CRISPR Gene-Editing Could Revolutionize Medicine If Scientists Can Agree on One Thing

Prescription drugs and vaccines have revolutionized health care, reducing death from disease and improving quality of life around the world. But how do researchers, universities and hospitals, and the pharmaceutical industry decide which diseases to pursue drug development?

In my work as director of the Health Outcomes, Policy, and Evidence Synthesis group at the University of Connecticut School of Pharmacy, I assess the effectiveness and safety of various treatment options to help clinicians and patients in make informed decisions. My colleagues and I are studying ways to create new drug molecules, deliver them to the body, and improve their effectiveness while reducing their potential harm. Many factors determine which avenues of drug discovery research people and pharmaceutical companies focus on.

Funding drives research decisions

Research funding accelerates the pace of scientific discovery needed to develop new treatments. Historically, major research supporters such as the National Institutes of Health, the pharmaceutical industry, and private foundations have funded studies of the most common conditions, such as heart disease, diabetes, and mental disorders. A breakthrough therapy can help millions of people, and a small markup per dose can generate huge profits.

As a result, research into rare diseases has been underfunded for decades because it helps so few people, and the costs per dose have to be so high to be profitable. Of the more than 7,000 known rare diseases, defined as those affecting fewer than 200,000 people in the US, only 34 had a therapy approved by the Food and Drug Administration before 1983. .

The passage of the Orphan Drug Act changed this trend by offering tax credits, research incentives, and extended patent life for companies actively developing drugs for rare diseases. . From 1983 to 2019, 724 drugs were approved for rare diseases.

Emerging social issues or opportunities can greatly affect the funding available to develop cures for certain diseases. When COVID-19 broke out around the world, funding from Operation Warp Speed ​​led to vaccine development in record time. Public awareness campaigns such as the ALS Ice Bucket Challenge can also directly raise money for research. This viral social media campaign provided 237 scientists with nearly US$ 90 million in research funding from 2014 to 2018, which led to the discovery of five genes connected to amyotrophic lateral sclerosis, commonly referred to as Lou Gehrigs disease, and new clinical trials.

How science approaches drug development

To develop breakthrough treatments, researchers need a basic understanding of which disease processes they need to improve or block. This requires the development of cell and animal models that can mimic human biology.

It can take years to evaluate potential treatments and develop a finished drug product that is ready for testing in humans. When scientists identify a potential biological target for a drug, they use high-throughput screening to rapidly screen hundreds of chemical compounds that may have the desired effect on the target. They then modify the best compounds to enhance their effects or reduce their toxicity.

If these compounds have poor lab results, companies tend to stop development if the estimated potential revenue from the drug is less than the estimated cost to improve the treatments. Companies can charge more money for drugs that reduce death or disability than for those that only reduce symptoms. And researchers are more likely to continue working on drugs that have greater potential to help patients. To get FDA approval, companies must ultimately demonstrate that the drug causes more benefits for patients than harm.

Sometimes, researchers know a lot about a disease, but the available technology is not enough to develop a successful drug. For a long time, scientists have known that sickle cell disease stems from a defective gene that causes bone marrow cells to produce poorly formed red blood cells, causing severe pain and bleeding. Scientists lack a way to fix the issue or solve it with current methods.

However, in the early 1990s, basic scientists discovered that bacterial cells have a mechanism to recognize and edit DNA. With that model, researchers began the painstaking work of developing a technology called CRISPR to identify and edit genetic sequences in human DNA.

Technology has finally advanced to the point where scientists have been able to successfully target the problematic gene in sickle cell patients and edit it to produce normal functioning red blood cells. In December 2023, Casgevy became the first CRISPR-based drug approved by the FDA.

Sickle cell disease makes a good target for this technology because it is caused by a genetic issue. It’s also an attractive disease to focus on because it affects nearly 100,000 people in the US and is costly to society, causing many hospitalizations and lost work days. It also disproportionately affects Black Americans, a population underrepresented in medical research.

Real world drug development

To put all these pieces of drug development into perspective, consider the leading cause of death in the US: cardiovascular disease. Although there are many drug options available for this condition, there is a continued need for more effective and less toxic drugs that reduce the risk of heart attacks and strokes.

In 1989, epidemiologists found that patients with higher levels of bad, or LDL, cholesterol had more heart attacks and strokes than those with lower levels. Currently, 86 million American adults have high cholesterol levels that can be treated with medications, such as the popular statins Lipitor (atorvastatin) or Crestor (rosuvastatin). However, statins alone do not achieve all of their cholesterol goals, and many patients develop unwanted symptoms that limit the dose they can receive.

So, scientists have developed models to understand how LDL cholesterol is made and removed from the body. They found that the liver’s LDL receptors remove bad cholesterol from the blood, but a protein called PCSK9 prematurely destroys them, raising levels of bad cholesterol in the blood. This led to the development of the drugs Repathy (evolocumab) and Praluent (alirocumab), which bind to PCSK9 and stop it from working. Another drug, Leqvio (inclisiran), blocks the genetic material coding for PCSK9.

Researchers have also developed a CRISPR-based approach to treat the disease more effectively.

The future of drug development

Drug development is driven by the priorities of their funders, whether governments, foundations, or the pharmaceutical industry.

Based on the market, companies and researchers tend to study more widespread diseases with devastating consequences for society, such as Alzheimer’s disease and opioid use disorder. However, the work of advocacy groups and foundations can improve research funding for other specific diseases and conditions. Policies such as the Orphan Drug Act also create successful incentives to discover treatments for rare diseases.

However, by 2021, 51 percent of US drug discovery spending will be directed at just 2 percent of the population. How to strike a balance between providing incentives to develop miracle drug therapies for some people at the expense of the majority is a question facing researchers and policymakers.

This article was originally published on The Conversation through C. Michael White on University of Connecticut. Read the original article here.

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