Gene therapy: A game changer for those with sickle-cell disease

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SickleWith advances in gene therapy, scientists have begun to talk of a cure for sickle-cell disease, an inherited condition that mainly afflicts people of African descent, reports The New York Times.

Scientists have long known what causes sickle-cell disease and its devastating effects: a single mutation in one errant gene. But for decades, there has been only modest progress.

Now, in a half-dozen clinical trials planned or underway, researchers are testing strategies for correcting the problem at the genetic level. Already a handful of the enrolled patients, who have endured an illness that causes excruciating bouts of pain, strokes and early death, no longer show signs of the disease.

It is still early in the course of these experimental treatments, and it is likely to be at least three years before one is approved. Although researchers hope the effects will last, they cannot be certain. “We are in uncharted territory,” said the report quotes Dr David A Williams, chief scientific officer at Boston Children’s Hospital as saying.

At the moment, the only remedy for sickle-cell disease is a dangerous and expensive bone marrow transplant, an option rarely used. An effective gene therapy would not be simple or inexpensive, but it could change the lives of tens of thousands of people. “This would be the first genetic cure of a common genetic disease,” said Dr Edward Benz, professor of medicine at Harvard Medical School.

The report says it also would mark a turning point for a large community of underserved patients. Most of them have African ancestry, but Hispanics and those with southern European, Middle Eastern or Asian backgrounds are also affected. Experts have long maintained that advances in treatment have been limited partly because sickle-cell disease is concentrated in less affluent minority communities. “Having tried for a number of years to raise philanthropic money, I can tell you it’s really hard,” said Williams.

The report says an estimated 100,000 people in the US have sickle cell disease. Worldwide, about 300,000 infants are born with the condition each year, a figure projected to grow to more than 400,000 by 2050. The disorder is most common in sub-Saharan Africa, where an estimated 70% of children with it die before adulthood.

In sickle-cell disease, blood cells stuffed with haemoglobin are distorted into sickle shapes. The misshapen cells get stuck in blood vessels, causing strokes, organ damage and episodes of agonising pain – called crises – as muscles are starved of oxygen. The report says children usually return to normal between crises, but teenagers and adults may suffer chronic pain. The misshapen cells don’t survive long in the blood – 10 to 20 days, compared to the usual 120 days. Patients may be severely anaemic and prone to infections.

The report says in the 1980s, when researchers first began thinking of gene therapy to correct genetic disorders, sickle-cell disease was at the top of the list. In theory, it seemed straightforward – just one tiny change in a single gene led to a lifetime of misery and an early death. Every patient had exactly the same genetic mutation. To cure the disease, all scientists needed to do was to fix this one genetic error.

But it was not so easy. The report says among the many problems that plagued gene therapy research, there were ones specific to sickle-cell disease. Haemoglobin genes are only active in the precursors of red blood cells, which are derived from bone marrow stem cells, and the genes are only active for about four or five days until mature red blood cells form, Benz said. Yet when they are active, the genes direct the cells to make enormous amounts of haemoglobin, so much that the red blood cell is like a bag holding gelatin.

That left researchers with a problem, the report says. “How do you manipulate a gene, or put a gene in, so it is expressed only in those cells and at high levels?” Benz asked.

In the new trials, subjects must have immature blood cells – stem cells – removed from their bone marrow. The stem cells are genetically modified, and then infused back into the patient’s bloodstream. The goal is for the modified cells to take up residence in the bone marrow and form healthy red blood cells.

Scientists are testing three methods for modifying stem cells. In the first, a form of gene therapy, a virus is used to insert a viable copy of the haemoglobin gene into the stem cells. Until recently, the viruses had a limited capacity to carry genes, and the haemoglobin gene simply would not fit. Only recently have scientists found viruses that can do the job.

The report says the second approach starts with the fact that the human genome can make two kinds of haemoglobin: foetal haemoglobin, active in the foetus but shut off after birth, and adult haemoglobin. Some researchers are trying to block the gene that turns off foetal haemoglobin and turns on adult haemoglobin, allowing patients with sickle-cell disease to produce foetal haemoglobin instead.

“We’ve known for decades that haemoglobin is different in a foetus — it doesn’t sickle, and it works as well as adult haemoglobin,” said Dr Stuart Orkin, a researcher at Harvard University who found the haemoglobin switch. A third strategy depends on gene editing with Crispr, a tool that lets scientists snip out parts of genes and paste in new sections. Several groups are doing early studies with Crispr.

With recent advances, all three approaches now seem feasible. Farthest along is a new iteration of gene therapy to produce foetal haemoglobin, currently in trials conducted by Bluebird Bio, a biotech company in Cambridge, Massachusetts.

The report says the company reported results for four patients of nine in the study who had been treated at least six months earlier. All four produced enough normal haemoglobin that they no longer had symptoms of sickle-cell disease.

Bluebird is now planning a larger study, in consultation with the US Food and Drug Administration, that will enrol 41 patients, all of whom will get gene therapy. The company hopes to finish the study and get approval in 2022.

Following recent scientific advances, the report says the NIH has launched an initiative called Cure Sickle Cell to speed progress. It will bring “significant new money,” said Dr Keith Hoots, a division director at the institutes, although the total has not yet been determined.

The New York Times report

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