Direction for teachers:

This lesson plan includes two sets of graphical analysis questions followed by a set of related comprehension questions. Have your students read the graph summary and answer the questions in the “The basics” and “Analyzing the data” sections of the lesson plan. You may want to have students complete the first set of questions as a class warm-up and then have students partner up to discuss the second set of analysis questions. If you’d like your class to also complete the comprehension questions, ask them to read the Science News article “A gene editing technique shows promise for lowering LDL cholesterol” and answer the set of questions in the section “Understanding VERVE-101.”

Directions for students:

Read the graph summary and answer the questions below in the sections “The basics” and “Analyzing the data.” Then read the Science News article “A gene editing technique shows promise for lowering LDL cholesterol” and answer the final set of questions titled “Understanding VERVE-101.”

Graph Summary: “Steep reductions”

Patients in a clinical trial took a genetics-based medicine called VERVE-101. These patients had heterozygous familial hypercholesterolemia, a genetic disorder that increases levels of LDL cholesterol, or “bad cholesterol,” which can clog arteries and cause heart disease and early death. A gene-editing medicine, VERVE -101, modifies DNA. Acting like a molecular pencil, VERVE-101 is a base editor that erases one DNA letter in the PCSK9 gene and writes in another, to inactivate the gene. The PCSK9 gene encodes a protein that breaks down another protein called the LDL receptor. The LDL receptor takes LDL out of blood and transports it into liver cells for its disposal, which helps to maintain healthy LDL cholesterol levels in the blood.

In a clinical trial, 10 people received a single dose of VERVE-101. Data from the trial are shown in the graph “Steep reductions.”

Answer the following graphical analysis questions to learn more about the outcomes of the trial and the scientists’ proposed next steps.

The basics

1. Define what is reported on the x-axis and y-axis. Be sure to include the units.

The x-axis shows the dose of VERVE-101 given to a patient in the clinical trial, in milligrams per kilogram. The y-axis shows the reduction of LDL cholesterol in the blood as a percent change.

2. What does a negative percent change indicate on the y-axis? What does a positive percent change indicate?

A negative percent change on the y-axis indicates a reduction in LDL cholesterol in the blood while a positive percent change indicates an increase in LDL cholesterol levels.

3. Explain the x-axis unit mg/kg. What do you think it means in this study?

The unit mg/kg is a proportion of mass. Since it is used when referring to an amount of a drug in a clinical trial for 10 patients, it likely means that the dose of the drug is based on the patient’s body weight. Milligram of VERVE-101 per kilogram of patient body mass.

4. What were the doses of the drug, and how many patients received each dose?

Doses were 0.1, 0.3, 0.45 and 0.6 mg/kg. Patients assigned to each condition were 3, 3, 2 and 1, respectively.

5. Explain what the one purple dot indicates.

The purple dot represents the one patient who received a 0.6 mg/kg dose. That patient had a 55% reduction of LDL level in their blood.

Analyzing the data

1. What is the graph’s general trend?

The higher the dose given to clinical trial patients, the larger the LDL cholesterol reduction percentage in patients’ blood.

2. From the data, would you say that the 0.1 mg/kg dose was effective in lowering LDL levels in the blood? Explain.

Two patients who received 0.1 mg/kg dose had a slight increase in LDL blood levels (8 and 3 percent increases) and one had a slight decrease in LDL blood level. Given that the average change for all three patients was a slight increase in LDL levels, a dose of 0.1 mg/kg VERVE-101 did not seem to have much of an effect. 

3. Explain the range or spread of outcomes for patients who received the 0.3 mg/kg dose. How does this compare to patients who received 0.45 mg/kg? What about the 0.6 mg/kg dose?

There was very little difference in the LDL levels for the 0.3 mg/kg patients. Two had a 9 percent reduction in LDL levels, and one had a 10 percent reduction. Outcomes varied by only 1 percent among the three patients. The 0.45 mg/kg patients had a 9 percent difference in LDL decreases; one had a 39 percent reduction, and one had a 48 percent reduction. There was only one patient who received the 0.6 mg/kg dose, so there were no additional data points or a spread of data for that dose.

4. If you were running another clinical trial of this drug, based on these data, which doses would you administer to patients? Explain your reasoning for each dose given in the previous trial.

I would run a trial with patients at the higher doses, around 0.45 mg/kg, 0.55 mg/kg and 0.65 mg/kg. LDL levels in patients receiving the 0.3 mg/kg dose decreased by about 9 percent on average, and the LDL levels in patients receiving the 0.45 mg/kg dose decreased an average of 43.5 percent. The increase in dose by 0.15 mg/kg appears to have a significant impact on the patients. On average, patients receiving the higher dose experienced an additional 34.5 percent decrease in LDL levels. The 0.15mg/kg increase from the 0.45 mg/kg to a 0.6 mg/kg dose didn’t correspond to as much of a decrease on LDL levels — only about an 11.5 percent decrease. So I would focus my new trials on doses around 0.45 mg/kg. I would want to know if higher doses were safe to administer, and at what level increasing the dose no longer corresponds to a drop in LDL levels. That would allow me to determine if higher doses should be included in trials.

5. What other questions do you have about the doses given in the first trial? What other information would you need to make dose suggestions for a future clinical trial?

How were these original doses determined? Why was only one patient given a dose of 0.6 mg/kg? What are safety implications of using higher doses with patients? I would also like to know much more information about the medication: its risk factors, the results of non-human animal studies, etc.

Understanding VERVE-101

1. What disease does VERVE-101 target?

The medicine targets a genetic disorder, known as heterozygous familial hypercholesterolemia, that leads to high levels of LDL cholesterol in a person’s blood.

2. Describe how VERVE-101 works. What technology is involved? Draw a simple diagram of how the medicine works within the body.

The medicine works by using a base editor to shut down a gene that raises blood LDL cholesterol levels. The medicine consists of two RNA molecules in a fat bubble. After the drug is infused into a patient’s bloodstream, it goes to the liver and enters liver cells. One RNA molecule signals the liver cells to build a protein that will act as a base editor. The other RNA molecule steers the base editor to the right spot in the DNA. Together, these molecules target the PCSK9 gene and shut it down. The fat bubble and RNA molecules then degrade in the body. Student diagrams should show these processes.

3. What are possible benefits of VERVE-101 based on the clinical trials highlighted in the article?

At the two higher doses, levels of LDL cholesterol in the patients’ blood dropped considerably and held steady at those lower concentrations. That may mean that the drug could someday be taken once to lower LDL cholesterol and decrease the risk of severe heart disease.

4. What are some possible risks of VERVE-101, based on the clinical trials highlighted in the article?

The medicine may not be safe, as two of the patients experienced heart-related problems after the trial: one heart attack and one heart failure. Both patients already had heart disease. Another risk of gene-editing medicines is that unintentional edits to genes not targeted by the medicine could occur, possibly leading to cancer.

5. What are the next steps involved in the process of getting VERVE-101 out to people who need it? Why are these steps necessary?

More trials are needed so that scientists can continue to investigate possible risks and side effects of the medicine. The next trials should include patients that don’t have advanced heart disease, to minimize risk of heart attacks during the trial. Trials should focus on the two higher doses of the medicine, which corresponded to a notable drop in LDL levels in the first trial.