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Tag: sickle cell anemia

Gene Editing Could Cure Sickle Cell Disease

Do you know anybody with sickle cell disease? Sickle cell disease is the most common genetic blood disorder in the world. 70,000 to 100,000 Americans have it. It’s very likely that you know of someone who suffers from the disease or carries the gene.

Sickle cell anemia, a form of sickle cell disease, is caused by a gene mutation that changes the shape of the hemoglobin protein. The shape change causes blood cells which should be round, to be a sickle, curved shape. The deformed cells can clog blood vessels, causing severe pain and other dangerous symptoms. Another form of sickle cell disease is called beta-thalassemia which occurs when the body doesn’t produce enough hemoglobin and red blood cells, leading to low oxygen levels. As a result, children experience growth issues and fatigue.

Sickle Cell Anaemia red blood cells in blood vessels

CRISPR Therapeutics and Vertex have created a treatment called exa-cel, which uses gene editing to cure the disease for at least a year. In December of 2023, the FDA approved this treatment, making the U.S. the second country to approve a CRISPR therapy, following the U.K in November. A company called bluebird bio created another type of gene therapy called lovo-cel, which was approved by the FDA as well.

In exa-cel, the CRISPR system targets the genes that produce hemoglobin. Sickle celled anemia is caused by mutations in the gene HBB. The mutation distorts the structure of hemoglobin, which is what causes the blood cells to to have a curved shape instead of round. Exa-cel helps Cas9, an enzyme, target a gene called BCL11A. This gene stops the body from making a type of hemoglobin only found in fetuses. With Cas9, exa-cel cuts its DNA, which switches off BCL11A in bone marrow stem cells, where red blood cells are produced. As a result, the cells start making the fetal hemoglobin they were originally unable to produce, leading to the creation of healthy-shaped red blood cells. In this new treatment, doctors take out a person’s bone marrow stem cells, edit them with exa-cel, dispose of the rest of their untreated bone marrow, and then put the edited cells back in.

As learned in AP Biology, deletions in DNA can change the process of gene expression. The first part of gene expression is transcription, which happens in three steps: initiation, elongation, and termination. In initiation, the enzyme RNA polymerase binds to a region on a gene called the promoter. This then signals the DNA strand to unwind which allows the RNA polymerase to read the bases. Then in elongation, the RNA polymerase reads the DNA and makes an mRNA strand with complimentary base pairs. During termination, the RNA polymerase crosses a stop sequence, the mRNA strand is complete, and it detaches from the DNA strand. The mRNA then goes on to translation, which is when it is read to make proteins. When exa-cel deletes the DNA that codes for the BCL11A gene, it is never transcribed or translated, it is never expressed, and therefore the body can produce hemoglobin.

Since these modified cells replenish the body over time, exa-cel is seen as a “curative” treatment that is expected to last for the recipient’s lifetime. However, Vertex and CRISPR Therapeutics have only monitored most of their trial participants for less than two years. While nobody is certain that the treatment is permanent and without side effects, this type of gene editing is very significant to the scientific world, and could help thousands of people!

Exa-cel has be tested in about 100 individuals diagnosed with either sickle cell anemia or beta-thalassemia. However, in 2019, the FDA granted the companies a “fast-track” approval, enabling them to test the therapy in smaller groups than what is typically required.

In these ongoing trials, 29 of the 30 participants with sickle cell anemia didn’t experience any pain for one year following their exa-cel transfusions out of the 18 months under observation. Additionally, after receiving exa-cel, 39 out of 42 patients with beta-thalassemia didn’t require blood or bone marrow transplants (standard treatments for the disease) for one year. Vertex and CRISPR Therapeutics plan to track all participants for up to 15 years.

While some could arise earlier, so far the only negative side effects of the treatment are fever and nausea. Additionally, the FDA is worried that the Cas9 enzyme might stay active and cut the genome in places other than BCL11A, leading to what’s called off-target mutations. However, the companies looked into the places where the enzyme would most likely cut in the genome and luckily didn’t find any signs of this happening in the trial participants.
Similar to many gene editing treatments, exa-cel and lovo-cell are estimated to be very expensive. Vertex, CRISPR Therapeutics, and Bluebird Bio have not disclosed the price, but projections indicate they could reach up to $2 million per patient. It is also unclear whether or not the treatment would be covered by insurance, specifically government programs like Medicaid. This is of particular concern given that sickle cell disease predominantly affects people of African descent. African Americans are more reliant on public insurance like Medicaid compared to other groups in the United States.
These treatments are a huge breakthrough in science and could help thousands of people. Unfortunately, they are inaccessible to most people. What do you think these companies can do to make them more accessible? I invite any and all comments to share!

CRISPR and the Battle Against Sickle Cell Anemia

File:Sickle Cell Anaemia red blood cells in blood vessels.png

What is Sickle cell anemia, and why is its treatment so important?

Sickle cell anemia is a genetic blood disorder characterized by the presence of abnormal hemoglobin, the protein in red blood cells responsible for carrying oxygen throughout the body. In individuals with sickle cell anemia, the hemoglobin molecules are shaped like crescent moons, rather than the normal disc shape, giving them the name “sickle cell”. This abnormal shape causes the red blood cells to become rigid and sticky, leading to blockages in blood vessels and reduced oxygen flow to tissues and organs, as shown in the image above. As a result, individuals with sickle cell anemia experience episodes of intense pain, fatigue, jaundice, and susceptibility to infections. Sickle cell anemia is a lifelong condition with no cure, but various treatments exist.

What is CRISPR, and how can gene editing therapy help those with sickle cell anemia?

File:CAS 4qyz.png

CRISPR is a groundbreaking gene-editing tool that utilizes a naturally occurring bacterial defense mechanism, specifically Type-I CRISPR RNA-guided surveillance complex (shown above), which functions like molecular scissors, cutting DNA strands at precise locations. By incorporating a synthetic guide RNA that matches the target DNA sequence, scientists can direct the Cas protein to specific genes within a cell. Once bound to its target, Cas initiates a process that either disables the gene or introduces desired modifications.

In December of 2023, the FDA approved for this tool’s use in the treatment of sickle cell anemia. Dr. Stephan Grupp, chief of the cellular therapy and transplant section at Children’s Hospital of Philadelphia, explains the new treatment, stating that: “It is practically a miracle that this is even possible.” Developed by Vertex Pharmaceuticals and CRISPR Therapeutics, this therapy, known as Exa-cel or Casgevy, utilizes CRISPR technology to correct the genetic mutations underlying sickle cell anemia. Individuals like Haja Sandi, grappling with frequent and excruciating pain, view this transformative treatment as a beacon of hope. In her search for CRISPR treatment, Sandi told the New York Times, “God willing, I will go forward with it.”

However, the path to widespread implementation still faces many obstacles, including the complicated and costly procedures involved, limited availability at medical centers, and struggles in securing insurance coverage.

As the healthcare community navigates the logistical complexities of the treatment, the introduction of gene-editing technology marks a significant milestone in the ongoing battle against sickle cell anemia. Ultimately, this new treatment for sickle cell sets the stage for potential advancements in treating other genetic disorders, possibly leading us to a much brighter future.

What are your hopes and/or concerns regarding the future of gene editing and its potential impact on society? Comment below!

Can Sickle Cell Anemia Be Treated by CRISPR/Cas9 Mediated Gene Therapy?

Founded by Dr. Emmanuelle Charpentier and Dr. Jennifer Doudna, CRISPR is a gene-editing tool that has enabled medical breakthroughs and changed biomedical research. The goal of CRISPR is to treat diseases by developing advanced cell therapies designed to target specific genes that cause or progress the course of a disease. Although in the process of clinical trials, CRISPR could potentially be a treatment for sickle cell anemia.

The CRISPR gene-editing system is split into two parts: Cas9 and a guide RNA. Cas9 is an enzyme that unwinds and cuts two strands of DNA in a specific location in the genome so that DNA can be added or removed. Cas9 has a similar function to the helicase enzyme we studied earlier this year; however, unlike helicase, Cas9 unwinds DNA in an ATP-independent manner and uses the binding energy between the guide RNA and target strand to unzip the DNA. The guide RNA (gRNA) guides Cas9 to a target-specific sequence in the DNA where it should bind and where the edit should be made. This target-specific sequence has a similar function to an RNA primer, which guides the DNA polymerase to this binding site to initiate DNA replication.

Sickle cell anemia is a genetic blood disorder that affects hemoglobin. Sickle cell anemiaSickle cell disease (SCD) causes the body to produce hemoglobin S, an abnormal form of the molecule that lessens its function. Hemoglobin S has a distorted shape, which causes obstructions, pain, infections, and inhibits circulation. Sickle cell anemia is a monogenic, autosomal recessive trait, which means that sickle cell anemia can be passed down through generations if there is one mutated sickle cell hemoglobin S gene present, even though it is a recessive trait (a recessive trait usually indicates that there needs to be two mutated genes for the trait to be present in offspring). CRISPR is a perfect solution for sickle cell anemia, as CRISPR involves an ex vivo gene-edited cell therapy where, theoretically, hemoglobin stem cells can be extracted from the patient, edited and corrected, and then put back into the body. Scientists are still in the clinical trial phase of using CRISPR to treat sickle cell anemia, but wouldn’t it be amazing if it worked for thousands of people!

I hope you guys found this post as interesting as I did. Feel free to leave a comment and tell me what you think!

CRISPR and Sickle Cell Disease

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?

Modifying Genes to Cure a Blood Disease?

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? 



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