Gene-editing therapies could one day control LDL cholesterol and other chronic disease risks with a single treatment, but their potentially long-lasting effects create major safety, monitoring, cost and equity challenges. In an outlook published in JAMA Internal Medicine, cardiologists Eric D. Smith, MD, and Venkatesh L. Murthy, MD, of the Frankel Heart and Vascular Center at Michigan Health University, outline the questions researchers and doctors must address before genomic therapies are used widely for common diseases.
Gene therapy is already used to treat certain serious diseases. These treatments can introduce functional copies of genes, suppress harmful gene activity or directly alter DNA. Unlike conventional drugs, which generally require repeated doses, some gene therapies are designed to work after a single administration.
More than 6,000 rare genetic diseases have been identified, but only a small number currently have therapeutic targets. Gene therapy has already produced significant successes in conditions including spinal muscular atrophy and sickle cell disease.
Researchers are now investigating whether similar approaches could help prevent or manage a broader range of conditions, including high cholesterol, heart disease, obesity and diabetes. That expansion raises a fundamental question: Just because scientists can permanently alter a person’s genetic activity, does that mean they should?
Why one-time gene therapy differs from daily medication
One of gene therapy’s most attractive features is the possibility of long-lasting effects without repeated treatment. Traditional medicines generally work as long as patients continue taking them. Genomic therapies act on genetic material itself by supplying healthy versions of genes, suppressing genes that produce harmful effects or altering specific DNA sequences.
This creates the possibility of treatments that work after a single dose, often described as “one-and-done” therapies. However, receiving a treatment once does not necessarily mean its effects will last forever.
Professor Smith explains that many gene therapies use engineered viruses to deliver genetic instructions to cells. The immune system may recognize these delivery vehicles and mount an immune response. If that happens, it may be difficult or impossible to administer the same treatment again, even if its effects eventually weaken.
Another important difference is the type of cells being modified. Current gene therapies generally target somatic cells, which are all the cells in the body other than those involved in reproduction. Unlike germline editing, these treatments are not intended to create genetic changes that are passed on to future generations.
Why common diseases create new risks
For people with rare and devastating genetic diseases, the potential benefits of gene therapy may clearly outweigh its risks. Some patients have few effective options, making experimental interventions worth considering.
The calculation becomes much more complicated when the same technology is used for common diseases. Established treatments already exist for conditions such as high cholesterol, heart disease, obesity and diabetes. Many of these medicines can be adjusted as a patient’s condition changes or stopped if troublesome side effects develop.
Permanent genetic interventions may not offer the same flexibility.
Murthy also highlighted concerns about the number of people who could eventually receive these treatments. Even rare and serious side effects could affect a substantial number of patients if a therapy is administered to millions of people. Treatments intended for widespread use therefore need especially stringent safety standards.
Five questions scientists say must be answered
To help determine when genomic therapy is appropriate, Smith and Murthy suggest evaluating five key factors:
- Severity of disease: How severe are the symptoms being treated, and how much benefit is the patient likely to receive?
- Existing treatments: Are effective treatments already available that can be adjusted or discontinued when necessary?
- Treatment durability: Is the target tissue suitable for an intervention intended to produce a lasting result after one administration?
- Shipping risk: Are the potential risks associated with delivering gene therapy justified by the severity of the disease?
- Long-term monitoring: Can researchers reliably track safety and effectiveness for many years, especially when large numbers of people are treated?
The final question may be particularly difficult. Clinical trials typically enroll relatively small groups of patients and monitor them for limited periods. Although these studies can identify many important safety concerns, they may miss very rare complications or problems that take years to appear.
Some side effects become apparent only after more people have been treated.
Tracking risks that may emerge years later
Smith argues that long-term monitoring cannot be treated as an afterthought. It must be an integral part of bringing gene therapy into medical practice.
Patient registries that collect information about people who receive specific treatments have already demonstrated the value of long-term follow-up. However, if treatment eventually reaches millions of patients, much larger surveillance systems will be necessary.
These systems should be independent and standardized so researchers can consistently assess whether a therapy’s effects persist and whether unexpected health problems emerge over time. Without reliable long-term data, physicians may struggle to understand the full consequences of genetic interventions that are not easily reversible.
Could some genetic changes be too risky to make permanent?
Another concern is whether a particular disease or biological process is suitable for a permanent treatment at all.
Murthy emphasizes that the ability to alter a genetic target does not automatically make doing so the best medical decision. Depending on a patient’s symptoms, treatment may need to be adjusted carefully over time. In some cases, the difference between an effective dose and a harmful one is very small. Too much or too little alteration of a biological process can cause serious complications.
Traditional medicines offer an important advantage in these situations because doctors can change or stop treatment as needed. Permanent gene therapy generally does not provide that option.
Scientists may eventually overcome this limitation by developing therapies with biological “off switches” or other mechanisms that can reverse their effects. Until such approaches are shown to work reliably, the ability to reverse or adjust treatment remains an important safety advantage of conventional medicine.
The cost challenge facing gene therapy
Safety is not the only barrier to bringing gene editing into mainstream medicine. Cost may also determine whether these treatments become broadly available.
Some existing gene therapies have a list price of more than $1 million per patient, while others cost significantly more. Such prices may be considered justified for certain rare and life-threatening diseases, particularly when treatment options are extremely limited.
Applying similar pricing to a disease that affects millions of people, however, would place enormous financial pressure on the health care system. Smith and Murthy therefore argue that affordability and access must be part of the discussion from the outset.
Even highly effective gene therapies could create new health care disparities if only a small number of patients can receive them. Researchers and policymakers must consider not only whether these treatments work, but also whether they can be delivered without worsening existing disparities.
Could gene editing prevent heart disease for decades?
Despite these challenges, using gene editing to prevent common diseases is becoming increasingly realistic. Researchers are already conducting initial studies into whether a single gene therapy can reduce LDL cholesterol, commonly known as “bad” cholesterol, over the long term.
LDL cholesterol contributes to the buildup of fatty deposits in the arteries, increasing the risk of heart attack and other cardiovascular diseases. Lowering LDL over the long term is an important strategy for reducing cardiovascular risk.
If gene editing can safely produce a sustained reduction in LDL cholesterol, it could eventually offer a new way to protect cardiovascular health without requiring patients to take medication indefinitely.
However, promising early results alone are not enough to justify widespread use. Before these treatments become routine options for common conditions, researchers need convincing evidence that their effectiveness is sustained, their risks remain acceptably low over many years and their costs are manageable. Reliable safety equipment is also essential.
For Smith and Murthy, the goal is not to suppress genetic medicine. It is to ensure that technologies with the potential to transform health care are deployed carefully and responsibly.
As gene therapy expands beyond rare diseases to conditions affecting millions of people, the central challenge will be ensuring that durable protection does not come at the expense of long-term patient safety.
Source: www.sciencedaily.com
