Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects
What Is Angiodysplasia Of The Colon?
Angiodysplasia of the colon refers to swollen blood vessels in the colon that may weaken and rupture, resulting in bleeding and lesions. Angiodysplasia may lead to various complications. However, it is typically treatable.
Angiodysplasia can occur in different areas of the gastrointestinal (GI) tract, including the stomach, small intestine, and colon.
The condition most commonly occurs in the colon, which is the longest part of the large intestine.
Angiodysplasia of the colon can cause GI bleeding and anemia, although the condition does not always cause symptoms. Doctors can usually treat the condition.
Experts do not fully understand the causes of angiodysplasia of the colon.
Researchers have proposed several possible causes of the condition, which include:
Researchers also believe that normal spasms that happen in the GI tract can lead to blood vessel enlargement over time.
As the enlarged vessels become congested and obstructed, small pathways may develop to provide alternative routes for blood flow. These changes can increase the risk of GI bleeding.
Risk factors that healthcare professionals associate with angiodysplasia of the colon include:
If angiodysplasia of the colon does not cause the blood vessels in the colon to bleed, a person may not have symptoms.
When bleeding does occur, the blood vessels in the colon may bleed intermittently and slowly. The blood is not typically visible in stools.
Rarely, a person with angiodysplasia may experience acute, heavy GI bleeding.
GI bleeding can lead to iron deficiency anemia, which can cause symptoms including:
To diagnose angiodysplasia of the colon, a healthcare professional may perform a physical examination and assess a person's vital signs at the start of their evaluation.
They may perform or order various tests to check for bleeding in the colon and other symptoms. Tests may include:
Learn about the anatomy of the colon.
Treatment for angiodysplasia of the colon can depend on various factors. These include whether there is bleeding in the colon, the rate of bleeding, and whether there are complications of the condition.
If a person does not have a history of GI bleeding or symptoms of anemia, a doctor may choose not to treat angiodysplasia but rather monitor the condition over time.
A doctor may base their treatment decisions on the severity of a person's symptoms.
Treatment can involve:
Common complications of angiodysplasia of the colon include iron deficiency anemia and chronic hidden bleeding, which doctors refer to as occult bleeding.
Rarely, angiodysplasia can result in massive GI bleeding. This can cause hemodynamic instability, which is insufficient blood flow.
If a person notices any symptoms of massive GI bleeding, such as blood in the stool or from the rectum, they should contact a doctor. Severe angiodysplasia can lead to serious blood loss, which may require treatment such as a blood transfusion.
A person should also contact a doctor if they have symptoms of iron deficiency anemia. Without treatment, this condition may lead to further complications, including heart failure.
The outlook for those with angiodysplasia of the colon is typically good. When bleeding does occur, it usually resolves without treatment.
The outlook may be worse if a person has 10 or more angiodysplasia lesions or lesions larger than 10 millimeters (mm).
Some people experience recurrent bleeding even with treatment. However, with monitoring and treatment, people can often manage the symptoms.
What does poop with a GI bleed look like?GI bleeding caused by angiodysplasia of the colon is often occult, or hidden, meaning it is not visible in stool. Blood may be visible if massive bleeding occurs and is typically bright red. Rarely, GI bleeding can cause black, tarry stools.
What foods should you avoid with GI bleeding?A doctor may advise a person to avoid eating foods that can irritate the gut, such as spicy foods and those high in fats and sugars.
Angiodysplasia of the colon is a condition in which the blood vessels in the colon become enlarged. This can lead to gastrointestinal bleeding.
Angiodysplasia can lead to complications, including iron deficiency anemia and chronic occult bleeding.
The condition does not always require treatment. If the bleeding is severe, a doctor may treat it with medication, cauterization, or surgery to resect part of the colon.
Gene-Based Therapeutic Approaches
Gene-transfer approaches are particularly useful when a disease-associated mutation encodes a protein with decreased function, called a loss-of-function mutation; in this case, normal cellular function is restored when a wild-type copy of the gene is introduced, because loss-of-function mutations are usually recessive. However, human disease can also be associated with dominant mutations in genes that encode hyperactive proteins, called gain-of-function mutations. Furthermore, human disease can be associated with dominant mutations in which the mutant proteins interfere with the function of wild-type proteins, called dominant negative mutations.
