Genodrug Delivery System - Novel Tool For Parkinson’s Disease

good work done.
All the best

Hy ,
how stem cells are used as dopamine producing cells in treatment of P.D.?

Regards,
Komal

Hello sir,
1. Viruses are another possible environmental trigger for PD. People who developed encephalopathy after a 1918 influenza epidemic were later stricken with severe, progressive Parkinson's-like symptoms. A group of Taiwanese women developed similar symptoms after contracting herpes virus infections. In these women, the symptoms, which later disappeared, were linked to a temporary inflammation of the substantia nigra. Various viruses triggering Parkinson’s disease includes : H5N1 avian influenza virus, many other Influenza virus, Hepatitis b virus.

2. Adenovirus mediated transfection is a simple and efficient method for transient expression of genes. . It is initiated by the virus binding to the cellular receptor. Internalization occurs through receptor-mediated endocytosis followed by release from the endosome. After endosomal release, the viral capsid undergoes disassembly as it moves to the nuclear pore. The method involves the use of DEAE-dextran to target DNA to the cellular endocytotic pathway and the use of human adenovirus to ensure efficient lysis of endosomal vesicles. The procedure allows effective delivery of DNA into the cytoplasm and, therefore, results in a higher fraction of cells expressing exogenous proteins

3. Limitations of adenoviral based transfection are as following:
(a)Expression is transient since the viral DNA does not integrate into the host
(b)Adenoviral vectors are an extremely common human pathogen and in vivo
delivery may be hampered by prior host immune response to one type virus.

References:
www.pdonlineresearch.org
www.vetscite.org
www.brainskills.co.uk
http://www.sciencedirect.com

hI Richa rajani,

The method of drug delivery described by you uses adenovirus.Adenoviruses are pathogenic and causes respiratory infection.On what basis adenovirus was choosen for this drug delivery method

Thankyou
Y mahalaxmi

Thankyou

Hello Ms.Richa,

I have a got a query that what will be the major drawback of genodrug delivery in PD ? As it also increase the dopamine level directly in the brain same like levodopa so is there any chances of appearing same adverse reactions as with levodopa with uses of genodrug delivery concept ?

Thankyou...

can you suggest the name of some other drugs for genodrug delivery system

1. What is the success rate of this genodrugs?
2. Was it practically available now a days?
3. How these particular genes were developed as it differ from person to person?

Dear RICHA
It’s nice presentation from your side.
1. In one of your side you have stated that u have stated that ‘Genodrug delivery approach is such a new gene technique, which combines gene therapy with aromatic Amino Acid Decarboxylase (AADC) gene and a pro-drug, Dopa’. Do you means to say dopa is prodrug?? Why there is necessity to use your concept in combination with prodrug? What are the disadvantages which enables you to use prodrug concept in parkinson treatment.
2. What is the cost effectivity of your concept in clinical terms ...
Thanks.

Dear Richa
Important disease selected.
This genodrug delivery system have any connection to pharmacogenomics?

Dear richa

can u comment how the GABAnergic cells are transfered to subtentia nigra to corpas stiratum in PD

What is the rate of success of Genodrug delivery system as the PD associated with aged persons? Is there any statistical study? what is the results?

hi, richa. It seems a good strategy in PD treatment, my question is:
1) Are there any market products for this delivery system in PD?
2) i would like to know the clinical trial results if any..

1. What kind of viruses triggers Parkinson disease?
2. What if mechanism of Adenovirus mediated transfection? What is important drawbacks ofdenovirus mediated transfection?

Hello mam,

thank you for the comments.
Here is the answer:
Genodrug delivery systems provide with required & continuous levels of dopamine. It does so by converting peripheral dopa to dopamine which otherwise goes in vain during the conventional drug delivery method and results in several side-effects and consumption of large amount of L-DOPA. In Genodrug delivery technique, neurons are infected with Amino Acid Decarboxylase (AADC) gene by an adeno associated viral vector, and not only convert peripheral dopa to dopamine but also provide a buffer for unmetabolized Dopa thereby assuring continuous availability of drug. This novel therapeutic approach has great potential to restore dopamine production, even in chronic stages of disease.

