Monday, November 29, 2021

He cannot heal his father. But the scientist’s research can help everyone else.

CAMBRIDGE, Massachusetts. When Sharif Tabebordbar was born in 1986, his father, Jafar, was 32 and already showed symptoms of muscle atrophy. A mysterious illness will define Sharif’s life.

Jafar Tabebordbar could walk when he was in his 30s, but stumbled and often lost his balance. Then he lost the ability to drive. When he was 50, he could use his hands. Now he has to support one hand with the other.

No one could answer the question that tormented Sharif and his younger brother Shayan: what kind of disease is this? And would they have developed it like their father?

As he grew up and watched his father gradually decline, Sharif vowed to solve the mystery and find a cure. His quest led him to a PhD in developmental and regenerative biology, to the highest level of academic medical research, and to the discovery, published in September in the journal Cell, that could change gene therapy – a drug that corrects genetic defects – for nearly all muscles. debilitating diseases. This includes muscular dystrophy, which affects about 100,000 people in the United States, according to the Muscular Dystrophy Association.

Scientists often use a disabled virus called adeno-associated virus, or AAV, to deliver gene therapy to cells. But damaged muscle cells, such as those afflicting Sharif Tabebordbar’s father, are difficult to treat. Forty percent of the body is made up of muscles. To transmit the virus to these muscle cells, researchers must deliver massive doses of drugs. Most viruses enter the liver, damaging it and sometimes even killing patients. The tests are stopped, the researchers are at an impasse.

Tabbordbar has been able to develop viruses that go directly to the muscles – very few of them go to the liver. His discovery could allow treatment at a low dosage and without disabling side effects.

Dr. Jeffrey Chamberlain, who studies therapies for muscle disease at the University of Washington and is not involved in Tabebordbar’s research, said the new technique “could take it to the next level,” adding that the same technique could also allow researchers to accurately target virtually any tissue. including brain cells that are just beginning to be seen as targets for gene therapy.

And Dr. Francis Collins, director of the National Institutes of Health, who helped fund the study, said in a blog post that it has “the potential to affect other organs,” thus “possibly providing treatment for a wide range of genetic diseases. “

Tabebordbar’s small office at the Broad Institute at MIT and Harvard has a glass door that leads directly to his lab table. This is not at home. No photographs, no books, no papers strewn about on the white counter that serves as a desk. Even the board is clean. There, filled with caffeine, he usually works 14 hours a day, except on the days when he plays football with a group at MIT.

“He’s incredibly productive and incredibly effective,” said Amy Wagers, Ph.D. Tabebordbara. Consultant, Professor and Co-Chair of the Department of Stem Cells and Regenerative Biology at Harvard. “He works all the time and has incredible passion and incredible dedication. And it’s contagious. This applies to everyone around him. This is a real skill – his ability to see a broader vision and communicate it. “

Tabebordbar and his wife live in Cambridge, Massachusetts. He loves to cook Persian food and throws a feast in his little apartment every Thanksgiving for a dozen friends. While working in the laboratory, he listens to Persian music, podcasts, or audiobooks. He loves biographies and has mentioned a passage he found significant in the autobiography of one of his heroes, English footballer Michael Owen.

Owen writes that when he learned that he was voted European Footballer of the Year in Europe, his reaction was low-key. “All I wanted to do was score the next goal, the next hat-trick and lift the next trophy,” Owen wrote. “In retrospect, I realize that I was ruthless in this regard, and I have no doubt that this mindset was the key to my success.”

“It looks like me,” Tabebordbar said. “It’s amazing that we have achieved this, but now,” he snaps his fingers, “we need to get to work. What’s next?”

Tabebordbar was born in Shiraz, Iran but moved to Rasht when he was 9 years old.

Based on his results on the national test, he was admitted to a high school that is part of the Iranian National Organization for the Development of Exceptional Talent. There, driven by a desire to help his father, he focused on the biological sciences. His mother, Tahere Falla, who dreamed of becoming a doctor but was unable to continue her education in Iran, pushed Sharif and his brother to success and celebrated their successes.

Upon graduation, Sharif was identified as one of eight to ten students in the country admitted to the accelerated program of Tehran University. This results in bachelor’s, master’s and doctoral degrees in just nine years.

“It was my dream,” he said. “I had to study very hard for this exam — English, Arabic, science.” It paid off – it finished seventh out of 1.3 million.

