Gunjan Sharma talks to Dr Rakesh Mishra, director, Tata Institute of Genetics and Society (TIGS) about rare genetic disorders and the need to find faster diagnostics tools and affordable drugs

What is the prevalence of rare genetic disorders in India? How do we classify them?

Genetic disorders are diseases that a child inherits from her/his parents. We can link such a disease to the lineage that parents carry. The probability of the occurrence of the disease increases when both parents carry it.

If both parents carry the disease-causing mutations, the chance of their child getting the disease is 25%,  and the chances of their child being a carrier of this disease is 50 %. A carrier may not necessarily have the disease but can pass it on to his or her child.

Such diseases are more common among the communities where endogamy—marriages between close relatives—is common. In India, though we are a large country, we have many small sections of the population where endogamy is very common.

Though we don’t have accurate data, around 96 million people are estimated to be affected with one or the other rare genetic disorder in the country; and though there are estimates of around 8000 genetic disorders, most of them are not characterised. In India we have about 450 such disease have been identified. These include hemoglobinopathies, blood-related diseases, muscle-related diseases, neurological disorders.

What are the biggest challenges in treating rare genetic diseases?

Since these are rare disorders, the first challenge is to diagnose them in time.

The symptoms of most of the rare diseases are similar to those of common diseases. So, in most cases, even the diagnosis takes 5 – 7 years and by then the condition of the child deteriorates and irreversible disabilities set in. 

Second, there is no or limited treatment for most of these diseases. It requires a huge investment in the research and development of a treatment. Since these are rare diseases, not many pharma companies like to invest huge amount of money in developing a drug that is not likely to yield a big return, simply because of the number of patients at a given time for a disease.

Third, even for diseases where treatment has been developed, the cost of the treatment is exorbitant. A family has to shell out several lakhs to crores of rupees / per year on the treatment, which most families cannot afford. We cannot imagine a family able to spend this kind of money for 10-20 years, the approximate life expectancy of most children born with a genetic disorder.

So, these families suffer financially, emotionally, and at times socially. Many a time,  mothers are blamed for giving birth to a child with such a rare disease.

What is Tata Institute for Genetics and Society (TIGS) doing to help patients with rare genetic disorders?

We are trying to develop technologies and genetic tests to help diagnose the disease at an early stage. We work closely with the clinic and patient groups to ensure that R&D outcomes reach patients as soon as possible.

We are working on developing mRNA therapeutics, as substitutes to protein or enzyme replacement therapy, and expect it to be cheaper to administer and faster to develop. In mRNA therapeutics, we inject a functional mRNA into the body that helps the cells in the body to make the missing protein. mRNA therapeutics got a big boost post the success of mRNA vaccines during the pandemic.

Gene therapy is another option, though more expensive, to treat genetic disorders. In enzyme replacement therapy, patients are given the protein encoded by the missing/defective gene. In the case of gene therapy, the approach is to try to repair or replace the defective gene.

Gene therapy approach is more challenging also as all the cells in the body (about 50 trillion of them in one human) have the defective gene and if not all, a large number of them in specific tissues or the respective adult stem cells need to be corrected. Great progress has been made across the world in the domain of cell/gene therapy. The challenge is to optimize/indigenize and make these technologies available and affordable to our population.

In what all kinds of genetic disorders would these therapies help?

Several diseases can be addressed by these latest technologies. Gene therapy which is one time treatment is developed for a couple of RGDs but it costs 15-20 crore. Several RGDs can be treated by regular dose for the entire life of the patient and that relatively less but still unaffordable. In fact, these therapies can be developed that can help in most of the genetic diseases but the challenge is to bring down the cost of the treatment. Currently, for a child with a body weight of 10 kg, the treatment may cost anything between 40- 90 lakh per year. It can go even higher.

How do you intend to bring down this cost?

About 75 to 80 % of the cost relates to investment in the research and development of the treatment. If a commercial pharma company invests money in developing a drug, it has to recover the cost from the patients.  Since we are a non-profit organisation backed by the Tata Trusts, we will not be charging the R&D cost from the patient. That means the treatment would cost about 80% less. To bring down the cost further,  we are working on making the material used in developing the drugs in our labs. This will reduce the cost towards import of the raw material.

You will be surprised to know that the cost of one Covid testing kit, in the beginning, was Rs 2000 – 4000. Now with successful efforts to completely indigenized the production, the production cost of COVID testing kits is as low as Rs. 10-20 per test. Indigenization, therefore, is a very effective approach to reduce the cost.  To add to all these, innovations and new scientific advances can further reduce the cost.

Is TIGS also working towards diseases prevention?

Yes, we are working on two fronts: One is to develop cheaper, yet effective, screening tools to help screen the target communities for specific diseases. This can help people who are carriers of the disease take decision regarding marrying each other.

Also, once affordable screening is available, we may encourage couples where both are carriers to go for prenatal screenings to prevent the birth of children with debilitating disabilities. Recent developments make it possible to do pre-natal screening with non-invasive procedures. Earlier we needed to take amniotic fluid but we know it can be done from the blood test of the mother well within the time that the parent can decide about the continuation of the pregnancy.

We need to educate people that when both parents are carriers, there is 25% chance that a child born in such cases can have the disease. Both parents need to understand and take decisions. Given that about 80% of rare disease are genetically inherited, social awareness can go a long way in substantially reducing the disease burden in society.

What kind of support do you need from the government and regulatory bodies?

We need to relax some regulatory processes to reduce the cost of drug development. For example, in the case of a normal drug, we do animal studies, followed by phase-1, phase-2, and phase-3 trials. In the case of rare disorders, we don’t have many people to do clinical trials on. So, we should be able to try the medicine on a patient post-animal studies. Recently, the USA regulatory body FDA announced that animal testing may not be necessary for drug development.

In fact, it is not impossible to make animal models for all of these diseases as it is difficult to replicate those gene mutations in animals or similar mutations don’t lead to similar diseases in the animal. For such a disease, we can only do toxicological studies in animals and not the efficacy study. If one proves that something is safe for the animals, then it should be allowed to be given to the patients. Of course, proper observation and follow-ups need to be part of such processes.

Besides, certain components of the treatment strategy or drug development are often protected by patents in other countries. We need international policies to make RGD interventions patent-free as they are rare disorders and need special routes to reach the patients.