Archive for the “Gene Therapy” Category

For a long time, mental retardation was believed to be incurable, as it is usually caused by gene mutations that disrupt brain development right from the beginning and even before birth. But thanks to a lot of hard-working scientists, there are trials now to improve the quality of life of such patients, along with their caregivers. The work has been focused on a condition known as “Fragile X syndrome”. In this disease, a mutation takes place in a gene called FMR1 , which is responsible for the production of proteins, that regulate neural development, usually leading to mental retardation according to the extent of such mutations.

Fragile X syndrome's common physical symptoms : elongated face, large ears, etc

Another important contributor to the condition is the metabotropic glutamate receptor-5, abbreviated to mGluR5. It is responsible for controlling the process of protein synthesis at the neuronal synapses, becoming hyperactive in case of fragile X. Being an interesting therapeutic target, a major pharmaceutical company developed AFQ056, an mGluR5-receptor blocker, in the hope that it’ll restore normal transcription levels. The results of the initial double blind clinical trials, conducted on 30 patients, were evaluated through the notes taken by the caregivers about the behavioral improvements of the patient. This included less repetitive behavior, less hyperactivity, less tantrums and having better chances of establishing communication with the patients.

What seemed like a puzzle is that some caregivers reported no change at all after the patients took the drug. So after data analysis, the researchers found that the only patients affected by the treatment were the ones (7 patients out of 30) having a certain genetic marker: complete methylation of the FMR1 gene regulator sequence, and therefore, complete lack of FMR1 transcription. Another disappointment was that the drug didn’t improve cognition or memory, but this, they say, might be attributed to the short duration of the trial, lasting for only 4 weeks.

The next step is to repeat the trial, but this time on 160 selected patients, after testing them for the marker and the experiment will last for 3 months, hoping to obtain better results that are more significant to the patients of this illness.

Sources: Wikipedia and Science News

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Researchers at Massachusetts General Hospital (MGH) are investigating a new way to block replication of hepatitis C virus “HCV” by targeting not the virus itself, but the genes that the virus exploits during its life cycle.

HCV has a high rate of replication that it can replicate a trillion particles per day. Also, due to its high rate of mutation, it can escape our immune system.

HCV replicates mainly within hepatocytes in liver by binding to receptors on the surface of the liver “CD81″ and human scavenger receptor class B1 “SR-BI”. Then it utilizes the intracellular machinery necessary for its replication. Upper right, virus particle enters cell followed by uncoating and release of positive-stranded HCV RNA genome. Viral genome is translated at the endoplasmic reticulum into the viral polypeptide (upper left). Viral replication complexes (red) are then assembled onto host-derived small membranous vesicles (yellow ovoids).

Transmission occurs by blood to blood contact, where it causes chronic liver infection in about 70-80% of patients & long term infections can cause liver failure or liver cancer.

HCV infection is usually treated with a six to eleven month regimen combining peginterferon and the antiviral drug ribavirin, but unfortunately, treatment is not successful in many patients and has serious side effects that some cannot tolerate.

Many drugs target viral enzymes, but due to the great ability of HCV to mutate, such approach lead to the emergence of resistant strains.

Recently, a new strategy has developed, which is to block human genes, which act as a cofactors for HCV infection. Using small interfering RNAs (siRNAs), researchers examined blocking of approximately 21,000 predicted messenger RNA transcripts in the human genome.

The siRNA scan found 96 genes that appear to have a role in viral replication, one gene codes for an enzyme called PI4KA, which is believed to be involved in the formation of membrane structures within the cell. Another group of genes contribute to formation of the coat.

So, by blocking these genes, HCV replication is stopped. At this time, these tested agents might not be suitable for therapeutic use.

Source & Image credits : Harvard Science.


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         Normally when we hear the word immunity, we think of defense against infections, graft rejection, inflammation, etc. But, what if this defense may cause more damage than the infection itself ? In this case, the immune system shows a certain privilege through acting smarter where it deviates its mechanisms in a way to down-regulate its own damaging mechanisms. This whole process is known as Anterior Chamber-Associated Immune Deviation (ACAID).

