Friday, January 28, 2022

Type 1 diabetes medication? For one person, it seems to have worked.

Brian Shelton’s life was controlled by type 1 diabetes.

When his blood sugar plummeted, he passed out without warning. He hit the wall with his motorcycle. He passed out in a client’s yard while delivering mail. After this episode, his boss told him to retire after spending a quarter century in the postal service. He was 57 years old.

His ex-wife Cindy Shelton took him to her home in Elyria, Ohio. “I was afraid to leave him alone all day,” she said.

Earlier this year, she noticed a call for people with type 1 diabetes to participate in clinical trials led by Vertex Pharmaceuticals. The company tested a treatment developed over decades by a scientist who vowed to find a cure after his young son and then his teenage daughter fell ill with a devastating disease.

Brian Shelton was the first patient. On June 29, he was given an infusion of stem cell-grown cells, but just like the insulin-producing pancreatic cells that his body lacked.

His body now automatically controls his insulin and blood sugar levels.

Shelton, now 64, may be the first person to recover from the disease with a new treatment, whose experts dare to hope that help can come to many of the 1.5 million Americans with type 1 diabetes.

“This is a whole new life,” Shelton said. “It looks like a miracle.”

Diabetes specialists were surprised, but called for caution. The study is ongoing and will last for five years and will involve 17 people with severe cases of type 1 diabetes. It is not intended to treat the more common type 2 diabetes.

“We’ve been looking for something like this to happen literally for decades,” said Dr. Earl Hirsch, a diabetes expert at the University of Washington who was not involved in the study. He wants the result, not yet published in a peer-reviewed journal, to be replicated in many other people. He also wants to know if unexpected side effects will occur and if the cells will last a lifetime or if the treatment will have to be repeated.

But, according to him, “in general, this is an amazing result.”

Dr. Peter Butler, a diabetes expert at the University of California, Los Angeles, who was also not involved in the study, agreed, offering the same caveats.

“This is a wonderful result,” Butler said. “The ability to reverse diabetes by giving them back the cells they lack is a miracle when insulin first appeared 100 years ago.”

And it all started with a 30-year search for Harvard biologist Doug Melton.

‘Terrible, terrible disease’

Melton never gave much thought to diabetes until 1991, when his six-month-old boy, Sam, began to shiver, vomit and gasp.

“He was so sick and the pediatrician didn’t know what it was,” Melton said. He and his wife Gail O’Keeffe rushed their child to Boston Children’s Hospital. Sam had a lot of sugar in his urine – a sign of diabetes.

The disease, which occurs when the body’s immune system destroys the insulin-secreting islet cells of the pancreas, often begins at age 13 or 14. Unlike the more common and milder type 2 diabetes, type 1 diabetes is rapidly fatal if patients do not receive insulin injections. … Nobody gets better spontaneously.

“It’s a terrible, terrible disease,” said Butler of the University of California, Los Angeles.

Patients are at risk of blindness – diabetes is the leading cause of blindness in this country. It is also the main cause of kidney failure. People with type 1 diabetes are at risk of leg amputation and death at night due to a drop in blood sugar during sleep. Diabetes greatly increases the likelihood of a heart attack or stroke. This weakens the immune system – one of Butler’s fully vaccinated diabetes patients recently died from COVID-19.

Added to the burden of disease is the high cost of insulin, the price of which is increasing every year.

The only medicine that has ever worked is a pancreas transplant, or transplant of clusters of insulin-producing pancreatic cells, known as islets, from an organ donor’s pancreas. But the lack of organs makes this approach impossible for the vast majority of patients.

“Even if we were in utopia, we would never have enough pancreas,” said Dr. Ali Naji, a transplant surgeon at the University of Pennsylvania who pioneered islet cell transplants and is now the principal investigator of the trial in which Shelton was treated. …

Blue tips

For Melton and O’Keeffe, caring for a baby with this disease was terrible. O’Keefe had to prick Sam’s fingers and feet to check his blood sugar four times a day. Then she had to inject him with insulin. For such a small child, insulin was not even sold at the right dose. His parents had to thin it down.

“Gail told me,” If I do this, you have to find out this damn disease, “Melton recalled. Over time, their daughter Emma, ​​four years older than Sam, also contracted the disease when she was 14 years old.

Melton studied the development of frogs, but gave up this work, determined to find a cure for diabetes. He turned to embryonic stem cells, which can potentially become any cell in the body. His goal was to turn them into islet cells for the treatment of patients.

One problem was the source of the cells – they came from unused fertilized eggs from a reproductive health clinic. But in August 2001, President George W. Bush banned the use of federal money for research with human embryos. Melton had to separate his stem cell lab from everything else at Harvard. He received private funding from Howard Hughes Medical Institute, Harvard and philanthropists to create a completely separate laboratory with an accountant who kept all his expenses separate, right down to the light bulbs.

