Take a stroll through your local pharmacy and look at the sheer number of drugs that are available, both prescription and over-the-counter. There are hundreds of them. But how many of them actually cure the targeted disease? Very few.
Nearly every medicine on the market today is used to treat diseases, or, in some cases, manage the symptoms of diseases. However, researchers are using an approach called gene editing that could cure many targeted diseases.
What is gene editing?
Gene editing involves the insertion, deletion, or replacement of deoxyribonucleic acid (DNA) in a cell. DNA is structured as a double helix that looks somewhat like a twisted ladder. The "steps" on this ladder are made up of pairs of the chemical bases cytosine, guanine, adenine, and thymine, which are typically referred to by their initials C, G, A, and T. Cytosine (C) always pairs up with guanine (G), while adenine (A) pairs with thymine (T).
Genes are sections of DNA that serve as a blueprint for how proteins are built based on the unique sequence of these four DNA bases. Gene editing requires some type of modification of the sequence of the DNA bases.
There are several types of gene editing that can be used by scientists. The oldest approach is zinc finger nuclease (ZFN) technology, which uses genomic "scissors" made up of engineered proteins that scientists used to cut DNA at specific locations. Another method, TALEN, which stands for "transcription activator-like effector nuclease," is similar to ZFN but allows more specific targeting of sections of genes.
The more well-known approach for gene editing today is CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats). With CRISPR, DNA-slicing enzymes produced by bacteria are used to edit targeted sections of DNA. A handful of CRISPR techniques exist that use different bacterial enzymes, including CRISPR-Cas9, CRISPR-Cas3, CRISPR-Cas13, and CRISPR-Cpf1.
Regardless of which editing tool is used, gene editing can be used to cut the DNA or perform DNA repair, perhaps in the cells of human embryos, to eliminate genetic mutations that lead to diseases. Over time, it's even possible that some genetic diseases will disappear altogether as the offending mutations are removed entirely from the human genome (the complete set of genes in humans).
Diseases currently being targeted
What diseases can be potentially cured by gene editing? There are over 10,000 diseases caused by mutations in a single gene (known as monogenic diseases), according to the World Health Organization (WHO). There are many more diseases caused by mutations in multiple genes.
Mutations, by the way, are permanent alterations in the DNA sequence within a gene. Some mutations are hereditary. These types of mutations typically occur in nearly every cell in the body. Other mutations are acquired and are present only in some cells. These mutations can be caused by environmental factors such as radiation or can result from DNA copying errors when cells divide.
For now, research is primarily focused on the use of gene editing to cure monogenic diseases. Here are 14 monogenic diseases that are currently being targeted.
|Alpha-1 antitrypsin deficiency (AATD)||SERPINA1||Results in lung disease and liver damage.||Affects around 1 in 1,500 to 3,500 individuals with European ancestry, but it's less common in other populations.|
|Amyloid transthyretin (ATTR) amyloidosis||TTR||Results in problems with the nerves connecting the brain and spinal cord to muscles, which over time can cause a wide range of serious health issues.||Believed to affect between 3% and 3.9% of African-Americans, but isn't as prevalent in individuals of European descent.|
|Beta-thalassemia||HBB||Can lead to low production of hemoglobin, which in turn can result in anemia and an increased risk of developing blood clots.||Affects around 1 in 10,000 people.|
|Cystic fibrosis (CF)||CFTR||Causes malfunctioning chloride channels that enable the flow of chloride ions and water across cell membranes, resulting in respiratory and digestive problems.||Occurs in 1 in 2,500 to 3,500 Caucasian newborns, but it's not as common in other ethnic groups.|
|Duchenne muscular dystrophy (DMD)||DMD||Interferes with the production of dystrophin protein, which leads to muscle weakness and damage.||Affects around 1 in 3,300 male births.|
|Glycogen storage disease Ia (GSD Ia)||G6PC||Leads to excessive levels of glycogen and fat, which can cause problems with the liver, kidney, and small intestine.||Affects around 1 out of 125,000 individuals.|
|Hemophilia types A and B||
F8 (type A)
F9 (type B)
|Interferes with blood clotting.||Around 1 in 4,000 to 5,000 males have hemophilia A, while 1 in 20,000 males are born with hemophilia B. Very rare in females.|
|Huntington's disease||HTT||Results in abnormally long huntingtin proteins, which are broken up into fragments that attach to neurons and interfere with the nervous system.||Affects 3-7 out of 100,000 individuals of European ancestry.|
|Leber congenital amaurosis 10 (LCA10)||CEP290||The most common cause of hereditary childhood blindness.||Affects 2-3 per 100,000 live births.|
|Mucopolysaccharidosis (MPS) types I and II||
IDUA (type 1)
IDS (type 2)
|Interferes with the breakdown of large sugar molecules called glycosaminoglycans (GAGs), causing the GAGs to accumulate in cells and resulting in tissues and organs becoming enlarged.||Severe MPS I occurs in around 1 in 100,000 newborns, while less severe forms of the disease occur in around 1 in 500,000 newborns. MPS II occurs in as many as 1 in 100,000 males.|
|Primary hyperoxaluria (PH) type 1||AGXT||Causes a buildup of the organic compound glyoxylate, which leads to recurring kidney and bladder stones and can eventually cause kidney failure.||Affects around 1 in 72,500 individuals.|
|Severe combined immunodeficiency (SCID)||IL2RG or JAK3 or ZAP70||Interferes with the immune system's ability to fight off bacterial, viral, and fungal infections.||Affects around 1 in 50,000 individuals.|
|Sickle cell disease||HBB||Causes red blood cells to have a shape similar to a sickle or crescent. These red blood cells die prematurely, resulting in anemia, repeated infections, and pain.||Occurs in 1 in 500 African-Americans and 1 in 1,000 to 1,400 Hispanic Americans.|
|Usher syndrome type 2a||USH2A||Causes hearing loss from birth and vision loss that often begins in the teenage years and progresses over time.||Affects 1-9 out of 100,000 people|
Four of these 14 genetic diseases that are farthest along in development include:
Amyloid transthyretin (ATTR) amyloidosis
The TTR gene provides instructions for producing the transthyretin protein, which carries vitamin A and a hormone called thyroxine throughout the body. Mutations in the TTR gene cause ATTR amyloidosis -- the buildup of the amyloid protein in organs and tissues, especially in the nerves connecting the brain and spinal cord to muscles.
