Tag: sickle cell anaemia

Categories : Diseases, Syndromes and Conditions PaediatricsTags :

Hydroxyurea for Children with Sickle Cell Anaemia Significantly Reduces Infections

On By ModernMedia
Sickle cell disease. Credit: National Institutes of Health

A clinical trial in Uganda has revealed that hydroxyurea significantly reduces infections in children with sickle cell anaemia. Their latest findings enhance strong evidence of hydroxyurea’s effectiveness and could ultimately reduce death in children in Africa, the continent most burdened by the disease.

The group’s research, appearing in the journal Blood, revealed that hydroxyurea treatment resulted in a remarkable 60% reduction in severe or invasive infections, including malaria, bacteraemia, respiratory tract infections and gastroenteritis, among Ugandan children with sickle cell anaemia.

“Our investigation provides powerful justifications for hydroxyurea’s use in children with sickle cell anaemia in Africa,” said Dr Chandy John, paediatrics professor at IU School of Medicine and co-lead investigator of the latest study.

“Given the high rates of infection in this region, we hope our evidence will encourage ministries of health to continue supporting and expanding access to hydroxyurea for young patients who can greatly benefit from the treatment.”

Sickle cell anaemia is a genetic blood disorder that alters the structure of red blood cells and affects oxygen distribution throughout the body, increasing susceptibility to serious health complications and life-threatening infections.

According to the World Health Organization, more than 300 000 children worldwide are born with sickle cell disease each year, with a high prevalence found in African countries.

While hydroxyurea has had U.S. Food and Drug Administration approval as a sickle cell disease treatment for children since 2017, its accessibility and acceptance in Africa have been comparatively limited.

As hydroxyurea has become more recognised in African countries for its effectiveness in treating sickle-cell-related complications, John and his colleagues noticed a knowledge gap about the treatment’s effect on infections.

This led the research group to incorporate hydroxyurea treatment and analysis into their established clinical trial, Zinc for Infection Prevention in Sickle Cell Anemia, led by Indiana University School of Medicine and collaborators in Uganda.

During the study, the researchers examined the effects of hydroxyurea on 117 children in Uganda and focused on a range of infections. After hydroxyurea treatment, results showed a substantial decrease in the incidence of these infections.

Additionally, eight of the nine deaths that occurred in the trial were children whose parents declined hydroxyurea treatment. The only death in a child on hydroxyurea treatment occurred four days after starting treatment, providing insufficient time for hydroxyurea to have an effect.

Of the five children for whom a cause of death was known, all five died of infectious causes.

The high death rate in the study, despite expert clinical care by study personnel, provides further evidence of the urgent need for additional interventions to decrease mortality in children with sickle cell disease in Africa.

“Infections commonly precede other complications related to sickle cell anaemia and often result in hospitalizations that can lead to death,” said Dr Ruth Namazzi, site principal investigator, first author and a lecturer in the Department of Pediatrics and Child Health at Makerere University in Uganda.

“We believe incorporating hydroxyurea treatment as the standard of care for sickle cell anaemia across Africa will not only reduce infections but will more importantly save countless lives.”

Source: Indiana University

Categories : Diseases, Syndromes and Conditions GeneticsTags :

A Life-changing Genetic Cure for Sickle Cell Patient

On By ModernMedia
Sickle cell disease occurs in people who inherit two copies of the sickle cell gene, one from each parent. This produces abnormal haemoglobin, called haemoglobin S. Credit: Darryl Leja, National Human Genome Research Institute, National Institutes of Health

Jimi Olaghere, who had suffered all his life from the chronic pain of sickle cell disease, recently received a genetic cure decades sooner than he would have believed possible.

Mr Olaghere is one of the first seven sickle cell patients who received a new gene-editing treatment going through its first clinic trials in the US. “It’s like being born again,” he said, adding that it has changed his life. “When I look back, it’s like, ‘Wow, I can’t believe I lived with that.'”

Mr Olaghere, 36 said: “You always have to be in a war mindset, knowing that your days are going to be filled with challenges.”

Sickle cell disease is caused by a mutated gene that results in abnormal haemoglobin, leading to blood cells becoming more rigid and taking on their characteristic sickle shape. These malformed cells often get stuck in blood vessels, giving rise to ischaemias and an increase in cardiovascular disease risk and organ damage. Mr Olaghere may need a hip replacement due to avascular necrosis.

The disease also causes chronic pain, which he likened to “shards of glass flowing through your veins or someone taking a hammer to your joints.”

Severe pain episodes known as crises are the hallmark of sickle cell disease. For years, Mr Olaghere was hospitalised on a monthly basis. Winters worsened the problem as the cold restricted surface blood vessels, increasing the risk of blockages. He moved to a warmer city, and became a tech entrepreneur as he didn’t think any employer would be sympathetic to going to the hospital so often.

His family urged him to participate in clinical trials or receive a bone marrow transplant. However, he thought it would take too much time and instead pinned his hopes on DNA editing “in the future, probably 20 to 50 years from now”.

But in 2019 he read about a new gene editing therapy and emailed the medical team right away. When he learned he was accepted, he said it was “the best Christmas present ever”. As the pandemic hit and flights were cancelled, he was still able to make the four-hour drive for treatment appointments.
In order to genetically edit his stem cells the stem cells were flushed out of his bone marrow and into the bloodstream for collection.

“You sit there for eight hours and this machine is literally just sucking all the blood out of you,” he said.

The process left him physically and mentally drained, and still needed  blood transfusions. Mr Olaghere had to go through this process, the most difficult of all for him, four times. 

The key to the treatment lies not in correcting the genetic defect that produces the cell but rather sidestepping it by getting the body to use an alternative: foetal haemoglobin 

Ordinarily, at around 40 weeks of pregnancy, a genetic switch called BCL11A is flipped and the body starts producing adult haemoglobin – which is the only form affected by sickle cell disease. 

“Our approach is to turn that switch off and increase the production of foetal haemoglobin again, basically turning the clock back,” explained Dr Haydar Frangoul, who treated Mr at the Sarah Cannon Research Institute.

Mr Olaghere’s stem cells were sent to Vertex Pharmaceuticals’ laboratories for genetic editing. By September 2020, the engineered cells were ready to be infused into his body. “It was the week of my birthday, actually. So it was almost like getting a new life,” he recalled.

The original faulty stem cells that remained in his body were killed off with chemotherapy, and then genetically engineered replacements were infused into his body to produce sickle-free blood.

“I remember waking up without any pain and feeling lost,” he said. “Because my life is so associated with pain, it’s just a part of who I am. It’s weird now that I don’t experience it any more.'”

Dr Frangoul said that the first seven patients’ results have been “nothing short of amazing” and represented a “functional cure” for their disease.
“What we are seeing is patients are going back to their normal life, none have required admission to hospital or doctor visits because of sickle cell related complications,” Dr Frangoul said.

So far, the genetic technique has been conducted on 45 patients with either sickle cell disease or beta thalassaemia. However, the data are still being gathered.

Source: BBC News

Categories : Diseases, Syndromes and ConditionsTags :

Discovery Offers New Treatment for Sickle Cell Anaemia

On By ModernMedia

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