It’s now possible to treat inherited blood diseases, such as sickle cell disease, with gene editing. Blood stem cells are extracted from the patient, modified, and infused back into their bone marrow—often requiring a step that kills off existing damaged cells to make space.
While effective, these kinds of therapies are expensive, intense, and tedious, requiring the collection of sufficient numbers of blood stem cells. An alternative is to directly edit these cells in the body. But they’re usually nestled inside the bone marrow and difficult to reach. This week, a team from the IRCCS San Raffaele Scientific Institute in Italy treated infant mice for three types of blood-related genetic diseases with a custom gene-editing shot that directly edited cells in the mice’s blood.
The treatment tapped “a unique window” of time. After birth, blood stem cells flow from the liver to the bone marrow. There, the elusive cells transform themselves into blood and immune cells. But they’re difficult to reach in adults. Infants, in contrast, have an abundance of circulating stem cells in the bloodstream—making them an easy target for gene therapy.
The team successfully reprogrammed the mice’s blood stem cells with a single gene-therapy injection. The edits were long-lasting and survived when transplanted into mice who had not been given the therapy. A dose of “mobilizing agents”—chemicals that stimulate cells in the blood and immune system—further boosted the effect in young adult mice.
Circulating blood stem cells are abundant after birth in people too, wrote the team. The approach could be used to edit blood stem cells directly in the body for multiple diseases. Doing away with the need to first extract the cells could make gene therapy more accessible.
It’s All About Timing
In 2024, the EU approved a gene therapy called Casgevy for the inherited blood disorders sickle cell disease and beta thalassemia. The US FDA soon followed with their own green light. In both treatments, doctors remove blood stem cells from a patient’s body and use CRISPR gene editing to transform a mutated gene into its healthy version.
The treatments are life-changing, but the process is cumbersome, hard on patients, and very expensive. It would be better to genetically alter cells still inside the body. Several studies are already on the way. One from biotech startup Verve Therapeutics uses base editing—swapping one DNA letter for another—to fix a mutation in the liver that causes sky-high cholesterol. Another targets a rare but potentially fatal disease based on abnormal proteins in liver cells.
Most of these therapies deliver their gene-editing payloads in lipid nanoparticles. These tiny bubbles of fat readily tunnel through multiple tissues but generally find their way to the liver first. In other words, diseases of the liver are relatively easy gene-editing targets. Editing blood stem cells inside bone marrow is much harder.
What if there’s another way? Soon after birth, blood stem cells roam the bloodstream before eventually settling into the bone marrow, where they become immune cells and blood cells. The team analyzed these stem cells in newborn, young, and adult mice, and found far fewer circulating cells as the mice aged, including in the liver and spleen. This suggested that there was a window of opportunity to target stem cells before they settle down.
In an initial test, the researchers labeled blood stem cells with a glow-in-the-dark protein to track their movement and the system’s efficacy. The team packaged a gene encoding the protein into a mutated virus called LV. Stripped of the ability to cause dangerous infections, LV is a common vehicle for shuttling genes inside the body (although it has limited cargo space).
After injection into the blood of recipient mice, the virus-carried glow-in-the-dark gene rapidly found its mark—locating and incorporating itself into circulating blood stem cells. Four out of five mice took in the edited stem cells as their own. Twenty weeks after surgery, the edited cells developed into an army of immune cells that settled inside the bone marrow, spleen, and thymus. They also grew and matured when transplanted into another animal, suggesting that the edited stem cells can maintain their function and propagate.
After validating the approach, the team tried the gene therapy itself in mice of multiple ages: Newborns, toddlers, and adults. It worked especially well in newborns, likely because they have plenty of blood stem cells in their bloodstream. Adding a “don’t eat me” signal to the viral carrier further shielded the corrective genes from the body’s immune system.
On-Demand Gene Therapy
The gene therapy’s flexibility is a perk. The team targeted three dangerous disorders. One, dubbed ARO—for autosomal recessive osteopetrosis—limits the body’s ability to produce blood-borne bone cells. People who inherit the disorder often have abnormally brittle bones, with symptoms emerging as an infant. Most don’t survive their first decade.
“This condition requires early intervention to prevent disease progression,” wrote the authors. After injecting the gene therapy into newborn mice with the disease, the team found it corrected enough cells that the animals could build bones normally. These mice also lived longer compared to peers who didn’t receive the treatment.
Mice with a metabolic disorder that severely inhibits immune responses also benefited. Untreated mice died before weaning. The mice that received the therapy survived far longer and were as healthy as their normal peers.
The most impressive results were in Fanconi anemia, a bone-marrow syndrome caused by defective DNA repair that especially affects blood stem cells. The disorder is difficult to treat because there aren’t enough stem cells to collect for gene editing. Several months after newborn mice received an injection tailored to the mutated gene, the production of immune blood cells reached normal levels and maintained them for at least a year.
The results suggest an early treatment window that rapidly closes with age. But adding several clinically approved drugs can expand the window. These medications, dubbed “mobilizer drugs,” force stem cells to circulate and increase gene-editing efficiency.
The team now wants to translate the findings to humans. Analysis of blood samples shows a large number of circulating blood stem cells in infants, suggesting people may also have a “unique and time-sensitive window” when a gene-therapy jab can correct blood-based disorders.
For now, it’s still more effective to edit blood stem cells outside of the body. But the study hints at the potential for “substantial therapeutic benefit” using the new approach, wrote the team. The technology could especially help patients with a limited number of blood stem cells.
“While the efficiency currently remains limited as compared to established ex vivo treatments, it may suffice, if replicated in human babies, to benefit some genetic diseases such as severe immunodeficiencies or Fanconi anemia,” said study author Alessio Cantore.
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