Cancer
Cancer transcends age, gender, racial, geographical, and economic
boundaries in its universal affliction. It is the leading cause of deathh
in the Western world. This disease has several forms, such as free-
floating cells that cause leukemia, or solid tumors. Cancer is created
by the body because of an only partially understood process, and
attacks from the inside out. Because it is a part of the body, the
immune system will not destroy it, and treating it is difficult as drugs
do not always have the capability to distinguish between healthy and cancerous cells.
Contemporary cancer treatments include surgery, radiotherapy, and
chemotherapy.The window for killing or removing cancerous cells
while safely preserving healthy cells is small and a major shortcoming of these treatments - and is the reason for a continuing high mortality rate. Past a certain point, there is nothing more doctors can do to save a patient without destroying healthy tissue.
Monoclonal Antibodies (mAbs) have been targeted against tumors using four criteria. The first is overexpression of the target antigen in tumor cells. Said antigen must be an integral part of disease progression, stable in its present form on the tumor surface, and is expressed by a large percentage of tumor cells and a variety of tumors.
mAbs allow for specific targeting of tumors, and this specificity allows for minimal side effects and a higher maximum dose. This is where aptamers' properties come into play. Aptamers being developed against cancer use different methods, including inhibition and conjugation to chemotherapy drugs, and follow the four criteria that have guided mAb-based anti-tumor drug development.
Aptamers have exciting potential to treat specific diseases and conditions for which current methods have reached dead ends. The properties of apatmers are ab exciting new tool to treat diseases that are currently incurable.
Aptamers can treat disease (therapeutics) in several ways.
1. Acting as an antagonist, inhibiting protein-protein and receptor-ligand interactions.
2. Acting as an agonist, activating cellular receptors.
3. Acting as a drug-delivery agent; the specificity and affinity of an aptamer is used to target diseased cells with pinpoint accuracy to deliver a drug dose.
Aptamer Applications
Text Citation 6: Applications for aptamers
Text Citation 6: Applications for aptamers
Video Citation 2: Aptamers as applied to cancer treatment: attacking cancer cells while leaving healthy cells alone.
Page Contents
Viruses and Bacteria
Aptamers can find application in the realm of virology in several ways.
The first is as a vaccine. Current vaccines are subject to genetic instability and heat sensitivity. Aptamers can overcome this heat sensitivity, as they are stable at room temperature. Additionally, the speed of SELEX selection means that aptamers could be quickly generated to respond to new viruses. An aptamer-based vaccine would trigger the immune response necessary to generate immunity.
The second is more direct interference. Aptamers have shown, in studies, the ability to inhibit viral enzymes, interfere with viral coats, and disrupt steps of a viral life cycle (including reverse transcription, chromosomal integration, proteolytic processing, viral expression, packing, and entry).
Aptamers selected against bacteria can act as antibiotics by inhibiting bacterial proteins or disrupting cell membrane formation. They can also be linked to an antibiotic agent, and, using aptamers' high affinity and specificity, seek out and bind to bacteria and deliver the antibiotic.
(Text Citation 9)
Parasites
Aptamers may provide a desperately needed solution to endemic diseases in developing countries. Parasites cause the majority of tropical diseases, and have been targeted by aptamers.
Trypanosoma cruzi, a
protozoan parasite
that causes Human
African Trypanosomia-
sis (commonly known
as African Sleeping Sickness), has been selected as a target for aptamers. RNA aptamers bind to the parasite receptors on the trypomastigote cell surface, and blocked cell invasion by 50-70%.
A second example of a parasite targeted by aptamers is the Plasmodium parasite, which is carried by mosquitoes and causes malaria. This devastating and often fatal disease causes millions of deaths annually. Aptamers have been developed against parasite proteins to disrupt the disease, and may eventually be used to supplement therapy for severe malaria.
Bacterium
Virus
Bacterium
Trypanosoma cruzi
Trypanosoma cruzi
Diagram detailing how the Plasmodium parasite, carried by mosquitoes, infects and causes malaria in the body (Click to expand).
Diagram detailing how the Plasmodium parasite, carried by mosquitoes, infects and causes malaria in the body (Click to expand).
Prions
Prions, which are malignant misfolded proteins, cause diseases such as Bovine Spongiform Encephalophaty (Mad Cow Disease) and Creutzfeldt-Jakob disease (the human version of Mad Cow Disease), which are fatal degenerative neurological disorders with no cure.
Aptamers targeting prions can distinguish readily between abnormal and normal proteins, even though they differ only slightly in structure. By binding to prions, they can prevent the accumulation of prions - this prion accumulation causes spongiosis, and therefore the disease.
Prions effect on the brain. Accumulation of prions cause spongiosis, or the destruction of parts the brain that leaves only holes in the brain tissue that resembles a sponge.
Prions effect on the brain. Accumulation of prions cause spongiosis, or the destruction of parts the brain that leaves only holes in the brain tissue that resembles a sponge.
Coagulation
Coagulation is the process of forming a clot. Aptamers can be used in surgery for specific areas to prevent disastrous clotting (anticoagulation).
Multiple aptamer-based drugs have been developed against thrombin, an enzyme involved in coagulation, to prolong clotting time in human blood plasma.
An aptamer targeting Factor IXa, another enzyme involved in coagulation, has entered Phase IIb clinical trials involving 800 patients with Acute Coronary Syndrome undergoing cardiac catheterization - or introduction of artificial tubes to clear blocked blood flow in clogged arteries. Coagulation must be prevented during this process to prevent dangerous blood clots from blocking arteries or catheters. This aptamer is coupled with an "antidote" that reverses its effects.
(Text Citation 9)
Autoimmune Diseases
Autoimmune diseases are caused when the body develops
antibodies against its own cells and/or tissues.
Myasthenia gravis, a neuromuscular disoder that causes
muscular fatigue and weakness, occurs from an antibody
response to a receptor called the nicotinic acetycholine
receptor (AChR). Animal models have shown that a RNA
aptamer targeting these autoantibodies inhibits this
autoimmune response.
Diagram of Acute Coronary Syndrome.
Thrombin-binding aptamer.
Diagram of Acute Coronary Syndrome.
Myasthenia gravis.
Myasthenia gravis.
Cancer
Cancer
See description at left.
See description at left.
Image at Right: An improved second generation aptamer-siRNA chimera (see Chimeric SELEX under "History") exhibited anti-cancer efficacy ability in a mouse model of prostate cancer.
A. First and second generation chimeric aptamers.
B. Bioluminescence imaging of mice bearing luciferase-expressing prostate cancer-positive tumors showed significantly lower signal after being treated with the second generation aptamer-siRNA chimera as compared to saline control.
C. H&E staining of tumor tissue after treatment showed readily detectable areas of necrosis (asterisks) in the second generation aptamer-siRNA chimera-treated tumors, but not frequently in saline-treated tumors. TUNEL staining was detected in scattered cells throughout the tumor section of each group.
• Viruses and Bacteria
• Parasites
• Prions
• Coagulation
• Autoimmune Diseases
• Cancer
Additionally, read in-detail how aptamers treat these specific diseases: