Doctors Can Now Edit Cells Inside Sick People

"Akintunde Odunsi is used to taking long, brisk walks. So he worried in 2021 when he started feeling so tired and short of breath that he had to turn back after a few minutes.

The retired stockbroker, 73 years old, chalked up the fatigue to grief over the death of his sister. His cardiologist found a different cause: a genetic mutation causing clumps of malformed proteins to build up in his heart, taxing its ability to pump blood.

Without treatment, he would die. After a desperate search, his family found a promising but risky option: an experimental drug that would edit his DNA inside his body to stop his disease, known as transthyretin amyloidosis.

Odunsi decided it offered his best chance. "Go for it," he told himself.

It sounds like science fiction, but Odunsi is among dozens of people participating in studies on a controversial new forefront of the gene-editing revolution.

Regulators approved last year the world's first medicine using Crispr, the Nobel Prize-winning tool for modifying genes. The medicine, for sickle-cell disease, a group of inherited blood disorders, involves extracting cells, editing them in a lab and putting them back in the patient's body.

The experimental therapies Odunsi and others are receiving, by contrast, edit their cells inside their bodies. "In vivo" gene editing, as the approach is called, could transform medicine. Several of the therapies are for cardiovascular disease, and if proved safe and effective could reach millions of patients.

"In vivo is the future, no question," said Dr. Kiran Musunuru, professor of cardiovascular medicine and genetics at the University of Pennsylvania.

In March 2022, Odunsi messaged updates to his wife on his iPad as a clear liquid dripped into his arm over 2 1/2 hours in a research facility in London. The infusion, from Intellia Therapeutics and Regeneron Pharmaceuticals, contained fat bubbles called lipid nanoparticles that carried gene-editing machinery to Odunsi's liver, where the protein causing his disease is produced. The machinery would target the spot it was looking for in Odunsi's genome and turn off the gene that produces the protein.

In vivo editing could be less expensive and reach more people than editing cells outside the body. It doesn't require the laboratories and expertise needed to extract and edit cells.

Editing inside the body might also be easier on patients. They don't have to undergo chemotherapy, for example, which is necessary for sickle-cell patients before receiving their cells that have been edited outside the body.

Cells in most of the body can't be extracted for editing, said Dr. John Leonard, Intellia's chief executive. "You have to go into the body," he said.

But in vivo therapies also carry the risk of an accidental edit to an unrelated gene. "We don't know what we don't know with gene editing," said Dr. Douglas Mann, a cardiologist and professor of cell biology and physiology at Washington University School of Medicine in St. Louis. The risks could outweigh the benefits for conditions with available treatments, he said.

Scientists haven't figured out how to deliver gene editors to many parts of the body. One reachable target is the liver, where many genes tied to cardiovascular conditions act. The liver's job is to process blood, so it easily takes up gene-editing machinery infused into the bloodstream, said Musunuru, a co-founder of Verve Therapeutics, a company developing in vivo therapies to lower cholesterol and triglycerides.

Verve reported in November that one therapy reduced levels of LDL cholesterol by as much as 55% in a small clinical trial. Verve is enrolling more patients, including in the U.S., and plans to start trials of two more therapies this year.

The idea is to lower cholesterol permanently after one treatment, replacing daily pills or intermittent injections, said Dr. Sekar Kathiresan, Verve's CEO. People often don't take regular drugs as prescribed, he said.

"It's early, but the result opens the door, we think, for a whole new way to treat this disease," Kathiresan said.

Verve's work also illustrates the safety concerns gene editing presents. A patient with a history of heart problems died of cardiac arrest five weeks after treatment. Investigators determined it wasn't related to the treatment. Another had a heart attack a day after his infusion. The patient, who had heart disease, didn't mention chest pains before his infusion that would have excluded him from the treatment, Kathiresan said.

Intellia is testing in vivo experimental therapies for the disease affecting Odunsi, also known as ATTR amyloidosis, as well as for hereditary angioedema, a rare genetic condition involving swelling attacks when blood vessels leak fluid into tissues. The goal is to show they work better than other drugs, Leonard said.

"I don't think it would be appropriate to get gene editing just to not have to take your medicine if the outcomes weren't superior," he said.

People with ATTR amyloidosis produce misfolded proteins that form deposits in the heart and lead to symptoms of heart failure. In a hereditary form of the disease, amyloid deposits form in the nerves, too.

James Green, a 57-year-old accountant in Letterkenny, Ireland, worried he had inherited the disease after his aunt and other relatives died prematurely with weakened limbs and shortness of breath.

Genetic tests confirmed his hunch in 2020. More tests showed amyloid on his heart and early nerve damage. He had run marathons before, but now felt weakness and burning in his legs.

Green chose Intellia's experimental gene-editing therapy over regular drug infusions. "It was really the prospect of it being a once-off treatment, and getting your life back on track," he said.

He received a low dose of the Intellia therapy in January 2021, lying in a bed at the research facility in London surrounded by medical staff. Follow-up tests indicated that within a month, levels of the disease-causing protein dropped more than 50% for Green and two other patients who got the same dose.

In May 2023, he returned for a full dose. His legs have strengthened and the burning sensation is gone. "It's really life-changing," he said.

In September, he went on a trek to Everest Base Camp in Nepal. He wants to return this year.

Protein levels in Green, Odunsi and other patients who got the full dose have dropped more than 90%, said Dr. Julian Gillmore, the trial's U.K. national coordinating investigator and head of the University College London Center for Amyloidosis. Odunsi's heart failure has improved, he said. The patients will be followed for several years.

Odunsi now takes 90-minute walks five days a week. "Every day is a celebration," he said. "It was worth the risk."" [1]

In Lithuania, the most talented young people cannot pass on purpose complicated (so that they don't pass) exams, so they dig in the bushes and wait for the Russians, who supposedly will come someday. Bandits led by Gabrielius Landsbergis run around Lithuania and loot everything they want. Lithuania became a branch of Haiti. What is Crispr? What, are you kidding me? There is no one left to do it. You say that the written ambition is to turn Lithuania into a biotechnological powerhouse? Forget it. The thugs, including the Landsbergis family, don't know what Cripr is. You say Vilnius University can explain? It can, but it is busy, sucking out loans to students guaranteed by the state of Lithuania from Scandinavian banks.

 

1. Doctors Can Now Edit Cells Inside Sick People. McKay, Betsy.  Wall Street Journal, Eastern edition; New York, N.Y.. 12 Mar 2024: A.1.