What is cell and gene therapy?

What is cell and gene therapy?

Most medicines taken today are molecules. A tablet, an injection, an antibody infusion – each is a quantity of a substance that enters the body, does something, and is cleared out. The medicine is used up and needs to be refilled.

A cell or gene therapy is designed differently. What it delivers is a set of instructions – usually a new gene written in DNA, sometimes a tool that edits or silences an existing gene. Once those instructions are inside the right cells, those cells start making a protein the patient was missing, or carrying out a job they could not do before. The treatment enables the patient's own cells to do the work.

The distinction between cell therapy and gene therapy is what material is being delivered to the patient. Cell therapy is when whole cells are processed and transferred into the patient – the cell is the product. Gene therapy is when genetic material is delivered to add to, edit, or override the cell's instructions – the DNA or RNA is the product.

Exhibit 1Cell therapy and gene therapy compared

Feature	Cell therapy	Gene therapy
What is delivered	Whole, living cells, processed in a laboratory and given to the patient.	Genetic material (DNA or RNA), delivered to change a cell's instructions.
Where it happens	Always outside the body (ex vivo): cells are collected, processed, and often grown in a laboratory before they are given.	Inside the body (in vivo), by direct injection, or outside it (ex vivo), by changing cells in a laboratory.
Main goal	Replace or repair damaged tissue or a missing immune function.	Fix or override a faulty, mutated, or missing piece of genetic code.

The two can overlap. When cells are given a new gene in a laboratory and returned, the product is both – a cell therapy made by gene therapy. CAR-T, described below, is the best-known example.

How does it work?

Most therapies start with a target: the faulty gene. Finding the faulty gene is possible because of advances in genomic sequencing, covered in What is genetic sequencing?

Once the target has been identified, cells' genetic instructions need to be changed so they can make (or stop making) specific proteins. This involves gene addition (inserting a healthy copy of a gene into cells to replace a missing or broken one), gene editing (using molecular tools like CRISPR to cut and change specific DNA errors), or gene silencing (turning off or blocking a harmful gene that is making a toxic or unwanted protein).

The hard part is delivery. DNA is a large molecule carrying a strong negative charge, and the fatty membrane around the cell pushes the DNA away. Even before getting to the cell, enzymes would break down the DNA or RNA within minutes.

Viruses are extremely good at delivering genetic material. A virus is little more than a protein shell wrapped around a small set of genes, built to attach to a cell, push its genes inside, and reach the nucleus.

Scientists figured out how to re-engineer a virus. The virus genes that are needed to copy itself are removed and the genetic material used for therapy is put into place. What is left is a delivery shell that can get into a cell – this is called a vector.

Exhibit 2How a virus becomes a gene therapy vector

1

Original virus

A virus is built to carry its genes into a cell.

2

Remove the virus genes

The genes the virus needs to copy itself are removed.

3

Insert the therapeutic gene

The therapeutic gene is put in their place.

4

The vector delivers the gene

What remains is a delivery shell, called a vector, that carries the gene into the cell.

Most therapies use one of two viruses. AAV (adeno-associated virus, a small virus that infects people without causing disease) carries a small amount of DNA and typically leaves it sitting inside the nucleus but separate from the cell's chromosomes. Lentivirus (a family of viruses that includes HIV, used with its disease-causing genes removed) carries more and inserts the new DNA directly into a chromosome. As a result, lentiviral DNA is generally passed on when the cell divides, whereas AAV-delivered DNA can be lost over successive cell divisions.

Exhibit 3Where the new DNA sits inside the cell

Imagine the cell's chromosomes are an instruction manual.

AAV: an extra sheet of instructions

The new DNA sits separately inside the nucleus, like a loose sheet alongside the manual. The cell can read it and produce the desired protein, but when the cell divides, the extra sheet may not be copied into the daughter cells.

Lentivirus: a new page bound into the manual

The DNA is physically inserted into a chromosome. When the cell duplicates its chromosomes before dividing, the inserted gene is copied too, so daughter cells inherit it.