At Tehran University, he majored in biotechnology. After four and a half years, he received his master’s degree, but began to enroll in doctoral studies. Programs at leading international universities are conducting research on muscular dystrophies, hoping it will lead to a discovery that could help his father. He ended up in Wagers’ lab at Harvard.

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All the time he was tormented by the question: what caused his father’s illness?

When his father came to Harvard for graduation in 2016, Tabebordbar took the moment to sequence Jafar’s genes and solve the riddle. No mutations were found.

“How is this even possible?” Tabeboardbar asked.

More detailed and sophisticated testing finally yielded the answer: his father suffers from an extremely rare genetic disorder, Fazioscapulobrachialis muscular dystrophy, or FSHD, which is estimated to affect 4-10 people in 100,000 people. It is not caused by a mutation in a gene. On the contrary, it is caused by a mutation in the region between genes, which results in the release of a toxic chemical that kills muscle cells.

To Tabebordbar’s dismay, he learned that he had a 50-50 chance of inheriting the mutation from his father. If he was, he would get sick.

He was checked by a friend who called him and reported the result.

Tabbordbar inherited the mutation, but, surprisingly, the mutated gene was missing the last piece of toxic DNA, which prevented the onset of the disease.

“You are the luckiest guy among the unlucky ones,” he recalled the words of his friend.

At Wagers’ lab, Tabebordbar worked on muscular dystrophy using CRISPR, a gene editing technique. He tried to use AAV to transport CRISPR enzymes into muscle cells, where he could correct the mutation. As others had figured out before him, it was not so easy.

In 2004, Chamberlain of the University of Washington reported that AAV could deliver gene therapy to the muscles of mice. But the treatment required “astronomical doses” of the disabled virus, Chamberlain recalled.

“At these very high doses, you are on the verge of other problems,” Chamberlain said, and the liver is overwhelmed.

Despite the risks associated with high doses of AAV, clinical trials of gene therapy are ongoing in patients with muscle disease, but only in children. Their smaller bodies can get by with smaller doses that contain fewer viruses.

The AAV gene therapy has been approved for the treatment of one fatal muscle disease, spinal muscular atrophy.

“It’s a terrible disease,” said Dr. Mark Kay, a gene therapy researcher at Stanford. Even because of the children’s doses, some children have died from the medicine designed to save them.

“But if they are not treated, they will die of the disease,” Kay said.

The Tabebordbar project at Harvard also suffered from high dose problems. Although he was able to correct muscular dystrophy in mice – reported at the same time by two other laboratories – it was not a guarantee that gene therapy would work in humans. Different species – even different strains of mice – may respond differently to the same gene therapy. And the doses of AAV were dangerously high.

An illness such as that suffered by Tabebordbar’s father is particularly severe. More common muscular dystrophies are caused by a mutation that causes patients to lack a certain protein. Gene therapy should replace this protein in some, but not all, muscle cells.

The disease that Tabebordbar’s father suffers from is due to a toxic substance produced by about 1% of muscle cells, which then spreads along the muscle fibers. To rid muscles of this toxin, gene therapy must penetrate every muscle cell.

“This is a much higher bar,” Tabebordbar said.

After graduating from Harvard, Tabebordbar thought he had a chance to develop a gene therapy for muscular dystrophy at a biotech company. But about a year later, the company called everyone into a conference room to tell them there would be a reorganization, and the muscular dystrophy program was scrapped. Tabeboardbar knew he needed somewhere else.

He took a job in the Pardis Sabeti laboratory at the Broad Institute and set to work. His plan was to mutate millions of viruses and isolate those that spread almost exclusively to muscles.

The result was what he hoped for – viruses that focused on muscles, mice, as well as monkeys, making them more likely for humans.

As scientists know, most experiments fail before anything succeeds, and this work is just beginning.

“I’ll run 100 experiments and 95 won’t work,” Tabebordbar said.

But he said that this is the person that is required of the scientist.

“This is my mindset, ‘it won’t work.’ It makes you very patient. “

Chamberlain said that after all the preclinical work done by Tabebordbar, the new viruses could soon go into clinical trials, within six months to a year.

Now Tabebordbar moved on to the next step. Except for a short stint in biotechnology, he spent his entire life in academia, but he decided he wanted to develop drugs. About a year ago, he co-founded pharmaceutical company Kate Therapeutics, which will focus on gene therapy for muscle disease, and will move there in the next phase of his career.

He hopes that his work will save others from suffering. Yet his father’s fate hangs over him. Jafar Tabebordbar missed the window when it was still possible to help him.

“He was born too early,” said his son.

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