manufactured locally. “Where infant mortality rates go down to 30 per 1,000, genetic ­diseases take priority for morbidity and mortality. This is a well-known fact,” says Bhat. Many Indian states have achieved those IMR levels, so newborn screening programme should be ramped up, she suggests. “We should be looking at these disorders.”

Shirol of ORDI says the average diagnosing period for a genetic disorder in India or ­worldwide is around seven years. But the larger problem is that India doesn’t have enough trained geneticists. There may be roughly about 100 clinical geneticists in the country in 30 ­centres, reckons Bhat. “That’s a hundred times less than what we need,” she says. There are only about half-a-dozen training programmes in the country, including her institute, offering speciality fellowship training in clinical ­medical genetics.

“We want clinicians to understand that this is not a small group (of patients),” says Sudha Bhattacharya. She likens it to cancers. “If you talk about each and every type of cancer, the number of patients may be small. But when you put them all together, it’s large. It’s the same thing here.”

Awareness has been slowly growing, thanks to multi-pronged efforts. Genomics research and diagnostics company Medgenome Labs, set up in 2013, says there has been a big up in the number of samples at its lab in the past two years. “Even today, 95 per cent of my samples come from metro cities,” says Dr V.L. Ramprasad, the chief operating officer. “Cystic fibrosis, for example, is a fairly regular diagnosis at his lab. What you would call rare elsewhere is not rare in India. Our scale is completely different.”  

Meanwhile, genome sequencing costs are dropping faster than Moore’s Law for semi­conductors. Think of it: by 2014, less than 15 years after the first human genome was ­sequenced, you could sequence a genome for $1,000 (roughly Rs 70,000). “So, a hundred ­dollars for a whole genome is on,” says Vijay Chandru of Strand. “If not in two years, in three or four years we’ll be at a situation where we can ­sequence the entire human ­genome for $100 (roughly Rs 7,000).” Genomic medicine ­research is also pushing the frontiers, holding out the promise of a one-time cure for genetic disorders that were so far being managed by regular infusions.

Of course, these technologies were pioneered on cancers. But in the recent past, the first gene therapies for two genetic diseases have received approval—the European Union gave American firm ‘bluebird bio’ a conditional ­marketing ­authorisation for gene therapy for patients (aged 12 and above) of beta thalassaemia who were dependent on blood transfusion, while the Novartis company AveXis won a US Food and Drug Administration nod for a ­treatment for spinal muscular atrophy (in ­paediatric patients under two).

Globally, there are several attempts to crack these puzzles. A 2018 report by Goldman Sachs listed at least 42 companies working on gene therapies across a wide range of genetic disorders. Generally, gene therapy relies on two ­approaches—the idea being to introduce a good gene into the body. One is ‘gene introduction’, which means delivering a ‘normal’ gene through a harmless virus which will find its way to the right location. The second method is by ‘gene correction’ which means correcting the defective gene by different methods. In India, the Centre for Stem Cell Research in Vellore, which is funded by the ­department of biotechnology, is investigating both vector-based and CRISPR/Cas9 based gene ­replacement and correction approaches for the treatment of haemophilia and the major haemoglobin disorders such as thalassaemia and sickle cell disease.

Some gene-editing approaches are nascent, like those using CRISPR Cas9—a protein that, like a pair of scissors, can cleave a DNA molecule so that a tailored change can be made at the site of cleavage. Think of a word processor file which has a typo somewhere in the middle. “You take the cursor there, press the back button, put in a new letter and you save the file. This is exactly what is happening,” says Debojyoti Chakraborty, senior scientist at CSIR’s Institute of Genomics and Integrative Biology, who is working on a gene-editing approach for sickle cell anaemia. “So there is a typo in the DNA, we take the Cas9 which is like the cursor, make a double-strand break and put in the new nucleotide and then the cell repairs the break and replicates. Therefore the information is saved.”

Chakraborty says proof-of-principle studies are mostly done and the lab is now going into pre-clinical studies likely on mouse models. “What we have been heavily investing in is trying to make this process very safe, very precise because Cas9 being a protein, it can also make mistakes,” he says. A mistake means instead of going to a site where the mutation is, the protein might go to another site where there is no mutation and still make a DNA break. “There is a lot of research across the world in trying to make this system very precise,” he says.

Like elsewhere, India too has guidelines now for fast-tracking orphan drugs. But that, in ­itself, as Vijay Chandru says, doesn’t solve the problem which is to get innovators to start working on these medicines. “We need to come up with the right financial instruments here,” he reckons. “In the meantime, you need something for these patients.”

It’s the parents’ groups that are pushing hard, in every direction. “The time is now right for India to forge into it because the technologies weren’t there earlier. Now, gene therapy is very much there,” says Sudha Bhattacharya. Ten years ago when their daughter Shilpi was ­diagnosed with GNE myopathy, geneticists Sudha and Alok were hopeful about a ­treatment because at least three labs in the world were working on it. But time is passing, and the urgency has only increased. “We must take it to the logical ­conclusion of going to the patients,” say the couple. For that, you need more hands on the deck. Elsewhere in the world, there are scores of startups doing only gene therapy,” they point out. “That’s something that has bothered us.”

Over the years, they set up an organisation to create awareness among the medical fraternity and scientists in the country about GNE myopathy. “You will be quite surprised. The number may not be large but almost every month a new patient is getting added to the list,” says Sudha. “Who’s going to do it if we in India don’t do something about it?”