Thursday 24 January 2013

credits


http://www.lpch.org/DiseaseHealthInfo/HealthLibrary/hrnewborn/hydrops.html
         http://medical-dictionary.thefreedictionary.com/neonatal+edema
         http://www.wisegeek.com/what-is-hepatosplenomegaly.htm
         http://en.wikipedia.org/wiki/Proteinuria
         http://en.wikipedia.org/wiki/Cardiomegaly
         http://www.med-ed.virginia.edu/courses/rad/hrct/septal1.htm
         http://www.medhelp.org/posts/Heart-Disease/Septal-Hypertrophy/show/250845
         http://medical-dictionary.thefreedictionary.com/dysostosis+multiplex
         ww.audioenglish.net/dictionary/dysostosis_multiplex.htm
         http://en.wikipedia.org/wiki/Ataxia
         http://education.yahoo.com/reference/dictionary/entry/myoclonus
         http://en.wikipedia.org/wiki/Angiokeratoma
         http://ghr.nlm.nih.gov/condition/galactosialidosis
         http://rarediseases.info.nih.gov/GARD/Condition/3953/QnA/30724/Galactosialidosis.aspx#4516
         http://themedicalbiochemistrypage.org
        



http://en.wikipedia.org/wiki/Acid_hydrolase

scientific article -Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice


Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice

Introduction

This article talks about a lysosomal storage disorder that is caused by the deficiency of the lysosomal enzyme arylsulfatase A(arsa),that is coupled with neurological impairment. This disease is characterized by myelin degeneration in the CNS and PNS. Due to the accumulation of ARSA substrate called galactosylceramide I3-sulfate.

This diseases can only be diagnoised in humans after the onset of symptoms so in order to solve the neurological disease a new strategy had to be devised. Hence through this article they have proven the complete normalization of established behavorial abnormalities,motor conduction and neruopathological conditions of ARSA(-/-) mice upon HSPC-GT(GENE-TRANSFER)

In this research they made use of macrophages and microglia cells to release the desired lysosomal enzyme so that in-vivo cross correction can occur

The animal model they made use for this research was a mouse model of MLD which was characterized with slow progressive CNS and PNS disease. They display delayed motor conduction,neuronal degeneration and widespread storage of metachromatic material that further amplifies along with age.
The experiment was kicked off by transplanting HSPC’S from ARSA donors using a vector(LV) THAT WAS EXPRESSIN THE ARSA gene. To optimize the detection of this enzyme in the mouse they made use of a C-terminal-tagged transgene that contains the HA peptide from the human influenza virus.
The mouses were also further divided into group A and group B due to the difference in the average ARSA ACTIVITY which were lower in the first 4 transplantation group(group A) than compared to the last 4 which was higher.(group B).

So how did this research manage to correct the neurological problem ?- through the transplantation of the HSPC’S and the GT to over express the lysosomal enzyme in the brain using the microglia  the deficits were managed to be normalized, and there was the prevention of demyelination even surprisingly the remyelination in the PNS which in turn might account for reversal of motor conduction defects.
The methods used for this experiment were motor learning tasks that were performed with an accelerating rotarad apparatus so as to mesure the performance of the mouses. Histopathology for eg semithin and ultrathin morphological analyses were performed. Transduction of hemopoietic progenitors and HSCT were performed by using the stem separation kit first then the vector was injected via the tail vein into the mouse.
The ARSA assays were performed by plating BM cells in a methylcellulose-based medium. After 10 days colonies were plucked and lysed for PCR analysis and for the detection of LV sequences.  immunofluorescence analysis and western blot analysis was carried out and finally for ARSA-HA specific activity detection a p-NC assay was adapted.
 Finally there were safety concerns of using LV gene transfer and the enzyme overexpression  in HSPC’S, this is because there is a NEED  for an high engraftment of transduced cells that relies in multiple vector integration which can lead to integration-dependant genotoxicity and there was also the  requirement of supranormal levels of enzymes to be produced so as to achieve significant therapeutic effects in the nervous system. However this problem was addressed by making use of the LV vector that compared to using the retrovector (RV)which suggests the risk of insertional mutagenesis could be significantly lower that compared to using RV’S, and hence through the use of LV the researches never detected any hematopoietic abnormalities.

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Wednesday 23 January 2013

Treatment to Fabry Disease


- Current treatment for Fabry disease involves enzyme replacement therapy (ERT) with intravenous infusions of recombinant human α-galactosidase A.

 This therapeutic regimen consistently decreases Gb3 levels in plasma and clears lysosomal inclusions from vascular endothelial cells. 

The effects of ERT on other tissues are not as obvious, suggesting that treatment must be initiated early in the course of the disease to be optimally effective or that some complications of the disease are not responsive to enzymes delivered intravenously.



 Enzyme Replacement Therapy
- We use an enzyme called Fabrazyme which is intended to replace the missing enzyme in patients with this progressive disease

-Fabrazyme (agalsidase beta) is used to treat patients with Fabry disease. Fabrazyme lowers the amount of a substance called globotriaosylceramide (GL-3), which builds up in cells lining the blood vessels of the kidney and certain other cells. 

-The lowering of GL-3 suggests that Fabrazyme may improve how Fabry disease affects your body; however a relationship of lower GL-3 to specific signs and symptoms of Fabry disease has not been proven.



SYMPTOMS OF THE FABRY DISEASE


Symptoms include :

-Pain


-Parathesia in the extremities (Paresthesia is an abnormal condition in which you feel a sensation of burning, numbness, tingling, itching or prickling. Paresthesia can also be described as a pins-and-needles or skin-crawling sensation. Paresthesia most often occurs in the extremities, such as the hands, feet, fingers, and toes, but it can occur in other parts of the body)




-Gastrointestinal disturbances (Gastrointestinal (GI) disturbances commonly include symptoms of stomach pain, heartburn, diarrhea, constipation, nausea and vomiting)

-Cardiomyopathy(It is a weakening of the heart muscle or another problem with the heart muscle. It often occurs when the heart cannot pump as well as it should, or with other heart function problems)




-Progressive renal impairment (Disorder characterized by the kidney's inability to filter wastes from the blood. It may be acute (occuring suddenly and usually reversable) or chronic (developing slowly over time as a result of permanent damage)


-Corneal(pertaining to the cornea)

Lenticular opacities(A cataract in which the opacity is confined to the lens.)




-Characterestic skin lesions called -Angiokeratomata

*These symptoms are all due to the deposition of G3b in the walls of small vessels, kidney tubule and glomeular cells, nerves and dorsal root ganglia. 
*The characteristic skin lesions of Fabry disease are the earliest signs that may lead to diagnosis in childhood. 
*Death usually occurs in early adulthood from renal and cardiac complications of the vascular disease.