Could Casper CRISPR-Cas9 Technologies be a game changer for sickle cell disease treatment?
May 24, 2022 Ishitaa Gupta, Kate Sheire
Introduction
Genetic editing is a concept gaining significant traction in the scientific and greater community because of its unlimited potential to address many health related societal burdens such as cancer, chronic illness, and genetic disorders. One such condition being examined is
sickle cell anemia, an inherited disorder that affects the shape of red blood cells, which carry oxygen to the entirety of the body. Most babies born with sickle cell anemia are found in developing and impoverished countries, where without access to healthcare, a majority of
affected individuals pass away before age 5. One of the most effective experimental technologies within gene editing is the CRISPR-cas9 methodology, which allows researchers to alter DNA sequences and correct genetic defects. CRISPR-cas9 is attempting to find an effective
treatment for sickle cell, by taking stem cells from the patient's own body, treating the faulty genes, then reinserting the modified cells to diminish symptoms.
What is Genome editing?
Genome editing or gene editing refers to a group of emerging technologies that are used to change the DNA of an organism. These technologies have provided scientists with the ability to manipulate a range of gene sequences by adding, removing or changing the genetic material of existing gene sequences. Today their applications range from synthetic biology, human gene therapy, disease modeling, drug discovery, neuroscience, and the agricultural sciences.
How does CRISPR-Cas9 work?
Clustered regularly interspaced short palindromic repeats (CRISPR) - CRISPR-associated protein 9 (Cas9) is one of the leading gene editing technologies. CRISPR refers to a specialized stretch of DNA, whereas the Cas-9 protein acts like a pair of molecular scissors that can cut
DNA strands when guided by RNA. Together these systems protect DNA from invading viruses and plasmids. In essence, short segments of foreign DNA are first inserted into the CRISPR stretch of DNA. These are then transcribed into CRISPR RNA, which recombine into a two strand structure and form trans-activating crRNA (tracrRNA). The tracrRNA directs the CAS-9 protein molecular scissors to degrade the pathogen DNA in a sequence specific manner.
CRISPR-Cas9 and Sickle cell disease:
Sickle cell disease currently only has four FDA approved medications to reduce disease severity, which fail to be a definitive cure covering the range of patients with sickle cell disease. Genetic editing technologies - in particular CRISPR-Cas9 - can be used to tackle this disease by either correcting the mutation in a rare population of stem cells (hematopoietic stem/progenitor cells or HSPCs), avoiding the sickling of red blood cells through fetal hemoglobin expression, or create correct stem cells (induced pluripotent stem cells or IPSCs).
Several studies have been testing these approaches, both in-vivo and ex-vivo. Ex-vivo studies have been found to have a high editing efficiency and ability to gradually remove unedited HPSCs in a patient, however their high cost might make these therapies inaccessible in certain global regions. Attempts to replicate ex-vivo techniques in-vivo have been made, however the requirement for delivery efficiency and high editing efficiency might lead to off-target cell or tissue editing. Other concerns include the uncontrollable expression of CAS9 that might cause genotoxicity or invoke an unwanted immune response. The future use of genetically-edited HSPCs as a cure for most patients with sickle cell disease looks promising, however the need for high editing efficiency and low-off target effects make it challenging to use the scientific evidence in clinical settings. It is also essential to reduce the invasiveness of gathering HSCs from patients and make sure that studies include patients with varied genetic and environmental influences.
The future use of genetically-edited HSPCs as a cure for most patients with sickle cell disease looks promising, however the need for high editing efficiency and low-off target effects make it challenging to use the scientific evidence in clinical settings. It is also essential to reduce the invasiveness of gathering HSCs from patients and make sure that studies include patients with varied genetic and environmental influences.
What does the market for CRISPR-Cas9 currently look like?
The “customer base” for the CRISPR-Cas9 in its application to sickle cell is extremely large. Sickle cell anemia affects over 100,000 individuals in the US alone. Worldwide, there are about 300,000 babies born with sickle cell disease every year, a large portion of which reside in
developing countries. Because the use of the technology is organized by patent distribution, there are several key players who dominate the market. Two such companies are Intellia Therapeutics and CRISPR Therapeutics, both of whom hold several patents related to sickle cell
treatment. In 2020 Intellia received a grant from the Melissa and Bill Gates foundation, which has allowed them to advance preclinical data on a bone marrow-tropic delivery system for invivo genome editing, which should treat diseases such as sickle cell. CRISPR, which holds a
collaborative patent with Vertex in hematopoietic stem cell therapy, is in the clinical stage of treatment development.
