Anemia Treatment with Gene Scissors

Mandy Boontanrart, an ETH Zurich molecular biologist, is investigating gene treatments that could be used to treat two of the most frequent types of inherited anemia. She has recently found a promising treatment for beta-hemoglobinopathies. The study has been published in the journal eLife.

Many genetic disorders have long been thought to be incurable. The alteration of the genome is too unexpected and intricate, and the outcomes are too unknown. This is because these disorders frequently include many genes that can be found on various chromosomes.

The CRISPR-Cas9 gene scissors, on the other hand, have completely rewritten the rulebook. Targeted manipulation of individual genes or even entire DNA building blocks has gone a long way in the last several years. As a result of these combined efforts, it is now possible to cure inherited disorders in humans.

The use of gene scissors in the treatment of beta-hemoglobinopathies

Mandy Boontanrart, a molecular biologist from the group lead by ETH Professor Jacob Corn, is one of many hoping to use CRISPR-Cas9 technology to treat a hereditary condition. She recently worked on a project that could revolutionize the treatment of inherited beta hemoglobinopathies. This word refers to two kinds of anemia: beta thalassemia and sickle cell anemia, both of which are among the world’s most common genetic illnesses.

Mutations in the HBB gene cause beta hemoglobinopathies. This gene codes for the beta globin protein chain, which is a component of hemoglobin. Hemoglobin, which is abundant in red blood cells, provides blood its color and is important for delivering oxygen throughout the body. Adult hemoglobin is composed of two alpha globins and two beta globins. Hemoglobin can be made up of two alpha globins and two delta globins in smaller proportions. Delta globins function exactly like beta globins but are only found in trace numbers in red blood cells.

There will be a lack of functional hemoglobin if the HBB gene has a mutation that causes beta globin production to malfunction. Typically, this causes red blood cells to die prematurely, resulting in anemia. All of the body’s organs are then chronically deprived of oxygen.

If the mutation is limited to just one copy of the HBB gene, carriers can lead a relatively normal life. “A person with a single mutation will have great difficulty becoming a professional athlete, but they will still be able to go jogging, swimming, and cycling,” says Boontanrart, who herself is a carrier of a mutated gene. But if both copies are damaged, the situation becomes problematic: “If you’re planning to have children with a partner who also has the mutation, the children might inherit both mutated genes—one from the father, the other from the mother. These children would have a serious illness.”

Increasing the synthesis of delta globin

There is currently no viable treatment for beta-hemoglobinopathies. Boontanrart and her colleagues show in their new work that the problem may be rectified by increasing the synthesis of delta globin, which would replace the malfunctioning beta globin. “Humans produce only trace amounts of delta globins naturally.” “This is linked to a special DNA control sequence that inhibits transcription of the relevant gene,” says Boontanrart. So the researchers came up with the notion of changing this control sequence to boost delta globin synthesis.

Boontanrart altered the DNA of progenitor blood cells with CRISPR-Cas9 gene scissors, inserting three additional sections ahead of the HBD gene, which holds the blueprint for delta globins. These insertions are intended to excite the cell machinery into producing more delta globin, which is exactly what occurred.

The results are promising. “We managed to significantly increase in the proportion of delta globin, to the point where it could offer a therapeutic benefit,” Boontanrart says.

However, inserting multiple DNA elements is still not without its challenges. “It’s more demanding than the techniques used by other research groups and pharmaceutical companies,” Boontanrart says. Researchers in the U.S. are also using the CRISPR-Cas9 system to tackle beta haemoglobinopathies by manipulating blood stem cells to produce fetal hemoglobin.

This is the most common kind of hemoglobin seen in fetuses, although newborns stop making it after a few months. The researchers in the United States intend to substitute beta globin with fetal hemoglobin in their proposed treatment. The Federal Drug Administration (FDA) is now reviewing this technique for approval.

Although this technique has a relatively large coverage, it has several limitations, according to Boontanrart. It is not recommended for pregnant or attempting to become pregnant women because fetal hemoglobin links to oxygen more strongly than adult hemoglobin. As a result of the treatment, the mother’s unborn child may be denied oxygen.

“In my opinion, increasing delta globin production is the better treatment option. Delta hemoglobin has very similar properties to beta globin and can be used to treat almost all patients,” Boontanrart says.

A spin-off is in the works

During her ETH Pioneer Fellowship in 2021, Boontanrart created the Ariya Bio initiative to put her research findings into practice. Ariya Bio is based in the ETH ieLab in Schlieren, on the suburbs of Zurich. The next year, ETH Zurich filed a patent application to protect the invention.

Boontanrart is now planning for preclinical investigations to begin in September. The researchers want to test their medication on animals first to see if it is safe and effective for living species. Previous tests were conducted on cell cultures.

Boontanrart says it’s too early to tell precisely when her treatment for beta thalassemia will be ready for the market. She hopes to complete all clinical trials and launch a product by 2030. “I’m optimistic the approval process will go faster for us than for the gene editing techniques currently under review, because they’re also helping to pave the way for our approach.”

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