Melton estimates that the project cost about $ 50 million over 20 years, during which a 15-person lab was able to successfully convert stem cells into islet cells.

The challenge was to figure out which sequence of chemical messages would transform stem cells into insulin-secreting islet cells. The work consisted of elucidating the normal development of the pancreas, figuring out how islets are formed in the pancreas, and conducting endless experiments in converting embryonic stem cells into islets. It was slow.

Years later, when nothing worked, a small group of researchers, including Felicia Pagluka, Ph.D., was in the lab one night in 2014 doing another experiment.

“We weren’t very optimistic,” she said. They added a dye to the liquid in which the stem cells were growing. If the cells are producing insulin, the fluid will turn blue.

Her husband has already called and asked when she will return home. Then she saw a faint blue hue that grew darker and darker. She and the others were delighted. They were the first to create functioning pancreatic islet cells from embryonic stem cells.

In the laboratory, they celebrated with a small party and a cake. They then made themselves bright blue wool hats with five circles of red, yellow, green, blue and purple to indicate the stages that stem cells must go through to become functional islet cells. They always hoped for purple, but until then they kept fixating on green.

The next step for Melton, knowing that he would need more resources to create a drug that could hit the market, was to create a company.

Moments of truth

His company Semma was founded in 2014 as a mixture of the names of Sam and Emma.

One challenge was to figure out how to grow islet cells in large numbers using a method that others could repeat. It took five years.

The company, headed by Bastiano Sanna, an expert in cell and gene therapy, tested its cells in mice and rats, showing they function well and cure diabetes in rodents.

At this point, the next step – clinical trials on patients – required a large, well-funded and experienced company with hundreds of employees. Everything had to be done in accordance with the strict FDA standards: thousands of pages of documents were prepared and clinical trials planned.

Chance intervened. In April 2019, at a meeting at Massachusetts General Hospital, Melton ran into a former colleague, Dr. David Altshuler, who was a professor of genetics and medicine at Harvard and deputy director of the Broad Institute. Over lunch, Altshuler, who became the chief scientist of Vertex Pharmaceuticals, asked Melton what was new.

Melton took out a small glass bottle with a bright purple ball at the bottom.

“These are the islet cells that we made in Semme,” he told Altshuler.

Vertex specializes in human diseases whose biology has been studied. “I think this might be an opportunity,” Altshuler told him.

Meetings followed, and eight weeks later Vertex acquired Semma for $ 950 million. With the acquisition, Sanna became executive vice president of Vertex.

The company will not announce prices for diabetes treatments until it is approved. But most likely it will be expensive. Like other companies, Vertex enrages patients with high drug prices that are difficult and expensive to manufacture.

Vertex’s mission was to ensure that the manufacturing process works every time and that the cells are safe when injected into patients. The staff, working under strictly sterile conditions, monitored vessels of solutions containing nutrients and biochemical signals in which stem cells were converted to islet cells.

Less than two years after the acquisition of Semma, the FDA authorized Vertex to begin clinical trials with Shelton as its first patient.

Like patients receiving pancreas transplants, Shelton must take medications that suppress his immune system. He says they do not cause side effects for him, and he considers them much less burdensome or risky than constant blood sugar control and insulin intake. He will have to continue taking them so that his body does not reject the injected cells.

But Dr. John Boose, a diabetes specialist at the University of North Carolina who has nothing to do with Vertex, said immunosuppression was giving him thought. “We need to carefully assess the trade-off between the burden of diabetes and the potential complications of immunosuppressive drugs.”

“Shelton’s treatment, known as an early safety trial, requires close monitoring and requires starting with a half dose that will be used later in the trial,” said Dr. James Markmann, Shelton’s surgeon at Mass General who works with Vertex. trial. No one expected the cells to function so well, he said.

“The result is so amazing,” said Markmann, “it’s a real leap forward in this area.”

Vertex was ready to disclose the results to Melton last month. He didn’t expect much.

“I was ready to give them an inspiring speech,” he said.

Melton, usually a calm person, was nervous at the moment of truth. He spent decades and all his passion on this project. By the end of the Vertex team’s presentation, a huge smile spread across his face; the data was real.

He left Vertex and went home to have dinner with Sam, Emma and O’Keeffe. When they sat down to eat, Melton told them about the results.

“Let’s just say there were many tears and hugs.”

For Shelton, the moment of truth came a few days after the procedure, when he was discharged from the hospital. He measured his blood sugar. It was perfect. He and Cindy Shelton had lunch. The blood sugar level remained within the normal range.

Brian Shelton burst into tears when he saw the dimension.

“The only thing I can say is thank you.”

Nation World News Desk
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