Gene therapies could one day control cholesterol and other chronic conditions with a single treatment instead of daily medication. But as researchers consider using gene editing for common diseases such as heart disease, obesity and diabetes, they must address difficult questions about permanence, long-term safety, affordability and access. An outlook in JAMA Internal Medicine by cardiologists Eric D. Smith, MD, and Venkatesh L. Murthy, MD, of the Frankel Heart and Vascular Center at Michigan Health University examines how the potential benefits of genomic therapies should be weighed against their risks.
Why one-time gene therapy is different from daily medication
Gene therapy is already used to treat some serious diseases. These treatments can introduce functional copies of genes, suppress harmful gene activity or make direct changes to DNA. Unlike conventional medicines, 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, although 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 prevent or manage a much wider range of health problems, including high cholesterol, heart disease, obesity and diabetes. That expansion raises a fundamental question: because scientists can permanently alter genetic activity, does that mean they should?
One of gene therapy’s most attractive features is the possibility of long-lasting effects without repeated treatment. Traditional medicines generally remain effective only while a patient continues taking them. Genomic therapies act on genetic material itself: they may provide healthy versions of genes, suppress genes associated with harmful effects or alter specific DNA sequences.
This approach can produce so-called “one-and-done” treatments. However, receiving a therapy once does not necessarily mean its effects will last forever.
Smith explains that many gene therapies use engineered viruses to deliver genetic instructions into cells. The immune system may recognize these delivery vehicles and respond to them. If the treatment’s effects later weaken, that immune response could make it difficult or impossible to administer the same therapy again.
Another important distinction involves the cells being modified. Current gene therapies generally target somatic cells, which are cells 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 balance is 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 drugs 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 the potential scale of treatment. Even a rare and serious side effect could harm a substantial number of people if a therapy is given to millions of patients. Treatments intended for widespread use must therefore meet particularly stringent safety standards.
Five questions researchers need to answer
Smith and Murthy suggest considering five key factors when determining whether genomic therapy is appropriate:
- Severity of the disease: How serious are the symptoms, 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?
- Durability of the treatment: Is the target tissue suitable for an intervention intended to produce lasting effects after a single administration?
- Risk of treatment: Are the potential risks of gene therapy justified by the severity of the disease?
- Long-term monitoring: Can researchers reliably track safety and effectiveness over many years, particularly if large numbers of people are treated?
The final question may be especially challenging. Clinical trials typically involve relatively small groups of patients who are followed for a limited period. Such studies can identify many important safety concerns, but they may miss extremely rare complications or problems that take years to appear.
Some side effects may become apparent only after a much larger number of people have received treatment.
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 introducing gene therapy into medical practice.
Patient registries that collect information about people who receive particular treatments have already demonstrated the value of long-term follow-up. However, if a therapy ultimately reaches millions of patients, a much larger surveillance system will be necessary.
These systems should be independent and standardized, allowing researchers to assess consistently whether a treatment’s effects persist and whether unexpected health problems develop over time.
Without reliable long-term data, physicians may struggle to understand the full consequences of genetic interventions that cannot easily be reversed.
Could some genetic changes be too risky to make permanent?
Researchers must also determine whether a particular disease or biological process is suitable for a permanent intervention.
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 over time. In some cases, the difference between an effective dose and a harmful one is very small. Altering a biological process too much or too little can lead to serious complications.
Conventional medicines offer an important advantage in these situations because doctors can change or stop treatment when needed. Permanent gene therapy generally does not provide that option.
Scientists may eventually address 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 adjust or discontinue treatment remains an important safety advantage of conventional medicine.
The cost and access challenge
Safety is not the only barrier to bringing gene editing into mainstream medicine. Cost could also determine whether these treatments become widely available.
Some existing gene therapies have list prices exceeding $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 health systems.
Smith and Murthy therefore argue that affordability and access must be considered from the beginning. 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 plausible. Researchers are conducting initial studies into whether a single gene therapy can produce a long-term reduction in LDL cholesterol, commonly known as “bad” cholesterol.
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, it could eventually offer a new way to protect cardiovascular health without requiring patients to take medication indefinitely.
However, promising early results alone would not justify widespread use. Before these treatments become routine options for common conditions, researchers need convincing evidence that their effectiveness will persist, risks will remain acceptably low over many years and costs will be 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 developed and 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