Akindude Odunsi is used to taking long walks at a brisk pace. So he worried in 2021 when he started feeling so tired and out of breath that he had to turn back after a few minutes. The retired stockbroker, 73, attributed the fatigue to his grief over his sister’s death. His cardiologist found a different cause: a genetic mutation that causes clumps of misfolded proteins to deposit in his heart, hampering its ability to pump blood. Without treatment, he would die. After a desperate search, his family found a promising but risky solution: an experimental drug that would modify his DNA inside his body to stop the disease, which is called transthyretin amyloidosis. Odunsi decided that this was his only hope. “Go ahead” he told himself.
It sounds like a science fiction scenario, but Odunsi is one of dozens of people involved in studies of a controversial breakthrough in the genetic modification revolution. Regulators last year approved the world’s first drug using Crispr, the Nobel Prize-winning gene-editing tool. The drug – for sickle cell disease, a group of inherited blood disorders – involves extracting cells, processing them in the laboratory and reintroducing them into the patient’s body.
The experimental treatments Odunsi and others are receiving, by contrast, modify their cells inside their bodies. In vivo genetic modification, as the method is called, could transform medicine. Several of the treatments are for cardiovascular disease, and if proven safe and effective could reach millions of patients. “In vivo therapies are the future – there’s no doubt about it,” said Dr. Kiran Musunuru, professor of Cardiovascular Medicine and Genetics at the University of Pennsylvania.
Internal pathology
In March 2022, Odunsi kept his wife updated with messages from his iPad as a clear liquid flowed down his arm for two and a half hours at a research center in London. The infusion, from Intellia Therapeutics and Regeneron Pharmaceuticals, contained fat bubbles called lipid nanoparticles, which carry gene-editing vectors to Odunshi’s liver, where the protein that causes his disease is made. These vectors look for the specific spot in the Odunsi genome, target it and turn off the gene that produces the protein.
In vivo modification may be less expensive and accessible to more patients than genetic modification of cells outside the body. It does not require the laboratories and expertise required to extract and modify the cells. In-body modification will also be easier for patients. They do not need to undergo chemotherapy, for example, which is necessary for patients with sickle cell disease before receiving their modified cells outside their body.
In most of the body, cells cannot be extracted to undergo modification, said Dr. John Leonard, chief executive of Intellia. “You have to get inside the body,” he said. But in vivo treatments also carry the risk of accidentally modifying an unrelated gene. “We don’t know what we don’t know in the case of genetic modification,” said Dr. Douglas Mann, a cardiologist and professor of cell biology and physiology at Washington University School of Medicine in St. Louis. The risks may outweigh the benefits for conditions for which treatments are available, he said.
Scientists haven’t found a way to move the gene processors to many parts of the body. A possible target is the liver, where many genes linked to cardiovascular disease are active. The liver’s job is to process the blood, so it readily takes up gene-modifying agents injected into the bloodstream, said Musunuru, co-founder of Verve Therapeutics, a company developing in vivo therapies to lower cholesterol and triglycerides.
Verve announced in November that a treatment reduced LDL cholesterol levels by 55% in a small clinical trial. Verve is now enrolling more patients, including from the US, and plans to start trials for two more treatments this year. The idea is to permanently lower cholesterol after a one-time treatment, replacing daily pills or intermittent injections, said Dr. Sekar Kathiresan, Verve’s chief executive. People often don’t take conventional medications as prescribed, he said. “It’s still early days, but the result opens up a perspective, we believe, for a whole new way to treat this disease,” said Kathiresan.
Genetic risk
Verve’s research also highlights safety concerns with gene editing. One patient with a history of heart problems died of an arrest five weeks after treatment. Investigators determined that his death was not related to the treatment. Another had a heart attack one day after receiving the treatment. The patient, who had heart disease, did not report chest pains prior to administration that would have been a reason for exclusion from the treatment, Kathiresan said.
Intellia is testing in vivo experimental treatments for the disease Odunsi suffers from, also known as ATTR amyloidosis, as well as for hereditary angioedema, a rare genetic condition that involves bouts of swelling when blood vessels release fluid into tissues. The goal is to prove they work better than other drugs, Leonard said. “I don’t think it would be right for someone to get gene therapy just so they don’t have to take their medication if the results aren’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 an inherited form of the disease, amyloid is also deposited in the nerves.
James Green, a 57-year-old accountant from Leetekenny, Ireland, worried he had inherited the disease after his aunt and other relatives had died prematurely, with weakened limbs and shortness of breath. In 2020, genetic tests confirmed his hunch. Further tests showed amyloid in his heart and early nerve damage. He had run marathons before, but now he felt weak and burning in his legs. Green preferred Intellia’s experimental gene therapy to routine drug administration. “The reason was that it really offered the prospect of a one-time cure that allows you to get your life back on track,” he explained. In January 2021 he received a low dose of the Intellia treatment, lying on a bed at the company’s research facility in London, surrounded by medical staff. The retest showed that, within a month, levels of the disease-causing protein had dropped by more than 50% in Green and two other patients who received the same dose. In May 2023 he returned to receive a full dose. His legs had gotten stronger and the burning sensation had disappeared. “It’s really a life-changing thing,” he said. In September he went trekking to Everest Base Camp, Nepal. He wants to go again this year. Levels of the protein in Green, Odunsi and other patients who received the full dose fell by more than 90%, said Dr. Julian Gillmore, the UK’s national co-ordinating investigator for the trial and head of the Amyloidosis Center at University College London. Odunsi’s heart failure has improved, he said. Patients will be followed for several years.
Odunsi now walks 90 minutes five times a week. “Every day is a celebration,” he said. “It was worth the risk.”
Betsy McKay can be reached at [email protected]
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