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Cystic fibrosis

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Cystic fibrosis Cystic fibrosis Presentation Transcript

  • Cystic Fibrosis
  • Cystic Fibrosis
    • Cystic fibrosis is a life-threatening genetic disorder that causes severe respiratory and digestive problems.
    • The chlorine transport systems of the exocrine glands (mucus secreting glands of the airways of the lungs, the gut and the reproductive system and the sweat glands) don't function properly.
    • As a result, thick sticky mucus and very salty sweat are formed.
    • It is the thick mucus which causes most of the symptoms.
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  • CFTR Proteins
    • People who inherit two copies of the faulty allele lack effective CFTR proteins.
    • This means that chloride ions build up in their cells instead of moving out through the channels and as a result water does not move out of their cells to dilute the mucus on the surfaces of their membranes.
    • So water moves into the cells by osmosis from the fluid surrounding the cells, making the mucus even more thick and sticky
  • CFTR Proteins
    • Cystic fibrosis occurs in about 1 in 2400 - 2500 babies born to white Europeans.
    • Because cystic fibrosis is caused by a recessive allele, many people carry the mutation without knowing it.
    • These carriers are phenotypically normal and usually have no idea that they are carrying the CF mutation.
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  • Inheritance of CF gene
    • It is only if two carriers have children together that the problems may become apparent.
    • Even then. because the allele is recessive, there is only a 1 in 4 chance that any child of these parents will develop CF.
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  • Symptoms of cystic fibrosis
  • The respiratory system
    • The thick, sticky mucus typical of cystic fibrosis builds up in the tiny airways of the lungs and reduces the flow of air into the alveoli.
    • It often blocks the smaller bronchioles completely and greatly reduces the surface area available in the lungs for gaseous exchange.
    • This means affected individuals often have severe coughing fits as their body attempts to get rid of the mucus.
  • The respiratory system
    • Bacteria and other pathogens that are breathed in and trapped in the mucus cannot be moved out of the respiratory system.
    • As a result thick, pathogen-laden mucus builds up in the lungs, and this provides the bacteria with ideal conditions in which to grow.
    • Body normally secretes antibodies into the mucus which inactivate pathogens.
    • Current research shows that the dehydrated surfaces of cells affected by CF lose their natural antibacterial properties, because the white blood cells and their antibodies cannot function effectively in the thickened mucus.
  • The digestive system
    • The enzymes of pancreas pass into the duodenum along a tube known as the pancreatic duct. Thin mucus is produced by the cells lining this tube
    • A faulty CFTR protein means the mucus produced in the pancreatic duct is also very thick and sticky. It often blocks the pancreatic duct, so that the enzymes do not reach the duodenum.
    • This has two damaging effects. If the digestive enzymes do not reach your gut, you cannot digest your food properly. This means you do not get enough nutrients from the food.
    • Also, the digestive enzymes trapped in the pancreas may actually start to digest and damage the cells of the pancreas. If they affect the cells which make the hormone insulin. then the person may end up with diabetes.
  • The digestive system
    • Mucus is secreted throughout the gut to protect the delicate lining from damage by the digestive enzymes and to act as a lubricant.
    • But, when this mucus is very thick and sticky, it forms a barrier between the contents of the gut and the lining of the intestine and clogs up the villi, reducing the surface area for absorption.
    • These two effects put CF patients at severe risk of malnutrition and they often struggle to maintain their body mass.
  • Reproductive system
    • Women with cystic fibrosis usually produce fertile eggs, but the thick mucus can block the cervix so sperm cannot reach them.
    • It can also block the oviducts., making fertilisation even less likely.
    • Men with cystic fibrosis arc often infertile. They may lack the tube that carries sperm out from the testis into the semen (the vas deferens).
    • If the vas deferens is present, it may be partly or completely blocked by thick sticky mucus so that only a reduced number of sperm (or no sperm at all) can leave the testis.
  • Sweat Glands
    • The faulty CFTR protein means that people with cystic fibrosis usually have sweat that is more concentrated and salty than normal.
    • Without functioning CFTR proteins, the chloride ions remain in the sweat, and so do the sodium ions.
    • As a result the sweat is very salty - in fact this is one of the tests used to diagnose cystic fibrosis.
    • Levels of sodium and chloride ions are very important for the proper functioning of many body systems including the nervous system and the heart.
    • If too much is lost in the sweat, the concentration of the body fluids changes, which can affect the heart.
  • Threat!
    • Cystic fibrosis is a life-threatening condition.
    • In the past, affected children almost always died before reaching adulthood.
    • However, the treatments available have improved enormously in recent years, and the average life expectancy for affected people is increasing all the time.
    • The parents of babies and very young children who are diagnosed with the condition now are told that their child may well have a near-normal life expectancy.
    • At the moment there are no cures for cystic fibrosis. Current treatments aim to reduce the symptoms and allow the body systems to work as effectively as possible.
  • Treating CF
    • Because the thick mucus of CF can block the pancreatic duct and coat the lining of the gut, digesting and absorbing food is difficult for most people with cystic fibrosis.
    • To help overcome the effect of the blocked pancreatic duct, people with CF may take enzymes when they have a meal.
    • These enzymes help to replace the missing pancreatic enzymes, so more of the food can be digested.
