New medical research applies the Crispr gene technique to the most inaccessible parts of the human body, treating incurable diseases.
A decade ago, biologists Jennifer Doudna and Emmanuelle Charpentier published a landmark paper, which described a natural immune system found in bacteria and its potential as a tool for editing the genes of living organisms.
A year later, in 2013, Feng Zhang and his colleagues at the Broad Institute at MIT and Harvard reported that they had harnessed this system, known as Crispr, to process human and animal cells in the laboratory.
Both groups' work has led to an explosion of interest in using Crispr to treat genetic diseases, as well as a Nobel Prize 2020 for Doudna and Charpentier.
The general idea
Many diseases result from gene mutations, so if Crispr could simply cut out or replace an abnormal gene, it could theoretically correct the disease.
But one of the challenges of Crispr's discovery of treatments has been figuring out how to get the gene-editing components to the part of the body that needs treatment.
A biotechnology company, the Crispr Therapeutics, has somewhat overcome this issue by processing patients' cells outside the body. Scientists there have used their technique to treat dozens of people with sickle cell anemia and beta thalassemia, two common blood disorders.
In these tests, researchers extract patients' red blood cells, process them to correct a disease-causing mutation, and then re-inject them into the body.
But this laboratory (ex-vivo) approach has drawbacks. It is complex to manage, expensive and has limited uses. Most diseases occur in cells and tissues that cannot be easily removed from the body, treated and restored.
Thus, the next wave of research with Crispr focuses on “in-vivo” processing, that is, directly inside the patient's body.
New in-vivo technique
Last year, the Intellia Therapeutics was the first to successfully use a new technique with Crispr against a disease called transthyretin amyloidosis, a potentially fatal genetic disease that can lead to heart failure.
And last week, the Cambridge, Mass.-based biotech company demonstrated its technique's potential in a second disease.
At a conference in Germany, the company announced that treatment with Crispr reduced swelling in six people with a rare disease called hereditary angioedema.
These two diseases involve two different genes, but in both cases Crispr was able to treat them safely and successfully. "This shows us that we can get exactly the same results in completely different genes," says John Leonard, CEO of Intellia.
How does the mechanism work?
Crispr's ingredients can't naturally enter cells on their own, so Intellia uses a delivery system called lipid nanoparticles, which are essentially tiny bubbles of fat, to deliver them to the liver.
In Intellia's trials, patients receive a one-time intravenous injection of these Crispr-loaded nanoparticles into veins in their arms. Since blood passes through the liver, lipid nanoparticles can easily travel there from the bloodstream. In the liver, the nanoparticles are taken up by cells called hepatocytes. Once inside these cells, the nanoparticles break down and let Crispr get to work editing the problematic gene.
In both diseases, a genetic mutation allows an aberrant protein to run wild and cause damage. In hereditary angioedema, Intellia's Crispr treatment is designed to disable the KLKB1 gene in liver cells, which reduces production of the protein kallikrein.
Too much kallikrein leads to the overproduction of another protein, called bradykinin, which is responsible for repeated, debilitating and potentially fatal attacks of edema.
According to an Intellia press release, before receiving Crispr infusion, patients experienced one to seven bouts of edema per month. During a 16-week observation period, the Crispr injection reduced these seizures by an average of 91 percent.
In transthyretin amyloidosis, mutations in the TTR gene cause the liver to produce abnormal versions of the transthyretin protein. These damaged proteins accumulate over time, causing serious complications in tissues such as the heart, nerves and digestive system.
One type of the disease can lead to heart failure and affects between 200.000 and 500.000 people worldwide. By the time patients are diagnosed with the disease, they are only expected to live another two to six years.
Intellia's Crispr therapy is designed to inactivate the TTR gene and reduce the build-up of the disease-causing protein. Vaishali Sanchorawala, director of the Amyloidosis Center at Boston University School of Medicine, says the reduction reported by Intellia is exciting. "This has the potential to revolutionize the outcome for these patients living with this disease," reports Sanchorawala.
A big question is whether the edits will be permanent. In some of the patients, Crispr shows promise over a year, Leonard says. But liver cells eventually regenerate, and scientists have not yet followed patients long enough to know whether new cells separated from the treated ones will also harbor the genetic correction.
Scientists working on in vivo therapies with Crispr have targeted the liver because many genetic diseases are linked to it. And because fats, such as lipids, are easily absorbed by the liver, scientists at Intellia and elsewhere have realized they can be used to deliver Crispr there.
Two other companies, Beam Therapeutics and Verve Therapeutics, are also using lipid nanoparticles to target the liver with gene editing. In July, Verve launched a trial to treat a genetic form of high cholesterol with a base treatment, a more expensive form of Crispr.
But Leonard points out that getting Crispr to other cells and organs is still an enigma. "Where it's hard to get to is the brain and the lungs," says Leonard.
Where Crispr goes next will depend on where researchers can send it.
In closing this article we want to ask one very sorry from the conspiracy theorist friends who must have blisters reading all of the above and especially the word genetic.