Researchers first look at a second drug to fight sickle cell anemia by increasing fetal hemoglobin (2023)

A class of drugs used for their ability to stop cancer cells from dividing is currently being studied for its potential to reduce the pain and damage caused by sickle cell disease, researchers report.

The drugs are called HDAC inhibitors, and researchers have early evidence that one called panobinostat can reactivate a gene at birth that makes fetal hemoglobin that cannot be sickled, he says.Congratulations to Abdullah, M.D., director ofBlood Disease CenteralreadyGeorgia College of MedicineEUAugusta Health University.

Hemoglobin is the oxygen-carrying component of red blood cells and, in sickle cell disease, is ineffective in this essential role. Potentially devastating consequences include frequent bouts of pain caused by blockages, especially in the tiny blood vessels produced by the sticky, oddly shaped red blood cells. Many patients experience rapid breakdown or hemolysis of red blood cells. This can cause anemia, damage to major organs, and shorten life expectancy.

Histone deacetylases, or HDACs, are enzymes that are one of many ways to block gene expression, which is a natural process for certain genes, such as the gamma-globin gene that produces fetal hemoglobin during the transition from childhood to adulthood. .

Fetal hemoglobin allows the developing baby to capture oxygen from the mother's blood, while the beta-globin gene makes the adult hemoglobin that carries oxygen. In the first few months after birth, most babies have little or no fetal hemoglobin.

attention yesBetty Pace, MD, Francis J. Tedesco Distinguished Chair ofPediatric Hematology and Oncologyand sickle cell researcher, are the principal investigators of a new three-year, $2.3 million grant (R33HL162681-01) from the National Heart, Lung, and Blood Institute, which is funding an early-stage clinical trial to see if the HDAC inhibitor, panobinostat, could reintroduce activation of this adult fetal hemoglobin gene to directly address the underlying problem of inefficient oxygen delivery.

"HDAC inhibitors are drugs known to alter the expression of certain genes," says Kutlar. “When you inhibit histone deacetylases, you allow re-expression of certain genes that have been turned off by certain mechanisms. This is important for sickle cell anemia because we know that in adults the fetal hemoglobin gene is turned off and we know that fetal hemoglobin works very well as a disease modifier.”

Two HDACs are involved in silencing the fetal hemoglobin gene, and panobinostat is a pan-HDAC inhibitor, meaning it silences more than one HDAC.

Hydroxycarbamide, the first treatment for sickle cell anemia approved by the US Food and Drug Administration in 1998, also increases fetal hemoglobin, although exactly how is not known, and is also used for some cancers. Kutlar notes that if panobinostat continues to show promise, his next steps will involve pairing two fetal hemoglobin promoters to see if there's a beneficial synergy.

For now, their Phase 1 study will test the safety and effectiveness of panobinostat in 18 patients taking either 15 or 20 milligrams several times a week. Researchers will monitor study participants' levels of fetal sickle cell hemoglobin, as well as levels of F cells, a subpopulation of red blood cells that contain fetal hemoglobin. Kutlar notes that the higher dose has been used in other disease states and is well tolerated by patients. But at even higher rates, side effects like diarrhea, nausea, and fatigue become problematic.

Researchers will also work with study participants to develop better ways to ensure they are taking their medications as they should now and in the future. And they'll look for clues that the treatment is a good choice for the individual patient. This includes looking at what happens to non-histone proteins such as NFkB, a regulator of our innate immunity, and p53, a protein within cells that is critical for controlling cell division and death. Histones are the proteins that form the spool around which our DNA is tightly wound, and they are also important for gene regulation.

The researchers have early evidence that the drug, which is taken in pill form, should directly combat the hemoglobin problem in sickle cell disease. Pace showed that panobinostat increased fetal hemoglobin expression in both cultured red blood cells and in mouse models of sickle cell disease, allowing reactivation of the fetal hemoglobin gene. A small early study of Kutlar showed a slight increase in fetal hemoglobin levels after giving patients 10 milligrams of the drug and it was well tolerated.

In this study in people with sickle cell disease, he will look at the drug in patients who are not taking hydroxycarbamide to ensure that the improvement in fetal hemoglobin is due to the new drug. He notes that the majority of study participants will likely come from the approximately 120 patients he currently sees at the Blood Disease Center who have chosen not to take hydroxycarbamide.

Results of a multicenter study of hydroxycarbamide in sickle cell anemiaPublishedcJournal of the American Medical Associationin 2003 indicated that the use of hydroxycarbamide, the only drug approved at the time, reduced mortality because it reduced pain crises and increased fetal hemoglobin.

However, Kutlar and colleagues report that some patients refuse the drug, fearing reported side effects such as reduced male infertility and increased risk of skin cancer and leukemia, as well as weight gain. .

Kutlar says the possibilities for this additional therapy are exciting. "It won't be a cure for sickle cell anemia, but it will be a significant disease modifier that will allow these patients to live longer without as much organ damage and hopefully not as much pain," he says.

Other treatment options include bone marrow transplants, which are believed to be a cure for sickle cell anemia, and gene therapies are another exciting option being explored, including the use of gene editing techniques such as CRISPR to increase hemoglobin expression. fetus or repair the genetic cause of the condition, he says kutlar. While these approaches also show promise, more drugs are still needed because it will likely take many years, if ever, before advanced techniques like these are widely available where the concentration of sickle cell disease is most significant, such as Africa or India, says Kutlar . Also, not all medications work for all patients.

The other three drugs currently approved by the FDA for sickle cell anemia are L-glutamine (Endari), which helps protect red blood cells from damage and was approved in 2017. The monoclonal antibody crisanlizumab (Adakevo), which helps prevent red blood cells red blood cells from adhering to blood vessel walls and voxeltor (Oxbryta), which helps prevent the formation of sickle cells by facilitating the transport of oxygen by cells and slowing down their degradation, were approved in 2019.

The MCG was the research center for hydroxycarbamide and the largest registrant of participants in the crizanlizumab trials. For more information about the new panobinostat study, callBlood Disease Centercall 706-721-2171 and ask for lead study coordinator and clinical nurse LaTanya Bowman or Kutlara.

Panobinostat (Farydak) has been used in this country and is still used in Europe to treat multiple myeloma and has been studied as a possible cure forHIV infection, so there is already significant experience in humans.

Kutlar notes that some adults with naturally high levels of fetal hemoglobin are resistant to sickle cell disease as a result, adding further evidence that drugs that raise this level are beneficial.

MCG, AU Medical Center and Georgia Children's Hospital are following approximately 1,500 adults and children with sickle cell disease.

Genetic disease affects approx.100,000 peoplein the US, according to the Centers for Disease Control and Prevention, and occurs mostly in people whose ancestors came from sub-Saharan Africa; Spanish-speaking regions in the Western Hemisphere, including South and Central America and the Caribbean; Saudi Arabia; India; and Mediterranean countries such as Türkiye and Greece. Closer to home, about 150 children with sickle cell disease are born in Georgia each year, about 3,000 are born nationwide.