The therapy for the future

I was never neat, tidy, or a perfectionist in school; nor am I now. “You must have inherited it from your father,” my mom used to comment while tidying up my room. I have heard my wife say the same to my son. It must be in the genes. The futility of altering genes is unquestionable. All that changed on January 19, 2021, when a toddler from Nashik, Maharashtra, received the first injection of a new gene therapy (Zolgensma) that cost a massive ₹16 crore for an incurable, rare genetic disease called spinal muscular atrophy. Gene therapy had finally reached our neighbourhood. There remains one last question: could such treatment someday offer a cure for common diseases such as high cholesterol or high blood pressure? The human genome, the blueprint of human biology, is deeply embedded, etched in indelible ink within (almost) every cell. The genes, which are DNA segments, have their code copied to RNA, which are used at the ribosome to produce essential chemicals with diverse functions, such as hormones that regulate blood sugar (insulin), enzymes that digest food (pepsin), and even the pigment that informs skin colour (melanin). An absent, weak or faulty gene could cause chaos by producing less effective or even harmful chemicals, leading to a range of diseases, including cancer. While traditional pharmacology aims to “chemically correct” the disrupted body metabolism without addressing the root cause, gene therapy offers the potential for a proper cure. Most major genetic mutations result in diseases affecting multiple body functions, leading to significant disability. In contrast, Common diseases such as diabetes, hypertension, and high cholesterol are not purely genetic defects of a single gene but involve mild variations in multiple genes. Their disease expression is influenced by environmental factors such as diet and lifestyle. Therefore, gene therapy is unlikely to be effective in treating them. Scientists have instead worked to alter the way DNA transcribes its code into RNA. One technique is to insert a small piece of RNA that interferes with a specific function (small interfering RNA, or siRNA), such as LDL cholesterol metabolism. LDL cholesterol is removed from the body by LDL receptors in the liver cells. Silencing the gene that stops LDL receptor degradation with siRNA looked like a good alternative. But how do you put siRNA into the liver? Perhaps inspired by crime movies in which robbers enter high-security areas posing as policemen, researchers recently inserted a siRNA piggybacked on a molecule called GalNAc (N-acetylgalactosamine), which the liver cells gobbled up quickly. Once inside the liver cell, the siRNA bid adieu to the GalNAc and started working. To date, six such “gene therapies” with siRNA have received FDA approval for clinical use. Surprisingly, one of them, called ‘Inclisiran’, effectively and safely lowers LDL cholesterol. Large trials involving a few thousand participants to date have been very encouraging. When combined with statin drugs, it reduced LDL cholesterol by around 50%. It is also helpful for individuals who can’t tolerate statins. The FDA in the U.S....

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