Sickle cell disease : new results could lead to new treatments

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In a breakthrough study of sickle cell disease, biomedical engineers in the University of Minnesota College of Science and Engineering have revealed that the building blocks of the disease are much less efficient at organizing than previously thought.

The findings open the door to new treatments, including new medicines that could be prescribed at lower doses, for the approximately 20 million people worldwide who suffer from the lifelong disease.

The study, which includes the most precise measurements ever of the disease at the molecular level, is published in Science Advances, a journal of the American Association for the Advancement of Science.

“Even though it has been known for decades what causes sickle cell disease at the molecular level, no one has ever studied the disease at this level of detail,” said David Wood, an associate professor of biomedical engineering at the University of Minnesota and a lead author of the study.

“What we found at the nanoscale was quite surprising.

We found that the disease self-assembly process is less efficient than we thought, which means that it could be easier to develop new medicines that would be effective at lower doses and would cause fewer side effects for patients.”

What is Sickle Cell Disease?

SCD is a group of inherited red blood cell disorders.

Healthy red blood cells are round, and they move through small blood vessels to carry oxygen to all parts of the body.

In someone who has SCD, the red blood cells become hard and sticky and look like a C-shaped farm tool called a “sickle”.

The sickle cells die early, which causes a constant shortage of red blood cells. Also, when they travel through small blood vessels, they get stuck and clog the blood flow. This can cause pain and other serious problems such infection, acute chest syndrome and stroke.

Types of SCD

Following are the most common types of SCD:

HbSS

People who have this form of SCD inherit two sickle cell genes (“S”), one from each parent.

This is commonly called sickle cell anemia and is usually the most severe form of the disease.

HbSC

People who have this form of SCD inherit a sickle cell gene (“S”) from one parent and from the other parent a gene for an abnormal hemoglobin called “C”.

Hemoglobin is a protein that allows red blood cells to carry oxygen to all parts of the body.

This is usually a milder form of SCD.

HbS beta thalassemia

People who have this form of SCD inherit one sickle cell gene (“S”) from one parent and one gene for beta thalassemia, another type of anemia, from the other parent. There are two types of beta thalassemia: “0” and “+”.

Those with HbS beta 0-thalassemia usually have a severe form of SCD.

People with HbS beta +-thalassemia tend to have a milder form of SCD.

There also are a few rare types of SCD:

HbSD, HbSE, and HbSO

People who have these forms of SCD inherit one sickle cell gene (“S”) and one gene from an abnormal type of hemoglobin (“D”, “E”, or “O”).

Hemoglobin is a protein that allows red blood cells to carry oxygen to all parts of the body. The severity of these rarer types of SCD varies.

Sickle Cell Trait (SCT)

HbAS

People who have SCT inherit one sickle cell gene (“S”) from one parent and one normal gene (“A”) from the other parent.

This is called sickle cell trait (SCT). People with SCT usually do not have any of the signs of the disease and live a normal life, but they can pass the trait on to their children.

Additionally, there are a few, uncommon health problems that may potentially be related to sickle cell trait.

Cause of SCD

SCD is a genetic condition that is present at birth.

It is inherited when a child receives two sickle cell genes – one from each parent.

Sickle cell disease is an inherited lifelong disorder that causes problems in the protein within red blood cells, called hemoglobin.

The hemoglobin molecules carry oxygen throughout the body.

With sickle cell disease, hemoglobin molecules form into fibers that act like stiff rods within the red blood cells.

The formation of these fibers stiffens the red blood cells and can change the shape from disc-shaped to crescent, or sickle, shape.

University of Minnesota researchers performed the highest-ever resolution measurements of single sickle hemoglobin fiber assembly in action using microscopes and cameras that can measure the molecules at the nanoscale. Credit: Wood, Odde, and Castle; University of Minnesota

When the red blood cells stiffen, they contribute to blockages in blood vessels that slow or stop the flow of blood.

When this happens, oxygen can’t reach nearby tissues.

The lack of oxygen can affect the entire body causing severe pain, increasing the risk of strokes, and causing infections.

The University of Minnesota researchers in this study performed the highest-ever resolution measurements of single sickle hemoglobin fiber assembly in action using microscopes and cameras that can measure the molecules at the nanoscale.

Their measurements show that the rates of sickle hemoglobin addition and loss have been underestimated in previous studies.

The new results reveal that the sickle hemoglobin self-assembly process is very rapid and inefficient.

They found that the process is 4 percent efficient versus 96 percent efficient as researchers previously thought.

“It’s kind of like building a tower by stacking LEGOs,” Wood said.

“For every 100 LEGOs only four actually stay on as part of the tower.

I would have to stack another 100 LEGOs to get another four to stay on.

This shows us that this is a much more inefficient process than previously thought and that it wouldn’t take as much medicine to disrupt this process.”

With sickle cell disease, hemoglobin molecules form into fibers that act like stiff rods within the red blood cells. The formation of these fibers stiffens the red blood cells and can change the shape from disc-shaped to crescent, or sickle, shape. Credit: Wood, Odde, and Castle; University of Minnesota

Currently only two FDA-approved medicines are available to those with sickle cell disease.

While newer alternatives to existing medications are now in development to treat the disease, including stem cell transplants and gene therapy, Wood said those treatments will probably not be available to the millions of people in the developing world who suffer from the disease.

Globally, it is estimated that 300,000 infants are born annually with sickle cell disease.

In the developing world, it remains a major killer of infants and children, particularly in sub-Saharan Africa and India, where an estimated 50 to 90 percent of infants born with sickle cell disease will die before age 5.

In the United States, nearly 100,000 individuals have sickle cell disease.

The Centers for Disease Control and Prevention estimates that sickle cell disease affects 1 out of every 365 black or African-American births, and 1 out of every 16,300 Hispanic-American births.

The U.S. median life expectancy for those with sickle cell disease is 47 years.

“We are hoping the new information we revealed in this study could make a big impact worldwide to develop medicines and other treatments that help millions of people,” Wood said.

Whole sickle blood flows in a microfluidic device with dimensions similar to small branches of the arteries and veins in the body (0.02 millimeters in width). Blood begins oxygenated and flows normally. As oxygen is reduced, the blood slows down and eventually stops flowing completely, similar to what happens in the body for those with sickle cell disease. When oxygen is re-introduced, the blood resumes normal flow. Credit: Wood, Odde, and Castle; University of Minnesota

Wood collaborated with fellow University of Minnesota Department of Biomedical Engineering Professor David Odde and post-doctoral researcher Brian Castle on this study. The research was built upon Odde’s previous work studying a similar assembly of microtubules in cancer.

“We thought we could apply what we learned studying microtubules, which are important targets for cancer treatment, to sickle cell disease, and we were right,” Odde said.

“This shows the power of collaborative research.

My area of expertise was studying microtubule self-assembly in cancer, and Professor Wood has been studying sickle cell disease for more than a decade. By teaming up, and bringing in Dr. Castle’s expertise on nanoscale imaging and analysis, we feel we have made a major breakthrough.”

More information: Brian T. Castle et al, Rapid and inefficient kinetics of sickle hemoglobin fiber growth, Science Advances (2019). DOI: 10.1126/sciadv.aau1086

Provided by University of Minnesota

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