CRISPR 2.0: Beyond Sickle Cell

The medical world celebrated a historic milestone in late 2023 when regulators in the UK and US approved Casgevy. This therapy, developed by Vertex Pharmaceuticals and CRISPR Therapeutics, became the first CRISPR-based treatment for Sickle Cell Disease. It was a victory for “ex vivo” editing, where cells are removed, modified in a lab, and returned to the patient.

However, science moves fast. We are already entering the era of CRISPR 2.0. This next phase moves away from the “cut and paste” mechanics of the first generation and toward precise “base editing.” More importantly, it is moving in vivo. This means doctors can inject the gene editor directly into the bloodstream or specific organs to tackle widespread issues like high cholesterol and rare genetic blindness.

The Evolution: From Scissors to Pencils

To understand why these new treatments for heart disease and blindness are revolutionary, you must understand the upgrade in the technology itself.

The original CRISPR-Cas9 system acts like a pair of molecular scissors. It finds a specific sequence of DNA and cuts both strands of the helix. The cell then tries to repair the break, which disrupts the gene. This is excellent for “turning off” a bad gene, which is how the Sickle Cell treatment works.

CRISPR 2.0, often referring to Base Editing or Prime Editing, acts more like a pencil and an eraser. Instead of cutting the DNA helix in half (which carries risks of unintended damage), these tools chemically change one DNA letter to another. For example, it can turn an ‘A’ into a ‘G’ to correct a mutation or disable a disease-causing signal.

Targeting the World's Biggest Killer: High Cholesterol

Heart disease remains the leading cause of death globally, and high levels of “bad” cholesterol (LDL) are a primary driver. While statins and PCSK9 inhibitors exist, they require daily pills or bi-weekly injections for life. Adherence is a major problem; many patients simply stop taking their medication.

Verve Therapeutics is currently leading the charge with a “one-and-done” gene-editing shot.

The VERVE-101 Trial

Verve Therapeutics is testing a drug called VERVE-101. This therapy uses base editing to target the PCSK9 gene in the liver. The PCSK9 gene creates a protein that stops the liver from clearing cholesterol from the blood. By chemically changing a single letter in that gene, VERVE-101 permanently turns it off.

Here are the concrete details from their recent heart-1 clinical trial:

  • The Patient Group: The trial focused on patients with heterozygous familial hypercholesterolemia (HeFH). This is a genetic condition that causes dangerously high cholesterol regardless of diet or exercise.
  • The Results: In early data released in late 2023, patients who received a higher dose of the therapy saw their blood PCSK9 protein levels drop by up to 84%. Consequently, their LDL cholesterol dropped by up to 55%.
  • Durability: Unlike a statin that wears off in 24 hours, this change is written into the DNA of the liver cells. The effect is designed to last a lifetime after a single infusion.

While the results are promising, safety is the priority. Verve noted some transient increases in liver enzymes in patients, which is a marker of liver stress. They are refining the delivery system, specifically the lipid nanoparticles (LNPs) used to transport the editor to the liver, to minimize these side effects.

Restoring Sight: In Vivo Editing for the Eye

The eye is an ideal target for gene editing because it is a small, contained system. It is also “immune-privileged,” meaning the body is less likely to attack the foreign gene-editing tool.

Editas Medicine conducted one of the most significant trials in this space, known as the BRILLIANCE trial, testing a therapy called EDIT-101.

Targeting Leber Congenital Amaurosis (LCA)

The trial focused on LCA10, a rare genetic disorder caused by a mutation in the CEP290 gene. This mutation prevents the light-sensing cells in the retina from working, leading to blindness in childhood. The gene is too large to fit into standard viral vectors used in older gene therapies, making CRISPR the only viable option.

  • The Procedure: Surgeons inject the CRISPR machinery directly under the retina.
  • The Goal: To cut out the specific mutation in the CEP290 gene, allowing the cell to produce the correct protein needed for vision.
  • The Outcome: The results were mixed but groundbreaking. Some patients, specifically those with less advanced retinal damage, reported significant improvements. They could navigate mazes in dim light and sensed light where they previously saw nothing.

While Editas paused enrollment for this specific trial to find a partner for further development, it proved that CRISPR could be safely applied directly to the human retina. This has opened the door for other companies like Beacon Therapeutics and Intellia, who are exploring similar in-vivo applications for other eye conditions.

The Delivery Challenge: Lipid Nanoparticles

The success of CRISPR 2.0 relies heavily on how the editing tools get into the body. You cannot simply inject raw CRISPR proteins into the blood; the body would destroy them immediately.

The solution lies in Lipid Nanoparticles (LNPs). These are microscopic fat bubbles that encapsulate the gene-editing instructions (mRNA). It is the same delivery technology used in the Pfizer and Moderna COVID-19 vaccines.

For the cholesterol treatment, LNPs are naturally absorbed by the liver, making it an easy target. However, reaching other organs like the brain, muscles, or heart requires “targeted” LNPs. Researchers are currently engineering these particles to seek out specific tissues, which would allow CRISPR 2.0 to treat muscular dystrophy or neurodegenerative diseases in the near future.

Frequently Asked Questions

Is this different from the gene editing used in food? Yes. GMO crops are often “transgenic,” meaning scientists add DNA from another species (like bacteria) into a plant. CRISPR 2.0 therapies involve rewriting the human patient’s existing DNA to correct a typo. No foreign DNA remains in the genome.

How much will these treatments cost? The pricing is currently very high. Casgevy, the sickle cell treatment, has a list price of $2.2 million. However, therapies for high cholesterol target millions of people, not just a few thousand. Verve Therapeutics has stated their goal is to eventually make the treatment comparable in cost to a long-term course of current biologic drugs, but initial pricing will likely remain high.

Are the changes passed down to children? No. These therapies are “somatic” cell edits. They affect the liver or the eyes of the patient only. They do not touch the reproductive cells (sperm or eggs), so the genetic changes are not passed on to future generations.

When will the cholesterol shot be available to the public? It is still in the early stages of clinical trials. The FDA requires three phases of trials to prove safety and efficacy. If the data remains positive, a commercial release for high-risk genetic patients could occur later this decade, perhaps around 2028 or 2029.