Reference:
http://www.parkinsonsdisease-guidebook.com
www.medicinenet.com
www.innovations-report.com

can you tell me whether nanotechnology is used in it's treatment or not??
If so name some & carriers for it....
Name some which can cross BBB to treat the disease.

Are there any such products in clinical trials and if so in what phase?

hello richa,
nice presentation.
my question is-
as you've mentioned, that genodrug delivery systems would provide with required & continuous levels of dopamine..how will the drug delivery combined with genotherapy, do that...
regards, sakshi

1. Name few virus involved in PD

2. What are the conditions required to combine AADC and Dola.

3. Which adenovirus is more suitable vector for this approach.

4. Which transport mechanism is involved in the transportation of drug with this approach?

hello KOMAL,
1.Rightly said levodopa (L-DOPA) is the precursor of dopamine and also forms the cornerstone of therapy for Parkinson’s disease but it is simultaneously true that it leads to several side effects, but that does not mean we can replace levodopa with carbidopa because it is only the helping hand for L-DOPA. The basic role of carbidopa is to help increase the effectiveness of levodopa and to reduce its side-effects. So I don’t think carbidopa alone would solve the purpose. Rather, the combination of two proves beneficial.
Large doses of the L-DOPA are required, because much of the drug is decarboxylated to dopamine in the periphery, resulting in side effects that include nausea, vomiting, cardiac arrhythmias and hypotension. But the ‘Genodrug drug delivery system’ solves this problem efficiently and helps in conversion of peripheral dopa to dopamine, thereby lessening the side effects and minimising the dose of drug.

2. Selegiline is a selective, irreversible inhibitor of Monoamine Oxidase type B (MAO-B). It decreases the metabolism of dopamine by preventing inter-neuronal degradation. Selegiline is rapidly absorbed from the gastrointestinal tract and crosses the Blood-Brain Barrier (BBB). Its inhibition slows down the breakdown of dopamine in the striatum. A dose of 5 to 10mg of selegiline per day is normally prescribed.

Reference:
http://www.parkinsonsdisease-guidebook.com
http://www.CNSforum.com
www.neurotransmitter.net

HY RICHA,

1.AS L-DOPA IS PRECURSOR OF DOPA & IT HAS SIDE-EFFECTS,SO IF PATIENT OF PARKINSON DISEASE USE CARBIDOPA IT PRODUCE SAME SIDE-EFFECT OR NOT & IS THEIR ANY NEED TO TAKE THIS IN MORE DOSE?
2.SELEGILINE IS ALSO USED IN A.D.SO HOW IT ACT IN DIFFERENT MANNER IN THIS CASE?

Dear Richa,
I have the following questions:
In parkinsons disease the side effects like Dyskinesia and On-Off effects are because of the fluctuating concentrations of dopamine release from L-Dopa.Can genodrug delivery overcome this?
2.Are there any possibilities of Dopamine release in the periphery?
3.Lastly in one of your slides it is mentioned that this approach facilitates the release of dopamine.How can this be possible as there is dopaminergic neurodegeneration?
4.Viral drug delivery has a limited application profile as tissue targeting is governed by the receptor specificity of the virus as directed by coat proteins.
My question is what makes the adenovirus selcetively transfect Nigrostriatal neurons?
5.Also what are the limitations of Adenoviral based transfections?

The Presentation is nice........

My query is, as the brain is the memory storage unit, when this disease attacks some part of the memory is lost(short term memory). Then after curing by Genodrug Delivery System is the person becomes normal from then onwards(as lost memory is lost)????

And the speech is also becomes soft to hard or vice-versa, is it possible to restore his/her normal voice????

Thank you,
SN RaviTeja K.