sickle cell disease

Tag: sickle cell disease

An article published in December of 2023 through ScienceNews identifies how the first CRISPR therapy approved in the U.S. will treat sickle cell disease. CRISPR therapy involves the process of changing the nucleotide sequence of a small segment of guide RNA in order to allow accurate targeting of almost any desired genomic locus for the purpose of correcting disease-causing mutations or silencing genes associated with disease onset (source). On December 8 of last year, the U.S. Food and Drug Administration approved gene editing, or CRISPR, therapy for use in patients ages 12 and older. The treatment, named Casgevy, is the worlds first treatment to alter cells using the Nobel Prize-winning molecular scissors. In addition, Lyfgenia, another gene therapy for sickle cell disease was approved on December 8.

Previously, patients relied on drugs such as hydroxyurea or bone marrow transplants which didn’t always work for everyone. Casgevy on the other hand relies on a patients own cells. CRISPR treatment alters the genetic blueprint of bone marrow cells that give rise to blood cells in order to make new healthy cells.

Approximately 100,000 people in the United States, most of them black or Latino, have sickle cell disease. Sickle cell disease is caused by a genetic defect in hemoglobin, the oxygen-carrying protein in red blood cells. While typical blood cell are flexible enough to slip through blood vessels, sickled blood cells are inflexible and often get stuck resulting in restrictions to blood flow and debilitating pain. People with severe forms of the disease may be hospitalized multiple times a year.

Many scientists are excited about this new treatment option. Kerry Morrone, a pediatric hematologist at Albert Einstein College of Medicine in New York City says CRISPR-therapy treatment for sickle cell disease can give patients a “new lease on life” commenting on the fact that people with the disease often miss school, work, or special events due to the excruciating pain.

Several clinical trials have tested the CRISPR based treatment Casgevy on participants. Victoria Gray, the first sickle cell patient to enroll in the trial recounted how the treatment changed her life. Gray had preciously described bouts of pain that felt like being struck by lightning and getting hit by a train at the same time. Now, pain-free, she is able to enjoy time with her family. Furthermore, Jimi Olaghere, another patient in the trial, told a similar tale. He says before treatment “sickle cell disease dominated every facet of my life” and “hospital admissions were so regular that they even had a bed reserved for me.” After the trial, he is pain free and able to present for his children while also doing the things he loves.

Of course with any new discovery, there are challenges. Patients who wish to be treated with Casgevy must first receive chemotherapy to wipe out existing bone marrow cells so the new ones have a chance to thrive. Chemotherapy can raise the risk of blood cancer and cause infertility. It also kills immune cells which puts patients at higher risk of dying from infections. In addition, the therapy may cost up to $2 million per patient, but healthcare costs for sickle cell patients are already high over their lifetime.

An article published the same day goes into more detail on how exactly this new treatment functions. The article states that the treatment also called exa-cel directs CRISPR to a gene, called BCL11A that typically prevents the body from making a form of hemoglobin found only in fetuses. The new therapy allows physicians to remove a person’s own bone marrow stem cells, edit them with exa-cel, destroy the rest of the person’s untreated bone marrow, and then re infuse the edited cells.

A second article published in January of this year goes into detail about the CRISPR system itself and how it can be used to treat many different conditions. The article states that CRISPR gene editing unlocks the ability to precisely target and edit specific genetic mutations that drive the growth and spread of tumors as well as new possibilities for the development of more effective and personalized cancer treatments. CRISPR gene editing is not only useful for the treatment of sickle cell disease, but also useful in the treatment of a much wider scale.

Similar to the methods in which CRISPR alters genes, in AP Biology class, we preformed a transformation lab in which we altered bacteria membranes through a heat shock in order to allow the plasmid, pGLO, to pass through the membrane and activate the gene for glow. CRISPR functions similarly to pGLO as they both are able to alter the genes inside of cells or bacteria in order to cure diseases or just make bacteria glow green as it did in AP Biology class.

I hope this article helped simplify the ways in which CRISPR therapy works to treat sickle cell disease and other major diseases as well as explaining how this new discovery opens of many new possibilities in the world of medicine and pharmaceutical development. I look forward to seeing where CRISPR gene editing and therapy goes and how many diseases it will be able to cure in the future. What do you think?

CRISPR and Sickle Cell Disease

By asteraceae

On March 8, 2024

In Student Post

A blood smear of someone with sickle cell disease under a microscope

Scientists are starting to use genetic editing tools to edit out genetic diseases, starting with sickle cell disease.

Sickle cell disease is a non-dominant genetic disease that is the result of the red blood cells becoming well, sickle shaped. These cells then die early, and catch on things in veins, resulting in clots.

In addition, the cells aren’t able to properly deliver their cargo to cells- oxygen. The recipients then also promptly die early, resulting in a multitude of complications, many of which are potentially fatal.

CRISPR (short for “clustered regularly interspaced short palindromic repeats”) technology utilizes Cas9 proteins, guided with a sliver of RNA, and it will comb through the DNA and clip the matching strands off, in which it will either be forced to mutate, or function correctly (should it be a mutation that we are seeking to eliminate).

In this case, CRISPR is being used to alter the genes that cause this disorder (that without morality, natural selection would have done its work in weeding it out) as a replacement for the support (i.e. blood transfusions) .

Before the actual editing process, the patient’s stem cells are collected and the patient undergoes high dose chemotherapy to clear the existing bone marrow so that the edited cells can take prevalence

Casgevy, the name of one of the gene editing drugs, does exactly that. Blood is drawn, the blood is treated, then the now edited blood is reinserted into the patients bone marrow. It is currently approved for people 12 and over, but that is likely a base number and one’s doctor would properly evaluate for.

29 of 44 treated patients had achieved 12 consecutive months within the span of 24 months without SCD complications, and all 44 treated patients had successfully accepted the mutated stem.

Common side effects included low platelet and white blood cell levels, mouth sores, headaches, itching, febrile neutropenia, vomiting, abdominal pain, and musculoskeletal pain.

How many other genetic diseases can CRISPR edit out?

Racial Discrepancies in Kidney Disease: Why They Exist and How Researchers Are Addressing Them

By sesaad

On October 24, 2022

In Student Post

Racial Discrepancies in Kidney Disease

“While Black people make up about 12% of the U.S. population, they comprise 35% of Americans with kidney failure.” (The New York Times) “They are 3 times as likely to have kidney failure compared to White Americans.” (Kidney.org)

What causes these statistics? According to the New York Times, it’s a mix of social, economic, and genetic factors.

One gene variant, APOL1, is responsible for the genetic predisposition to kidney disease. Having two copies of this variant is prevalent in people of sub-Saharan descent, and it’s the main contributor to kidney disease. The variants make bodies resistant to efforts taken to moderate one’s blood pressure, a significant risk factor of kidney disease.

Dr. Olabisi, a kidney specialist at Duke University, advises against attributing all racial disparities of kidney disease to genetics. To do so would be to ignore the drastic effects of social and economic inequalities that lead to these jarring statistics.

Identifying the Gene Variant

About a decade ago, Harvard researchers began looking for the cause of kidney disease. They found that the APOL1 gene, which normally destroys harmful protozoa, had variants that intensified the function of the gene, making it detrimental to the body.

These variants evolved in people of Sub-Saharan descent because they originally protected against African sleeping sickness. There is another type of variant that averts malaria but can cause sickle cell disease. Similarly, the APOL1 variant protects against one disease, but possibly causes another.

As we learned in class, sickle cell anemia is rooted in a difference of amino acids in the primary structure of the hemoglobin of red blood cells. In position 6 of the structure, there should be glutamic acid. However, there is valine, causing the protein to fold oddly in its tertiary structures. In its quaternary structure the cells don’t react with each other as they should. As a result, he cell creates a “sickle” shape, which cannot transfer oxygen through it as successfully as the round shape.

Researchers have delved into numerous hypotheses over the year. They considered using medications to block the gene’s variants from harming the body. To find out if APOL1 was required for the kidneys to function, they consulted an Indian farmer whose kidneys functioned properly even though he didn’t have the APOL1 gene. They created a drug, and while the the dose still has to be adjusted, it’s on its way to being successful.

Semantics of Genetic Predispositions

The topic of genetic predispositions raises concerns among academics about the rhetoric that we use to describe people who are affected by the APOL1 gene variants.

Many people of different ethnicities and races have certain genetic predispositions to diseases. For example, Ashkenazi Jews have genetic predispositions to diseases such as Gaucher disease, which affects the spleen and liver, and African Americans people are more likely to have sickle cell disease.

Professor of biological sciences at North Carolina Agricultural and Technical State University warns against harmful rhetoric when he says, “We don’t want to fall into the myth of the genetically sick African.” I agree with his statement

It is scientifically accurate that different ethnicities have genetic predispositions to certain diseases. However, acknowledging that can be a slippery slope, especially when you consider that the most commonly known genetic predispositions effects marginalized members of society. This rhetoric partially absolves societal leaders (scientists, public servants) of effecting change in implementing preventative measures, such as improving healthcare. This rhetoric can easily slip into having Social Darwinist undertones that portray marginalized groups as genetically inferior. Do you think awareness of the language we use is important in academic spaces? Please answer in the comments if you have an opinion on this.

Ongoing Research

On another note, two twin brothers’ experiences helped further researchers’ understanding of the variants. They were asked to be part of a study that tested an arthritic drug on Black Americans to see if it could cure kidney disease. They tested positive for the APOL1 variants, which came to explain one of their kidney failures.

Researchers believe that the APOL1 variants are harmful when there are secondary factors involved, such as an antiviral response to lupus like interferon.

Dr. Olabisi’s study is pending, but in the meantime, Vertex, a drug company, wants to conduct its own research. There’s only one problem: scientists haven’t agreed on how the variants cause kidney disease, so it is unclear what a new drug should obstruct. Vertex, though, has still had some success.

They predicted that “the variants spurred APOL1 proteins to punch holes… in kidney cells” (The New York Times)

After testing on animals that were given the APOL1 variants, they found a drug that worked by identifying that it eliminated 47.6% of protein in urine, which points to improved kidney function. This is a significant step the ongoing research of trying to determine how to treat kidney disease.

In Dr. In Olabisi’s study, he plans to test 5,000 members of his community for kidney disease and the APOL1 variants, and then prescribe them with the drug used for arthritis.

These scientists and doctors are optimistic about the future of their research, and therefore, the future of kidney disease treatment and prevention, especially as it pertains to those disproportionately affected.

Clinical Trials to Cure Sickle Cell Disease Using CRISPER Technology

By lipidliv

On March 20, 2022

In Student Post

The University of Illinois Chicago participates in clinical trials to cure severe red blood congenital diseases such as sickle cell anemia by safely modifying the DNA of patients’ blood cells. In the CRISPR-Cas9 Gene Editing for Sickle Cell Disease, researchers reported that gene editing modified stem cells’ DNA by deleting the gene BCL11A. This gene is responsible for suppressing fetal hemoglobin production. Then, stem cells start producing fetal hemoglobin so that patients with congenital hemoglobin defects make enough fetal hemoglobin to overcome the effect of the defective hemoglobin that causes their disease.

Sickle cell disease is an inherited defect of the hemoglobin that causes the red blood cells to become crescent-shaped. These cells can lyse and obstruct small blood vessels, depriving the body’s tissues of oxygen.

The first two patients to receive the treatment have had successful results and continue to be monitored. Rondelli is on the steering committee for an international clinical trial. The gene manipulation does not use a viral vector as with other gene therapy studies, but this is done with electroporation which is known to have a low risk of off-target gene activation, according to Rondelli. As the strand for the hemoglobin production is very small, being off-target would not allow the treatment to work.

The treatment is created by a small strand of DNA from stem cells that don’t have the gene BCL11A. Researchers do this by editing the strand of DNA by splitting the DNA with a Helicase protein. Then once it is split, it begins to replicate the DNA using small RNA fragments. The researchers then use a specific strand of RNA that does not have a defect. Since they do not have this particular gene, they can produce hemoglobin freely. Now that the cells are producing hemoglobin, they should be able to create enough to stop the blood cells from crescenting. They insert the DNA by electroporation, where the doctors then introduce electronic waves that allow the cell to open. Once the cell is open, the DNA can enter the blood cells.

This clinical trial is still in its early stages, so it is not used around the world. Though it is promising, it has not been through enough trials. I am not sure if it will get to that stage, do you?

CRISPR to the Rescue

By harrisynthesis

On March 20, 2022

In Student Post

If you are reading this right now, it means you are not blind. Aren’t you so fortunate to have healthy vision? Others aren’t as lucky. The genetic disorder of blindness is something that effects many people. However, what if I told you that there may be a way to prevent the passing of a genetic mutation such as blindness? It’s called CRISPR.

Before I get into how CRISPR can help prevent blindness, must know what CRISPR is. CRISPR, short for CRISPR-Cas9, is a tool used for editing genes of organisms by modifying the DNA. By changing the DNA sequence, this causes for a change in gene function. Essentially, CRISPR acts as a scissor that is able to cut and edit the DNA sequence.

The way genes are manipulated is by having the components of one CRISPR sent over to another CRISPR, which then alters the structure of the sequence manually, and is called “gene editing”. This phenomenon was discovered only in 2017 when a University in Japan was able to capture and reveal to the world the exact process of this gene editing. Genes are compromised of chemical bases that bind together to form a sequence and every sequence creates something different. For example the sequence GATC when genetically edited with CRISPR can turn into CATG by just switching the C and G. This may seem small but can have a much larger effect on the organism.

This method can directly be used to alter the genetic mutation that causes blindness in a person by finding the spot in the genetic code in that is the root of the mutation and editing it to become normal. Another new way that CRISPR gene editing can be used is to combat sickle cell disease. This disease that causes the creation of mutated hemoglobin resulting in blood clots can also be fixed. Sickle cell disease effects 100,000 people in the US, and can only currently be treated with bone marrow transplants, but this can lead to other health issues according to Dr. Markus Mapara who studies CRISPR.

Through CRISPR, as found by Dr. Dounda and Dr. Charpentier, they can direct the Cas9 protein part of CRISPR, through a programable RNA, to locate specific areas of genetic code, in particular ones that are the root of a mutation that causes health issues such as Sickle cell disease. As we mentioned before, the CRISPR can then remove and replace the specific area with one that doesn’t result in the genetic mutation.

While there may be other treatments for these diseases, CRISPR is certainly the safer, healthier, and more effective way to combat them. They also haven’t had too much research on it yet, so we are only getting more and more information as time goes on. I personally don’t have any genetic mutations that I know of, but I know many people who do and who this could help. Hopefully we will be able to master the technique and put an end to genetic mutations!

Modifying Genes to Cure a Blood Disease?

By kylsquared

On January 21, 2020

In Student Post

Helen Bolando, a 16 year old living with sickle cell disease, recently became the youngest recipient of an experimental treatment at Boston Children’s Hospital. This treatment made her the youngest person to have her DNA manipulated in hopes of reversing sickle cell’s effects.

What is sickle cell disease?

Sickle cell disease is a disorder caused by a gene mutation that causes the shape of blood cells to resemble that of a crescent. Characteristics of sickle disease include a low red blood cell count and frequent infections. Due to their shape, blood cells in individuals with sickle cell cells break down too early, causing a lack thereof. This lack of blood cells is known as sickle cell anemia and causes a multitude of symptoms ranging from fatigue and shortness of breath, to delayed growth in children. Painful episodes are also common due to the shape of the red blood cells. Their crescent shape causes blockages in blood vessels, depriving organs and tissues of oxygen, sometimes leading to organ failure.

A new gene therapy?

Researchers at Boston Children’s Hospital have found that hemoglobin genes (genes found in the blood) are only active in the preceding red blood cells. These genes are only active for 4-5 days before red blood cells mature and when they’re active, they communicate with other cells through communication such as long distance signaling, as we’ve learned earlier in our bio class . The question for researchers is as follows: “How do you manipulate a gene, or put a gene in, so it is expressed only in those cells and at high levels?” New treatments to solve this burning question include the extraction of immature blood cells from patient’s bone marrow. These stem cells are then genetically modified and re-infused in hopes of creating new, healthy blood cells. Even more interestingly, scientists have found that fetal blood cells have an absence of sickle cells and are testing ways to block the gene that stops fetal hemoglobin production and begins that of adult hemoglobin.Bluebird Bio, a biotech company in Cambridge, Mass conducted a study during which nine patients were treated with gene therapy. Results stated that four patients of the nine who were treated at least six months earlier, produced enough hemoglobin to no longer have the symptoms of sickle-cell disease!

Researchers are making incredible strides in solving this painful disease using extremely creative and innovative techniques! Are there any other methods of solving sickle cell disease you can think of based on what we’ve learned so far about cell communication?

Red blood cells affected by sickle cell disease

A normal capillary vs. capillary affected by sickle cell anemia

Editing Sickle Cell Disease…

By mytosis

On March 12, 2019

In Student Post

CRISPR gene-editing has recently been involved in the studies of sickle-cell anemia, a gene mutation that causes a decline in children’s health. Sickle cell anemia makes it difficult for oxygen to transport sufficiently throughout the body due to unhealthy blood cells. Some symptoms of the condition are shortness of breath, pale skin, colder body temperatures, headaches, etc…

Photo by SciTechTrend

Looking at sickle-cell anemia from a molecular standpoint, the mutation alters the red-blood cell by producing the wrong form of molecule which is referred to as a subunit. Out of the four subunits in hemoglobin, an “adult-expressed” subunit also known as “beta” is produced. In contrast, fetal subunits create “gamma” subunits which are the appropriate molecules in red blood cell development for children. The unfortunate results of a mutated gene are crescent-like and inflexible red blood cells, which can form blockages against the flow of blood and oxygen through blood vessels.

In the past, scientists have been able to increase the gamma production in hemoglobins by “reversing” beta subunits to gamma subunits through a form of therapy, yet in a recent study scientist dove deeper to prevent the mutation as a whole. With gene editing technology, CRISPR has been reported to be useful in putting an end to the hereditary mutation. In that, scientists can identify the mutation and cut the DNA target out by using CRISPR. A specific piece of the DNA, also known as the “control section”, is introduced to gamma subunits during a process of molecular conversion therapy and the ends of the control section are placed together after the mutated code for the gene is removed. Ultimately, this is said to reduce the adult-expressed subunits and stimulate higher levels of gamma subunits in fetal hemoglobins so that young children affected by sickle cell can avoid invasive treatments in their future.

The Child that Saved Millions

By kelsium

On March 12, 2018

In Student Post

Thousands of years ago a child was born in west Africa with genetic mutation that altered the shape of his/her hemoglobin. This mutation wasn’t harmful because each person has two copies of every gene and the other gene was normal and so they lived and passed on their mutated gene that would save millions of lives.

The gene spread across all of Africa and into parts of southern Europe and India. Every so often two people with the gene would make a child that had two copies of the gene. The child would no longer be able to produce normal hemoglobin. As a result, their red cells became defective and clogged their blood vessels. The condition, now known as sickle cell anemia, leads to extreme pain, difficulty with breathing, kidney failure and even strokes. Most people with this disease die before 40.

In the early 1900s doctors in the U.S first noticed this disease and called its sickle cell anemia because of the way the cells look. Most cases were found in African Americans and studies showed that 8 percent of African Americans had some sickle-shaped blood cells, yet the vast majority had no symptoms at all.

By 1950 doctors had discovered that sickle cell anemia was an incomplete dominance trait and the people who had one copy of the mutated and one of the normal gene showed no symptoms. They soon found out the sickle cell anemia was not unique to the U.S in fact the gene turned up in high rates across Africa, southern Europe and into India. Genetically speaking this made no sense because having two copies of the trait was so deadly it would be most likely that the mutation would have become rarer with each generation.

In 1954 a geneticists Anthony C. Allison observed that people in Uganda who carried a copy of the sickle cell mutation had lower rates of getting malaria. Later research confirmed Dr. Allison’s findings. It seems that the sickle cells defend against malaria by starving the single-celled parasite that causes the disease. The parasite feeds on hemoglobin, and so it’s likely that it can’t grow on the sickle cell version of the molecule.

Babies Save the Day?

By buddhabear28

On October 4, 2011

In Student Post

No, a bionic baby did not come and save today’s world from global warming but in fact, embryonic cells could potentially save those who suffer from Sickle Cell Disease.

Sickle Cell Disease occurs as a result of a DNA letter change in the gene for hemoglobin, the main protein that carries oxygen for red blood cells. It is possible for the single mutation in the amino acid sequence to affect the entire protein because, as I learned in class, the chain of amino acids, formed by peptide bonds, constitutes the primary structure of proteins.

A recent study conducted by researchers at Johns Hopkins have found that sickle cell disease, a disease that can be very debilitating and affects mostly African Americans, can be cured with the use of stem cells. This is important because the only cure that has been found so far is bone marrow transplants, which can be very painful and is not always successful. The researchers isolated a patient’s own bone marrow cells and used them to generate induced pluripotent stem cells, which are adults cells that can be reprogrammed into embryonic cells. These embryonic cells can then be coaxed into red blood cells, through the use of growth factors.

Despite this progress, Dr. Linzhao Cheng states that, “these immature red blood cells still behave like embryonic cells, and as a result are unable to turn on high enough levels of the adult hemoglobin gene” . The cells still need to be coaxed into mature red blood cells.

Even if these cells can be coaxed into maturity, can they be used to cure Sickle Cell Disease? Can babies actually save the day?

BioQuakes

AP Biology class blog for discussing current research in Biology

Tag: sickle cell disease

CRISPR Gene Editing: The Key to Pharmaceutical Development

CRISPR and Sickle Cell Disease

Racial Discrepancies in Kidney Disease: Why They Exist and How Researchers Are Addressing Them

Clinical Trials to Cure Sickle Cell Disease Using CRISPER Technology

CRISPR to the Rescue

Modifying Genes to Cure a Blood Disease?

Editing Sickle Cell Disease…

The Child that Saved Millions

Babies Save the Day?

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