In the case of a dominant mutation, introduction of the corresponding wild-type gene is usually not sufficient to rescue the disease-associated phenotype(s); rather, researchers would prefer to "turn off" expression of the mutant gene, or to inhibit the function of the mutant protein it encodes. To achieve this goal, researchers have turned their attention to RNA-based approaches, which target the RNA (either pre-mRNA or mRNA) transcribed from the dominant negative gene and effectively inhibit expression of the mutant protein.
Figure 2 shows examples of RNA-based strategies for the treatment of disease. Five approaches have been used experimentally to modify RNA levels: antisense oligonucleotides (ASO), RNA interference (RNAi), trans-splicing, segmental trans-splicing, and ribozymes.
ASO strategies use short single-stranded DNA (ssDNA) molecules, usually between 18 and 30 bases long, which are complementary to the mRNA to be targeted (Figure 2a). The ssDNA binds to the target mRNA, and the resulting DNA-RNA hybrid molecule is then degraded by the intracellular enzyme ribonuclease H (RNase H).
RNAi involves the use of double-stranded RNA molecules (dsRNA), typically 22 base pairs long, corresponding to a region of the target gene (Figure 2b). The dsRNA is processed within the cell in such a way that it becomes part of an RNA-induced silencing complex (RISC) that recognizes and degrades the corresponding target mRNA.
Trans-splicing is a gene-transfer approach that targets a pre-mRNA containing a disease-associated mutation within one of its exons (Figure 2c). In this case, the transgene is used to replace the exon carrying the disease-associated mutation (exon C* in Figure 2c) with a wild-type copy of the exon. The transgene contains a hybridization domain, which is complementary to a region of the 5′ flanking intron between the donor and branch-point sites for RNA splicing, followed by the splicing branch point, the splice acceptor site, the wild-type exon sequence, and the rest of the gene. Trans-splicing leads to the production of a wild-type copy of the mature mRNA and thus a corresponding wild-type protein.
Segmental trans-splicing is an approach used to get around the size limitations associated with gene-transfer methods that involve vectors. (Sometimes, a given cDNA is too large to be carried within a single viral vector.) In this case, the gene is divided into two smaller pieces, which are delivered together using two separate gene-transfer vectors (Figure 2d). The vector carrying the second half of the gene includes a hybridization domain complementary to an intron located at the 3′ end of the first half of the gene, similar to that described for trans-splicing. In this case, trans-splicing leads to the production of a mature mRNA encoding the full length of the wild-type protein of interest.
Ribozymes are RNA molecules with inherent catalytic activity that recognize a particular mRNA and cleave it (Figure 2e). Ribozymes containing a hybridization domain followed by a ribozyme nucleolytic motif that recognizes a target mRNA and the corresponding wild-type gene sequence can be used to selectively cleave a target mRNA that contains a mutation after the ribozyme cleavage site. Once the target gene is cleaved, the ribozyme-derived hybridization motif binds, and RNA splicing leads to the formation of a wild-type copy of the mature mRNA.
Many of these RNA-based strategies have been developed in recent years, and numerous questions remain regarding the cellular mechanisms involved in mRNA targeting. Furthermore, researchers must exercise caution with respect to the specificity of any given mRNA-targeting approach, whether ASO, RNAi, trans-splicing, or ribozyme based, to ensure that only the mRNA of interest is targeted.
Connective Tissue Disease Types
Connective tissue disease is a group of disorders involving the protein-rich tissue that supports your organs and other parts of your body. Examples of connective tissue are fat, bone, and cartilage. These disorders often involve your joints, muscles, and skin, but they can also involve other organs and organ systems, including the eyes, heart, lungs, kidneys, gastrointestinal tract, and blood vessels. There are more than 200 disorders that affect connective tissue. Causes and specific symptoms vary by type.
Since there are so many connective tissue diseases, your symptoms will depend on the disease you have. In general, though, symptoms may affect your:
There are two main types of these diseases. Inherited connective tissue diseases come from genetic problems passed down from your parents. Autoimmune connective tissue diseases happen when your immune system mistakenly attacks your own body. You might get an autoimmune connective tissue disease because of:
Some connective tissue diseases — often called heritable disorders of connective tissue (HDCTs) — result from changes in certain genes. Many of these are pretty rare. The following are some of the more common ones:
Ehlers-Danlos syndrome (EDS)
EDS is a group of more than 10 disorders. It is characterized by overflexible joints, stretchy skin, and abnormal growth of scar tissue. Symptoms can range from mild to disabling. Depending on the specific form of EDS, other symptoms may include:
Epidermolysis bullosa (EB)
People with EB have fragile skin that can easily tear or blister as a result of a minor bump, stumble, or even friction from clothing. Some forms of EB may involve the digestive tract, respiratory tract, muscles, or bladder. EB is usually obvious at birth and results from defects in several proteins in the skin.
