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Gene targeting induced selective loss of chromosome 21 in Down syndrome
Gene targeting uses homologues recombination techniques to change endogenous genes of interest by inserting new, or deleting and altering existing genes. Genetic recombination is facilitated by enzymes (usually of microbial origin) that cut and rejoin interrupted DNA strands during transformation of the genetic material. Size of the gene and its transcriptional activity are not limiting factors, allowing scientists to experiment with all kind of genes they want. Genes could be altered permanently, or just during certain development phase; they could be modified in specific tissue or in the whole organism. So far, gene targeting was applied in lot of different animal and plant species (from drosophila, human and mice to corn and tobacco). Methodology for each model organism is well known. Basically, genetic construct first need to be generated in the bacterial cell. It contains parts of the targeted gene, reporter gene and selectable marker. After genetic construct is inserted in embryonic stem cells, these cells will be injected to the embryo.

Targeting could be applied in numerous ways to provide different information on the investigated genes. Besides basic insight of gene functionalities, targeting could provide more information on gene related diseases and improve drug development project by guiding the process in the most suitable direction. That is the case with isogenic human disease models: selected cell are genetically altered to reflect exact genetic background of the disease. In vitro examination provides novel insight in the disease biology and allows scientists to test new therapeutic agents. Most cancers are investigated using this model. Although it is still new, it might become a standard in genetic disease investigation because it is less expensive and less complicated (in the technical sense) than conventional disease/drugs testing methodologies. Another way to apply targeting is in the field of protein engineering (novel proteins are designed).

Recently published article revealed that genetic targeting could be used for the elimination of the entire chromosome. Scientists from the University of Washington described targeted removal of the excess chromosome 21 in the fibroblast derived from the person with Down syndrome. Chromosome “free” cells were then transformed into induced pluripotent stem cells (iPS) for further investigation.

Adenoviral vector selectively inserted thymidine kinase neomycin phosphotransferase reporter gene (TKNEO) in the APP gene of the fibroblast DNA. APP gene encodes amyloid precursor protein that is integral part of cellular membranes in various tissues. Amyloid precursor protein is degraded via proteolysis to beta amyloid. Impaired version of beta amyloid can be easily recognized by its filamentous form. This protein is well studied due to tight association with Alzheimer’s disease: filamentous form of beta amyloid accumulates in the brain forming amyloid plaques, which are typical pathological finding in the brain of persons diagnosed with the disease. Reason why this specific gene is targeted is not clear, but TKNEO managed to be successfully incorporated in just one copy of the chromosome 21. When cells were selected against the TKNEO, the best way for them to survive was to eliminate extra chromosome which now pose a threat for their survival. Vast majority of the cells did exactly that. Most prominent survival method was spontaneous loss of extra chromosome during mitoses and the frequency observed indicated that selective pressure pushed the cells in this direction. Other survival methods: epigenetic mutation, silencing of the TKNEO gene, targeted deletion of the gene, and point mutation were noted at much lower rate. At the end, all Down syndrome derived cells that remain in trisomic state end up killed. Only cells that spontaneously reverted to their disomic state remained alive. Newly derived generation of the disomic cells were further transformed in iPS thanks to selective transcriptional and growth factors applied. These cells showed high proliferation rate.

This experiment showed for the first time that genetic targeting could affect the number of chromosomes beside certain genes and/or their parts and it certainly paved the path for the future clinical and research analysis. Treatment of Down syndrome using this method is still far from possible. Scientists are not sure if this method is 100% safe or associated with potential genotoxicity. For the moment, described technique will be used for gathering information about disease that could help scientists create better future therapeutics.
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Down syndrome (DS) which is also known as trisomy 21, is actually a chromosomal condition which is caused by the presence of part or of all of a third chromosome 21. This is one of the most common chromosomal abnormalities in humans. It affects physical growth as well as is associated with mental retardation. This type of disorder is being monitored worldwide and many researches are going on to treat this in better way.
One such research from National Institute of child health and human development suggests that prenatal treatment with neuroprotective peptides have potential in improving the learning performance in Down syndrome. This study is based on previous research on NAP and SAL (small peptides) of two proteins that are important during fetal brain development. These two proteins enhance brain cell ability to receive and transmit signals and further enable them to survive. NAP stands for NAPVSIPQ and SAL for SALLRSIPA.
The experiment was done in test pregnant mice (Ts65Dn) along with control mice. Thirty three out of the control mice were given placebo while other 30 received actual protein and later were compared with 11 and 10 Down syndrome mice respectively. Injections were administered from 8th day of conception which thus resembles the stage of first trimester condition in human pregnancy.
The results showed that none out of the Down syndrome mice who were injected with placebo demonstrated learning. On the other hand, prenatal exposure to peptides had resulted in significantly better learning around (P<0.01). These were compared with controls for validation of experiments.

This type of research is not only a new hope to treat Down syndrome but also shows a new way to medical science to think & research in treating various diseases prenatally !
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Gene targeting induced selective loss of chromosome 21 in Down syndrome00