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           ACAID is endogenous to specific sites such as the anterior chamber of the eye and the brain. The process is considered as saving in cases of ocular infections where the visual axis is easily deflected by inflammation leading to blindness. Also ACAID is considered beneficial in case of allografting as it downregulates the immune processes responsible for allograft rejection. The process was discovered by Medwar in 1940, when he first noticed that surprisingly certain tumors proliferate more rapidly in the anterior chamber of the eye than anywhere else. Medwar’s further studies demonstrated the role of the process in transplantation immunology.

          As an example of ACAID, upon antigenic inoculation of anterior chamber of the eye, the immune deviation presents itself as follows: Instead of Natural Killer T-cells perform certain functions attributed to T-Helper & T-Cytotoxic cells, the antigen injected into the eye APCs (Antigen Presenting Cells) that carry antigen to the spleen. These APCs activate NKT cells which in turn produce certain cytokines as TGF-ß that induce the generation of CD8+Tr cells which by production of cytokines such as TGF-ß and IL-10, can downregulate subsequent Th1-mediated DTH reactions against the same antigen.









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Thus, regarding the beneficial effects that can be drawn from ACAID, current research is being conducted for inducing ACAID to avoid graft and transplant rejection. ACAID can be induced by animal injection with non-ocular APCs, e.g., peritoneal exudate cells (PECs) that have been precultured with TGF-ß and antigen in vitro. Such procedure is believed to be a step forward toward the success of transplantation.

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Mitochondria contain their own DNA  which is about 17,000 bp. Mutation in mtDNA can lead to a series of disorders known as  mitochondrial disorders which will be very vivid in organs requiring high energy supply as brain, heart, eye & skeletal muscles. Owing to its oxidative function, mitochondria are having a high rate of mutations estimated to be 10 times that of nuclear DNA . However, mitochondrial disorders  result also from mutations in nuclear DNA in the  regions coding for mitochondrial components . For individuals having mitochondrial disorders resulting from mtDNA mutations , they have a mixture of mutated  mtDNA & normal mtDNA  which is a pattern of distribution known as mitochondrial DNA heteroplasmy. The proportion as well as the distribution of defective mtDNA influence the  location , onset as well as severity of diseases.



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                     Conventional treatment of mitochondrial disorders is mainly supportive where patients are treated with co-enzyme Q10, which is a cofactor required for electron transfer from complexes I & II to complex III. However Gene Therapy & Modern Targetting Systems stepped in offering a radical & permenant cure for mitochondrial disorders. One of  most promising strategies of Gene Therapy is allotropic expression which involves the  engineering of normal genes then their introduction to nucleus. This method showed success in a mitochondrial disorder characterized by respiratory deficient phenotypes caused by a mutant MATP8 gene , where the engineered ATP gene has succeeded in production of ATPase 8 protein.

Modern targetting systems have developed offering a unique solution to mitochondrial disorders & overcoming the dilemma of heteroplasmy as well. Cell membarne Crossing Oligopolymers (CMCO’s) are molecules  that are capable of penetrating cell membrane & selectively bind to mutated mtDNA inhibiting its replication. This technique has been successful in handling Oxidative Phosphorylation deficiency (OXPHOS deficiency).

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May 2008

Gene Therapy: Seeing the future with new eyes

For the first time, doctors have used gene therapy to restore some vision in children with a congenital vision problem called Leber Congenital Amaurosis or “LCA” caused by a faulty gene (RPE65) 

The procedure involved the injection of a solution containing the normal gene, carried on an adenovirus vector, into the back of the retina of the affected eye.

In Britain, three patients have been treated with this experimental therapy. One has significantly improved & has been video-taped prior to the treatment & then six months later, traveling through a maze. Video HERE

The other two patients, aged 17 and 23, did not report any improvement, but did not suffer any side effects either.

Similarly, a US research team experimented on three patients, one aged 19 and two aged 26, and are reported to have improved vision as measured by standard eye tests, however, one developed a hole in the retina, thought to be due to the surgery itself.

This is a very significant milestone especially because researchers have been dealing with patients in the late stages of the disease & more hope is yet to come in those with the less-advanced form.

This is only the second time gene therapy has been proved successful in humans, after trials showed it was effective in the rare inherited disorder SCID (Severe Combined Immune Deficiency)

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