Genetic editing is a concept gaining significant traction in the scientific and greater community because of its unlimited potential to address many health related societal burdens such as cancer, chronic illness, and genetic disorders. One such condition being examined is
sickle cell anemia, an inherited disorder that affects the shape of red blood cells, which carry oxygen to the entirety of the body. Most babies born with sickle cell anemia are found in developing and impoverished countries, where without access to healthcare, a majority of
affected individuals pass away before age 5. One of the most effective experimental technologies within gene editing is the CRISPR-cas9 methodology, which allows researchers to alter DNA sequences and correct genetic defects. CRISPR-cas9 is attempting to find an effective
treatment for sickle cell, by taking stem cells from the patient's own body, treating the faulty genes, then reinserting the modified cells to diminish symptoms.
What is Genome editing?
Genome editing or gene editing refers to a group of emerging technologies that are used to change the DNA of an organism. These technologies have provided scientists with the ability to manipulate a range of gene sequences by adding, removing or changing the genetic material of existing gene sequences. Today their applications range from synthetic biology, human gene therapy, disease modeling, drug discovery, neuroscience, and the agricultural sciences.
How does CRISPR-Cas9 work?
Clustered regularly interspaced short palindromic repeats (CRISPR) - CRISPR-associated protein 9 (Cas9) is one of the leading gene editing technologies. CRISPR refers to a specialized stretch of DNA, whereas the Cas-9 protein acts like a pair of molecular scissors that can cut
DNA strands when guided by RNA. Together these systems protect DNA from invading viruses and plasmids. In essence, short segments of foreign DNA are first inserted into the CRISPR stretch of DNA. These are then transcribed into CRISPR RNA, which recombine into a two strand structure and form trans-activating crRNA (tracrRNA). The tracrRNA directs the CAS-9 protein molecular scissors to degrade the pathogen DNA in a sequence specific manner.
CRISPR-Cas9 and Sickle cell disease:
Sickle cell disease currently only has four FDA approved medications to reduce disease severity, which fail to be a definitive cure covering the range of patients with sickle cell disease. Genetic editing technologies - in particular CRISPR-Cas9 - can be used to tackle this disease by either correcting the mutation in a rare population of stem cells (hematopoietic stem/progenitor cells or HSPCs), avoiding the sickling of red blood cells through fetal hemoglobin expression, or create correct stem cells (induced pluripotent stem cells or IPSCs).
Several studies have been testing these approaches, both in-vivo and ex-vivo. Ex-vivo studies have been found to have a high editing efficiency and ability to gradually remove unedited HPSCs in a patient, however their high cost might make these therapies inaccessible in certain global regions. Attempts to replicate ex-vivo techniques in-vivo have been made, however the requirement for delivery efficiency and high editing efficiency might lead to off-target cell or tissue editing. Other concerns include the uncontrollable expression of CAS9 that might cause genotoxicity or invoke an unwanted immune response. The future use of genetically-edited HSPCs as a cure for most patients with sickle cell disease looks promising, however the need for high editing efficiency and low-off target effects make it challenging to use the scientific evidence in clinical settings. It is also essential to reduce the invasiveness of gathering HSCs from patients and make sure that studies include patients with varied genetic and environmental influences.
The future use of genetically-edited HSPCs as a cure for most patients with sickle cell disease looks promising, however the need for high editing efficiency and low-off target effects make it challenging to use the scientific evidence in clinical settings. It is also essential to reduce the invasiveness of gathering HSCs from patients and make sure that studies include patients with varied genetic and environmental influences.
What does the market for CRISPR-Cas9 currently look like?
The “customer base” for the CRISPR-Cas9 in its application to sickle cell is extremely large. Sickle cell anemia affects over 100,000 individuals in the US alone. Worldwide, there are about 300,000 babies born with sickle cell disease every year, a large portion of which reside in
developing countries. Because the use of the technology is organized by patent distribution, there are several key players who dominate the market. Two such companies are Intellia Therapeutics and CRISPR Therapeutics, both of whom hold several patents related to sickle cell
treatment. In 2020 Intellia received a grant from the Melissa and Bill Gates foundation, which has allowed them to advance preclinical data on a bone marrow-tropic delivery system for invivo genome editing, which should treat diseases such as sickle cell. CRISPR, which holds a
collaborative patent with Vertex in hematopoietic stem cell therapy, is in the clinical stage of treatment development.