In a promising step towards a new treatment for sickle cell anaemia, researchers have discovered a small molecule that boosts levels of foetal hemoglobin, a healthy form that adults normally do not make.
Current treatment options are few, including bone marrow transplants and gene therapy, and only address a subset of symptoms. Opioids are used for pain management, with their hazard for addiction and abuse.
The researchers presented their results at the spring meeting of the American Chemical Society (ACS).
“Using our proprietary small molecule probe and CRISPR guide RNA libraries, we screened a disease-relevant cell model that allowed us to pinpoint a treatment target,” said Ivan V Efremov, PhD, senior director, head of medicinal chemistry of Fulcrum Therapeutics.
Sickle cell disease occurs when genes for two of haemoglobin’s four proteins contains an error, resulting in a rigid, sickle-like shape. This has consequences in reduced oxygen transport, and painful blockages of the irregularly shaped cells called vaso-occlusive crises. The red blood cells die fast, leading to anaemia. These patients are also at high risk of developing stroke, heart disease, kidney failure and other potentially deadly conditions.
While in the womb, humans make “foetal” haemoglobin that carries oxygen normally but three or four months after birth, cells switch to an adult haemoglobin version. Although the adult haemoglobin expressed by sickle cell patients is defective, stem cells in their bone marrow still have the capacity to produce foetal haemoglobin.
Some individuals have a hereditary persistence of foetal hemoglobin, and so tap this resource automatically. “They have the sickle cell mutation, but additional mutations result in continued expression of fetal hemoglobin into adulthood,” said Christopher Moxham, PhD, chief scientific officer of Fulcrum Therapeutics. With foetal hemoglobin levels of around 25-30%, he said, enough red blood cells function well enough that patients may become asymptomatic.
The team developed a drug, called FTX-6058, that mimics the effect seen in patients with the hereditary persistence of foetal hemoglobin. It attaches to a protein inside bone marrow stem cells that will mature into red blood cells and reinstates their foetal haemoglobin expression. “What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution,” Dr Efremov said. “If some red blood cells did not express this, they could still sickle and cause disease symptoms.” Fulcrum began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments showed an increase in fetal hemoglobin levels to around 25-30%.
“What distinguishes FTX-6058 is that we are targeting the root cause of sickle cell disease,” Dr Moxham said. “Other drugs approved in this space, particularly since 2019, are treating the disease’s symptoms, either the anemia or the vaso-occlusive crises.”
Preclinical experiments showed that FTX-6058 outperformed another foetal heamoglobin booster, hydroxyurea, approved in the 1990s.
A phase 2 clinical trial is planned for people living with sickle cell disease which should begin by the end of 2021. The researchers are also further characterising the therapeutic molecule. Fulcrum is also considering exploring the use of FTX-6058 in people living with β-thalassemia, a blood disorder in which haemoglobin production is reduced.
Source: Medical Xpress