Research is in progress to use CRISPR-Cas9 to perform a technique known as gene knockout on the TTR gene. Gene knockout involves the inactivation or deletion of a specific DNA sequence in a gene.
The HBB gene contains instructions for producing the beta-globin protein. Beta-globin is a component of hemoglobin, a protein in red blood cells that carries oxygen from the lungs to the body's tissues and returns carbon dioxide from the tissues back to the lungs. Mutations in the HBB gene cause beta-thalassemia, which can lead to low production of hemoglobin and can result in anemia and an increased risk of developing blood clots.
CRISPR-Cas9 is being used to edit DNA sequences in the HBB gene to disrupt the impact of mutations. In this process, cells from patients are removed, the HBB gene is edited, then the modified cells are put back into the patients.
Hemophilia type B
The F9 gene (also referred to as the Factor IX gene) contains instructions for creating proteins known as coagulation factors. These coagulation factors help promote blood clotting. Hemophilia type B results from a mutation in this gene. The blood in patients with hemophilia type B doesn't clot as it should, which can lead to too much blood loss after injuries.
ZFN gene editing is being used to place a normal functioning copy of the F9 gene in patients' liver cells. The goal is for the corrected gene to then create coagulation factor proteins that cause blood to clot as it should.
Leber congenital amaurosis 10 (LCA10)
Leber congenital amaurosis can result from mutations in up to 14 genes. LCA10, the most common form of the disease, is caused by a mutation in the CEP290 gene. This gene carries instructions for creating a protein used in many types of cells, including photoreceptor cells in the eyes.
Research is under way using CRISPR-Cas9 to cut out the genetic mutation in the CEP290 gene that causes LCA 10. A sub-retinal injection is used to deliver the gene-editing therapy to photoreceptor cells in patients' eyes.
Biotechs leading the way
Four biotechs are pioneering use of gene editing in treating these diseases.
CRISPR Therapeutics (NASDAQ:CRSP)
Sickle cell disease
MPS type I
GSD type Ia
Duchenne muscular dystrophy
Editas Medicine (NASDAQ:EDIT)
Usher syndrome type 2a
Sickle cell disease
Duchenne muscular dystrophy
Intellia Therapeutics (NASDAQ:NTLA)
PH type 1
Sangamo Therapeutics (NASDAQ:SGMO)
MPS type I
MPS type II
Most of these biotechs' gene-editing research is still being conducted in preclinical studies. That means it's very early in the drug development process. Sangamo is the farthest along, with its hemophilia and MPS programs in phase 1 clinical testing. However, CRISPR Therapeutics plans to begin phase 1 testing of its lead candidate targeting sickle cell disease and beta-thalassemia this year. Editas intends to submit for approval within the next few months to advance its LCA10 program into phase 1.
Key gene-editing partnerships
Partnerships are important to biotechs that don't yet have products on the market. Most important, these deals provide funding for continued research. Clinical-stage and preclinical-stage biotechs can quickly run out of money. In addition, partnerships with big drugmakers lend some measure of credibility to early development programs.
All of these biotechs have big partners for at least some of their experimental drugs. Vertex Pharmaceuticals, which won FDA approval for its third treatment for cystic fibrosis, teamed up with CRISPR Therapeutics on its programs targeting cystic fibrosis and blood disorders, such as sickle cell disease.
Allergan signed a deal with Editas in 2017 for options on exclusive licensing of its LCA10 program. Editas is also collaborating with Juno Therapeutics, which was acquired by Celgene earlier this year, on using gene editing to engineer T cells for treating cancer.
Intellia attracted the attention of Regeneron to co-develop the ATTR program. The small biotech is also working with Novartis on using gene editing for engineering CAR-T cells (chimeric antigen receptor T cells) and hematopoietic stem cells.
Sangamo has several big partners. Pfizer is collaborating with the biotech on the development of a hemophilia A drug. Bioverativ, which was bought by Sanofi this year, is working with Sangamo on its beta-thalassemia and sickle cell disease programs. Shire joined forces with the company to co-develop its Huntington's disease drug.
A different dynamic
It will be several years before any of the aforementioned diseases might be cured by gene editing. And there's a chance that use of gene editing won't be able to cure some -- or perhaps even all -- of the diseases. Potential issues have already arisen with the CRISPR method of gene editing, although some turned out to be much ado about nothing.
Investors also have something else to think about. Curing a disease presents a much different dynamic than treating it. Companies that develop treatments can count on money pouring in for long periods of time. With a cure, however, there's an initial burst of revenue for a few years, but then it dwindles. Gilead Sciences has already experienced this with its hepatitis C drugs.
That doesn't mean biotechs like CRISPR Therapeutics, Editas, Intellia, and Sangamo won't work hard to cure the diseases they're targeting. They will -- and it could result in great news for patients one day. But cures for these diseases will have to be very expensive to provide the companies and their investors adequate returns on investment.