Breakthrough CRISPR Treatment and the Road to In-Body Gene Therapy for Blood Disorders

Sunday - August 6 2023, 11:35 UTC - 1 year ago

As gene-editing technology continues to evolve, researchers from the University of Pennsylvania have developed a new single-shot gene therapy treatment that directly reprograms faulty blood cells within the patient's bone marrow, potentially allowing patients with blood disorders access to similar life-changing care without the need for chemotherapy or radiation.

Sickle cell disease is debilitating. Due to faulty genetic code, red blood cells morph from round and plump into jagged monstrosities that scrape and puncture blood vessels. Over time symptoms build up, eventually damaging major organs like the liver, heart, and kidneys.

The disease was incurable—until gene editing came along.

In 2020, a breakthrough technology that used CRISPR improved disease symptoms in six patients for at least half a year. It was a tough journey: scientists removed faulty blood stem cells and disabled a genetic switch to help make them healthy again. Patients then received a hefty dose of chemotherapy to wipe out diseased cells and make room for the engineered cell transplants. The story had a happy ending: after infusion with the edited cells, one teen could go swimming with his friends without pain and enjoy life as a kid.

Yet the Hallmark ending isn’t available to everyone. Although it’s life-changing and effective, the "ex vivo"—outside the body—procedure can only benefit a lucky few. It’s laborious, complex, and extremely costly.

Can we bring a similar treatment to the masses? .

According to a new study, the answer is a tentative yes. By loading gene editing tools intonanoscale blobs of fat, a team from the University of Pennsylvania created a single shot that directly reprograms faulty blood cells inside bone marrow in mice.

Using a similar strategy, they also designed a clever way to kill off existing diseased cells without any need for toxic chemotherapy.

"What really struck me was, damn, how efficient it is," said Dr. Paula Cannon at the University of Southern California, who was not involved in the study.

Straight to the Marrow .

Genetic blood disorders are brutal. Sickle cell disease aside, others, such as beta-thalassemia, reduce the ability of red blood cells to carry oxygen, resulting in severe anemia, weakness, and an increased risk of developing blood clots.

All blood cells originate from a nest of stem cells inside the bone marrow. Called hematopoietic stem cells, these troopers divide throughout life to not only literally give us blood, but also build a cellular army for the immune system.

The classic approach for tackling blood disorders is a bone marrow transplant to completely replace diseased cells with healthy donor ones. Unfortunately, finding a suitable donor is like winning the lottery—even family members may not have the immune profile to minimize potentially life-threatening rejection.

Thanks to CRISPR, these days patients have another option: gene therapy. Here, the patient’s stem cells are removed from the bone marrow and edited to correct genetic mistakes. The next step is "conditioning," which uses chemotherapy or radiation to wipe out the patient’s stem cells, making space for the genetically engineered stem cells. It’s a grueling procedure, and potentially comes with terrible side effects like infertility or cancer from damaging DNA.

There’s no doubt that gene therapy works. Can we simplify it to a single jab in the arm? .

A Fatty Solution .

The team’s inspiration came from Covid-19 vaccines.

At the heart of the technology are tiny fatty blobs called lipid nanoparticles, which are akin to mini-rafts loaded with medical cargo like drugs or gene-editing machinery.