Tag: sickle cell disease

Categories : GeneticsTags :

Carriers of Sickle Cell are at Increased Risk for Certain Conditions

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

Individuals that have sickle cell trait, who did not which increases the risk of blood clots, a risk that is the same among diverse human populations that may not traditionally be associated with sickle cell disease. The study provides estimated clinical risks for people with sickle cell trait, which can inform clinical practice guidelines.

The study, published in Blood Advances, was led by researchers at National Human Genome Research Institute (NHGRI), part of NIH, The Johns Hopkins University School of Medicine, Baltimore, and the company 23andMe, South San Francisco, California. The researchers examined the largest and most diverse set of people with sickle cell trait to date, which includes data from over 19 000 people of various ancestral backgrounds with sickle cell trait. 

While people with sickle cell trait typically do not have any associated health complications, they are carriers for sickle cell disease. In rare cases, sickle cell trait has been found to be a risk factor for health complications such as muscle breakdown, presence of blood in the urine and kidney disease.

Previous research investigating the relationship between sickle cell trait and blood clots have only included individuals of African genetic ancestry and self-identified Black participants because of the incorrect assumption that the genetic carrier state only affects those who identify as Black or African American. While sickle cell trait in the United States is most prevalent in individuals who self-identify as Black or African American, individuals from all ancestral backgrounds may have sickle cell trait. Sickle cell trait is often found in individuals living in or from West and Central Africa, Mediterranean Europe, India and the Middle East.

“Because sickle cell trait is often associated with people who identify as Black or African American, it is not widely studied in other populations, a bias that has led to unintended harm for those with sickle cell trait,” says Vence Bonham Jr, J.D., who co-led the study and serves as acting deputy director and associate investigator at NHGRI. “In particular, the racialisation of sickle cell trait has resulted in biased estimations of health risks. The results of our study will help clinicians properly contextualise the risk of blood clots amongst people with sickle cell trait without unintended bias.”  

Individuals in this study are part of the 23andMe research program and have volunteered to participate in the research online and provided informed consent, which includes allowing their de-identified data to be analysed and subsequently shared with research collaborators. Using data from this research cohort, which consists of over four million participants, researchers calculated the risk of blood clots in the veins, also known as venous thromboembolism. Through statistical analyses, participants were grouped based on their genetic similarities into genetic ancestry groups. The study found that people with sickle cell trait have a 1.45-fold higher risk of venous thromboembolism than those without sickle cell trait, a risk that is similar across all studied genetic ancestry groups.

To help clinicians estimate the risk of blood clots in people with sickle cell trait in comparison to other genetic carrier states, the researchers analysed risk in people who are carriers for Factor V Leiden, a well-known inherited blood-clotting disorder. The study found that carriers for Factor V Leiden, which is more prevalent in people of European genetic ancestries, had an even higher risk of venous thromboembolism than people with sickle cell trait.

The researchers found that people with sickle cell trait have a higher risk of pulmonary embolism than those without sickle cell trait.

While previous studies have demonstrated that in individuals with sickle cell trait, the risk of blood clots occurring in the lungs is higher than the risk of clots occurring only in the legs, this study supports the link more definitively with a larger sample size.

“This study, therefore, provides important insights about patterns of venous blood clots and suggests a unique mechanism of blood clotting in people with sickle cell trait,” said Rakhi Naik, M.D., clinical director for the Division of Hematology at Johns Hopkins University, Baltimore, who co-led the study. “Knowing the risks of blood clots in people with sickle cell trait is important for situations such as surgeries or hospitalizations, which add to the risk of developing serious blood clots.”

Source: NIH/National Human Genome Research Institute

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