    • People with CF need to eat a carefully balanced diet, and also to eat more than other people to make up for what they cannot digest.
    • They need more high-energy foods, such as high-fat and high-carbohydrate foods, and an adult with CF needs twice as much protein as someone unaffected by the condition.
  • Treating CF
    • Physiotherapy is very important for removing as much of the thick, sticky mucus from the lungs as possible.
    • This makes it easier to breathe and take in enough oxygen. It also reduces the risk of serious lung infections.
  • Drug therapies
    • Most people in the UK who have cystic fibrosis take a cocktail of medicines to improve their health and protect them against the symptoms of the disease.
    • These drugs include: Antibiotics — these destroy many of the bacteria that could potentially cause life-threatening lung infections.
    • Mucolytics — these are drugs to make the mucus more runny and so easier to move such as salbutamol and steroids
    • Insulin — if problems with the pancreas lead to diabetes, insulin will need to be given regularly to control the blood sugar concentration.
  • Transplant surgery
    • In some cases the damage that cystic fibrosis causes to the lungs is so severe that the lungs cannot function properly.
    • The heart may also be affected.
    • In this case the only solution is a lung, or heart and lung, transplant.
    • The new organs will not be affected by cystic fibrosis, although the rest of the body will still have the other problems associated with the disease.
  • Gene Therapy
    • Much current research into treatments for cystic fibrosis aims to remove the symptoms entirely or even cure the disease.
    • The hope is that faulty alleles might be replaced by healthy ones in a process known as gene therapy.
    • Gene therapy involves taking a copy of the healthy gene and finding an effective way of getting it into the cells that need it, so that they can produce the correct protein.
  •  
  •  
  • Genetic Engineering
    • Copying genes and inserting them into other organisms is known as genetic engineering or genetic modification, and this is the first stage in gene therapy.
    • The best-known approach is to use special enzymes called restriction endonucleases to chop up healthy DNA strands, cutting them at specific sites.
    • These enzymes cut the DNA into small pieces which can be handled more easily.
    • Each type of endonuclease will only cut DNA at specific sites within a particular DNA sequence, hence the name.
  • Sticky Ends
    • Some restriction endonucleases can cut the DNA strands in a way that leaves a few base pairs longer on one strand than the other, forming a sticky end.
    • Sticky ends make it easier to attach new pieces of DNA to them.
    • DNA ligases are also used as 'genetic glue’ to join pieces of DNA together.
  • Reverse Transcription and cDNA
    • Artificial copies of the healthy gene can also be made by taking an mRNA molecule transcribed from the gene and using it to produce the correct DNA sequence — effectively reversing the transcription process, using the enzyme reverse transcriptase.
    • DNA made like this is known as complementary DNA or cDNA and it can act as an artificial gene.
  • Vectors
    • The next stage is to attach the isolated gene to another piece of DNA, known as a vector, which will carry it into the target cell.
    • Plasmids, the circular strands of DNA found in bacteria, are often used as vectors.
    • Once the plasmid gets into the host nucleus it can combine with the cell’s DNA to form recombinant DNA.
    • Plasmids are particularly useful in the formation of genetically modified bacteria.
  • Vectors
    • Other vectors are needed to carry new DNA into human cells.
    • Vectors that have been tested for the treatment of cystic fibrosis include harmless viruses and liposomes (spheres formed from a lipid bilayer).
    • The viruses infect lung epithelial cells and insert the viral DNA (including the added gene) into the cell’s DNA.
    • Liposomes fuse with the cell membrane and can pass through it to deliver the new DNA into the cytoplasm.
    • Viruses are much better at getting DNA into the nucleus at the moment, but they can cause an immune reaction in some people.
  • Gene Therapy
    • Once the healthy new DNA is inside the lung epithelial cells, the healthy genes should be transcribed and translated, producing the normal, active CFTR protein and relieving the symptoms
    • This sounds good in theory, but the practice has shown that it's not quite that easy.
  • Difficulties in Gene Therapy Extra cellular barriers
    • There are many barriers to overcome before the new DNA in the vectors can reach the epithelial cells of the airways.
    • This is partly because cystic fibrosis blocks the airways, making it difficult for sprays to penetrate the lungs, and partly because the surface is coated with thick, sticky mucus.
    • Some research groups are trying to get the vectors to the lung cells by a completely different route — through the blood.
  • Difficulties in Gene Therapy Intracellular barriers
    • Once the vector is inside the cell, the next challenge is to get the new DNA into the right place.
    • This is proving very difficult, particularly when liposomes are used as the vectors.
    • It has been estimated that only about 1 in every 1000 plasmids that enter a cell in a liposome get into the nucleus to be transcribed.
    • Research is looking at modifying the vectors to get the new genes into the cells and then into the nuclei more effectively.
    • So far viruses seem to be giving the best results.
  • Difficulties in Gene Therapy Keeping the gene expression going
    • The final problem is that even when the new gene is taken into the nucleus and transcribed, it doesn't work for long - about two weeks at best.
    • Research teams are looking at ways to extend this and even make it permanent, by using different vectors.
    • If stem cells could be used this might lead to a permanent cure.
  • Difficulties in Gene Therapy Epithelial shedding
    • Another problem was that epithelial cells are continually shed and replaced by new cells made by the body.
    • These new cells only contain the faulty gene so the new DNA is lost.