Then there is a choice about where the change is made. Cells can be taken out of the patient (or a donor), changed in a laboratory, and given to the patient. Or the vector can be infused into the patient and left to find the right cells on its own.

Exhibit 4Where the change is made

The difference matters for a practical reason. When a patient's own cells are taken out, the product is a batch made from one person, for that person. A product made from donor cells, or a vial of vector, can be made and stored in advance, like any other medicine.

What are the main types?

Exhibit 5The four main types of cell and gene therapy

Engineered T cells, for blood cancers

T cells are the immune system's killers. They patrol the body looking for cells that are infected or abnormal, and destroy the ones they recognize. In a patient with leukemia or lymphoma, the T cells have not been recognizing the cancer.

So the cancer is pointed out to them. A few hours on a machine separates the patient's white blood cells from the rest of their blood. In the laboratory, a vector delivers a gene for a new receptor – a chimeric antigen receptor. This is where the name CAR-T comes from. Now the T cells can see the cancer. The modified cells are grown for a week or two, frozen, and infused back.

The infused cells find their target, kill it, and multiply, so the number of cells doing the work is many times the initial infusion. How much the engineered T cells multiply varies by patient, and patients whose cells multiply more tend to respond better.

Modified stem cells, for inherited blood diseases

Sickle cell disease and beta thalassemia are caused by a fault in the gene for hemoglobin, the protein that carries oxygen in red blood cells. Red blood cells themselves live only a few months, so correcting those cells would not yield a lasting result. So instead, the therapy targets what makes the red blood cells: the hematopoietic stem cell, the self-renewing marrow cell that produces blood for life.

Those stem cells are collected from the patient's blood, given a working copy of the hemoglobin gene, and returned. The faulty gene is left in place, but the new copy makes enough proper hemoglobin to compensate. Because these stem cells renew themselves, the effect is durable.

Gene therapy infused into the body

When the disease is in an organ that cannot be taken out and put back – the eye, the liver, the motor neurons of the spinal cord – the vector is infused or injected, and has to reach the right tissue on its own.

Natural variants of AAV favor different tissues – liver, muscle, the retina, and one that crosses from the bloodstream into the brain and spinal cord. Choosing a variant is choosing a destination.

These types of gene therapies are generally given only once. The immune system recognizes the virus shell and raises antibodies against it, and those antibodies block any second dose.

Gene editing

The approaches above deliver new genetic instructions into a cell. Gene editing takes a different approach: it changes the DNA that is already there. CRISPR is a tool that can be directed to a specific location in the genome, where it cuts the DNA. The cell then repairs the break, allowing scientists to disrupt or alter a chosen genetic sequence.

How well does it work?

In the best cases, one treatment changes the course of a disease. Patients with otherwise untreatable cancers have entered lasting remission. Children with severe inherited disorders have survived and reached developmental milestones that would once have been unlikely or impossible. And patients who previously required lifelong treatment have been able to stop it after a single intervention.

But the results are far from uniform. Some therapies may be cures. Others help partly, and a few have not yet shown a convincing benefit.

Much of that variation comes down to which cells were changed. A one-time treatment lasts when the changed cells renew themselves, as blood-forming stem cells do, or rarely divide, as nerve and muscle cells do. It can fade when the new DNA sits outside the chromosomes in tissue that keeps dividing. And in CAR-T, how much the engineered cells multiply varies from patient to patient in ways that are not yet understood.

Because many of these diseases are rare, trials often involve relatively few patients and lack randomized control groups. The best results are clear, but it will take time and larger studies to establish how consistently these therapies deliver lasting benefits.

What are the risks?

The risks can be serious, arising from both the treatment process and the lasting changes these therapies can make.

First, the treatment itself can be demanding. Therapies that modify a patient's blood-forming stem cells typically require intensive chemotherapy beforehand to clear space for the modified cells. This temporarily weakens the immune system, creates a risk of serious infection, and can damage fertility.

Second, the body can react severely. CAR-T cells can trigger an excessive immune response, causing high fever, dangerously low blood pressure, or neurological problems. Gene therapies infused directly into the body face a different problem: the immune system can react to the viral vector, sometimes causing severe organ damage, particularly in the liver. These reactions can often be managed, but some have been fatal.

A more fundamental concern is the permanence of genetic changes. Unlike a conventional drug that can be stopped, some of these therapies make lasting changes that cannot easily be reversed.

A common worry is that these therapies permanently alter a person's DNA. But they do not rewrite a person's entire genetic code. They add or modify genetic instructions in specific cells, leaving the rest of the body largely unchanged. And because these changes do not affect reproductive cells, they are not passed on to future children.

The uncertainty is real, however. Genetic changes can have unintended consequences, some of which may not emerge for years. Ultimately, the question is whether the potential benefits outweigh both the risks of treatment and the consequences of leaving the disease untreated.

Why is it so expensive?

Cell and gene therapies are among the most expensive medicines ever developed, with some costing several million dollars for a single treatment. There are two main reasons: how difficult they are to manufacture, and how much lifelong medical care they might replace.

First, limited economies of scale. Some therapies are made one patient at a time. A patient's cells are collected, genetically modified, tested, and returned. The entire process must be repeated for the next patient, making it difficult to achieve the economies of scale of conventional pharmaceuticals. Other gene therapies can be manufactured in larger batches, but the virus has to be grown in living cells, purified, and tested batch by batch, and the diseases they treat often affect relatively few people.

Second, the price reflects what the treatment might replace. A single intervention costing millions of dollars can look reasonable when compared with decades of blood transfusions, clotting-factor infusions, or other ongoing care. In some diseases, the cumulative cost of conventional treatment can exceed the price of gene therapy many times over. But that calculation depends on the treatment's benefits lasting as expected.

Exhibit 6The economics of a one-time treatment

Even when the long-term math favors the treatment, paying for it can still be challenging. Insurance companies would face a very large bill today for savings that may arrive decades later, perhaps after the patient has switched insurers.

To address this, manufacturers have begun offering arrangements such as refunds if the therapy fails to deliver, or payments spread over several years. The federal government has also negotiated agreements for sickle cell gene therapies that give state Medicaid programs rebates if patients do not achieve the expected results.

What is next?

The goal is to make these treatments simpler to deliver, more precise, and affordable enough to reach far more patients.

One major effort is making CAR-T directly inside the body. Today, a patient's immune cells must be collected, shipped to a manufacturing facility, genetically modified, and returned. Researchers are developing ways to deliver the genetic instructions directly to T cells through an infusion. If it works, a custom-made treatment becomes something closer to a conventional drug: made in advance, shipped in a vial, and given without the weeks-long wait for a custom batch.

Another approach is to use cells from healthy donors, genetically modify them, and manufacture treatments in advance. One batch could serve many patients. The challenge is preventing the patient's immune system from rejecting the donated cells, or the donated cells from attacking the patient. These off-the-shelf CAR-T therapies remain investigational.

Preparation could also become gentler. Stem-cell therapies currently require intensive chemotherapy to clear space in the marrow, which deters many eligible patients. Researchers are testing gentler alternatives, such as antibodies that clear out only the targeted stem cells.

Gene editing is also becoming more precise. Newer technologies such as base editing can change individual letters of DNA without cutting both strands, while prime editing can make more complex corrections. Both are being tested in patients, although neither has yet produced an FDA-approved therapy.

Editing is also moving inside the body: every editing therapy approved so far works on cells taken out of the patient, but the first editing therapies designed to work inside the body are now in late-stage trials and under regulatory review.

The same tools are also being tried beyond blood cancers and rare inherited diseases. CAR-T is being tested in autoimmune conditions such as lupus, while gene editing is being explored as a way to lower cholesterol. Early results are encouraging, but treating common diseases raises the bar considerably. Patients who already have effective conventional treatments may be less willing to accept the risks and costs of a permanent genetic intervention.

The next challenge is not simply to make these therapies work, but to make them safe, reliable, and practical enough for much broader use.

Takeaways

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