An innovative gene therapy has managed to reduce the level of LDL cholesterol for the first time in people with familial hypercholesterolemia, according to preliminary results of a clinical trial presented on Sunday at a meeting of the American Heart Association in Philadelphia (USA).
The treatment consists of inactivating the gene that produces the enzyme PSKC9 in the liver. This enzyme, necessary for the proper functioning of the human body, promotes a high level of LDL cholesterol, which is a disadvantage for people with cardiovascular risk factors.
An RNA drug to reduce cholesterol that arrived in Spain this month, inclisiran, also acts by inhibiting the PSKC9 enzyme. Likewise, there are approved antibodies against PSKC9 approved in Europe since 2015. These treatments are indicated in cases where the usual treatment, based on the combination of a healthy diet and a statin, is not enough to achieve adequate cholesterol levels.
The advantage of gene therapy over currently existing treatments is that it may be administered only once for its effectiveness to be maintained in the long term, and possibly for life. But first it must be demonstrated in clinical trials that it is effective and safe.
The first is being carried out in people with familial hypercholesterolemia with diagnosed cardiovascular disease. This is a phase 1 clinical trial started in July 2022 in which different doses will be tested in 44 patients to determine which is the most appropriate.
The results of the first ten patients presented by the company Verve Therapeutics, which has developed the treatment, have been positive. In the three patients who received the highest doses (0.45 and 0.6 milligrams per kilo of weight), the level of LDL cholesterol was reduced between 39% and 55%. In a patient who received the therapy more than six months ago, cholesterol reduction has remained stable throughout this period.
The treatment is based on lipid nanospheres that are administered by intravenous injection. When they reach the liver, they modify the PSKC9 enzyme gene with a technology called gene base editing. The Boston-based company Verve Therapeutics compares it to an eraser and a pencil. As explained on its website, base editing consists of deleting a letter from the genome and writing another in its place, thus modifying the protein that is produced. In the case of PSKC9, the correction is sufficient to inactivate the enzyme.
Valuing the potential of this new technology, the multinational Eli Lilly has paid 60 million dollars to Verve Therapeutics to collaborate in the development of gene therapy and will contribute 250 million more depending on the results obtained. “Until now we thought of gene editing as a treatment reserved for very rare diseases for which there are no other options. "But if we can make gene editing safe and available on a large scale, why not address a more common disease?" Daniel Skovronsky, chief scientific and medical officer at Ely Lilly, told The New York Times, which has advanced the news.
“Of the more than three million people who have familial hypercholesterolemia in the United States and Europe, very few are at the desired level of LDL cholesterol,” said Deepak Bhatt, director of Mount Sinai Fuster Heart Hospital in New York, in a statement. released by Verve Therapeutics. “I am very encouraged by the initial clinical trial data demonstrating the potential of single-dose gene editing as a new strategy to treat patients with familial hypercholesterolemia.”
The clinical trial that is currently underway is due to conclude in 2024. In the first half of next year, Verve Therapeutics will select the most suitable dosage for subsequent clinical trials. As reported by the company, a phase 2 clinical trial is planned to begin in 2025 with a larger sample of patients.
