Scientists have announced the development of a small molecule which could help to produce a treatment that will target the root cause of sickle cell disease.
Presenting their findings at the spring meeting of the American Chemical Society (ACS), researchers said the small molecule has the potential to boost levels of foetal haemoglobin.
Dr Ivan V Efremov, senior director, head of medicinal chemistry of Fulcrum Therapeutics, who presented the work, said: “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.”
The team developed FTX-6058, which mimics the effect seen in patients with the condition known as hereditary persistence of foetal haemoglobin. The drug attaches to a protein inside bone marrow stem cells that are destined to become mature red blood cells and reinstates their foetal haemoglobin expression.
“What is really key is FTX-6058 upregulates foetal haemoglobin across all red blood cells, a pancellular distribution,” said Dr Efremov. “If some red blood cells did not express this, they could still sickle and cause disease symptoms.”
Last year, Fulcrum began a phase 1 trial in healthy adult volunteers after preclinical experiments showed an increase in foetal haemoglobin levels to about 25-30%.
Dr Christopher Moxham, chief scientific officer of Fulcrum Therapeutics, said while other drugs for sickle cell disease treat its symptoms, such as anaemia or vaso-occlusive crises, FTX-6058 aims at the root cause of sickle cell disease.
The research team is now designing a phase 2 trial for people living with sickle cell disease, which could begin at the end of the year.
They are also further characterising the therapeutic molecule, using genomic technologies and additional cell assay systems. FTX-6058 is also being looked at as a potential treatment for beta-thalassaemia.
[embed virtual press conference of the presentation: https://www.youtube.com/watch?v=VujNS1DQryc ]
Efremov I, Appiah K, Cacace A, Dong Y, Johnstone S, Kazmirski S, Li Q, Moxham C, Rahl P, Roth M, Stuart B, Thompson L, Wallace O, Xie K, Zhou F. (2021) “Discovery of clinical candidate FTX-6058: a potent, orally bioavailable upregulator of fetal hemoglobin for treatment of sickle cell disease”, American Chemical Society Spring Meeting, 5-16th April 2021.
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