Marfan syndrome
Marfan syndrome affects the bones, ligaments, eyes, heart, and blood vessels. People with Marfan syndrome tend to be tall, have extremely long bones, and thin "spider-like" fingers and toes. Other problems may include eye problems due to abnormal placement of the eye lens and enlargement of the aorta (the largest artery in the body), which can lead to a fatal rupture. A mutation in the gene that controls the structure of a protein called fibrillin-1 causes Marfan syndrome.
Osteogenesis imperfecta
It is a condition of brittle bones, low muscle mass, and lax joints and ligaments. There are several types of this condition. Specific symptoms depend on the specific type and may include:
The disease happens when a mutation in two genes responsible for type 1 collagen lowers the amount or quality of the protein, which is essential to the structure of bones and skin.
Researchers don't know the cause of other forms of connective tissue disease. In some cases, they believe something in the environment could trigger the disease in people who are vulnerable. In these diseases, the body's normally protective immune system makes antibodies that attack the body's own tissues.
These diseases include:
Polymyositis and dermatomyositis
These are two related diseases in which there's inflammation of the muscles (polymyositis) and skin (dermatomyositis). Symptoms of both diseases can include:
Dermatomyositis may also affect the skin around your eyes and on your hands.
Rheumatoid arthritis (RA)
Rheumatoid arthritis is a disease in which the immune system attacks the thin membrane (called the synovium) lining the joints, causing joint pain, stiffness, warmth, swelling, and inflammation throughout the body. Other symptoms may include:
RA can lead to permanent joint damage and deformity.
Scleroderma
Scleroderma is a term for a group of disorders that cause thick, tight skin, scar tissue buildup, and organ damage. These disorders fall into two general categories: localized scleroderma and systemic sclerosis.
Localized scleroderma is confined to the skin, and sometimes, the muscle beneath it. Systemic sclerosis also involves the blood vessels and major organs.
Sjögren's syndrome
Sjögren's syndrome is a chronic disease in which the immune system attacks the moisture-producing glands, such as those of the eyes and mouth. The effects can range from mildly uncomfortable to crippling. Although dry eyes and mouth are the main symptoms of Sjögren's, many people also have extreme fatigue and joint pain. The condition raises your chances of lymphoma and may cause problems with your kidneys, lungs, blood vessels, digestive system, and nerves.
Systemic lupus erythematosus (SLE)
SLE, or simply lupus, is a disease that causes inflammation of the joints, skin, and internal organs. Symptoms may include:
Vasculitis
Vasculitis is a general term for more than 20 different conditions that cause blood vessel inflammation. It can involve any of the blood vessels and affect blood flow to the organs and other body tissues.
Mixed connective tissue disease
People with MCTD have symptoms of several diseases, including lupus, scleroderma, polymyositis or dermatomyositis, and rheumatoid arthritis. When this happens, your doctor will diagnose you with mixed connective tissue disease.
While many people with mixed connective tissue disease have mild symptoms, others may have life-threatening health problems.
To diagnose connective tissue disease, your doctor will give you a physical exam and ask about your personal and family medical history. You may also take one or more of these tests:
Treatment for connective tissue disease will depend on which kind you have. Treatments range from vitamin supplements to physical therapy and medications. In addition to your regular doctor, you could also need to visit specialists such as eye or skin doctors. Talk to your doctor if your symptoms get worse or if you have new ones.
Connective tissue disease is a group of more than 200 disorders affecting the tissue that supports organs and other parts of the body. There are two types — those that you inherit from your parents through your genes and autoimmune connective tissue diseases. To figure out if you have a connective tissue disease, your doctor will give you a physical exam and run different blood, urine, imaging, and tissue sample tests. There are many different treatments for the condition, depending on which kind you have, including medication and physical therapy.
Is connective tissue disease serious?
Connective tissue disease can sometimes cause serious and deadly health problems, such as:
What is undifferentiated connective tissue disease?
It's a condition with signs and symptoms of an autoimmune disease but doesn't fit the specific criteria for any known connective tissue disease. Doctors diagnose undifferentiated connective tissue disease when they've ruled out other similar diseases. Symptoms can vary a lot from one person to another and may look like other connective tissue diseases.
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