use of doxycycline to decrease GDNF in animal model to "decrease potential side effec
 

(may be a foolish question--though given the results of this study in an animal model, utilizing doxycycline (a tetracycline class drug) to functionally decrease production of GDNF, would this apply to humans? Should individuals with PD not take doxycycline? Or does this effect not matter clinically?I do not have the original study, so do not know what the "side effects" from GDNF are defined as. I do recall (couple yrs ago?) study utilizing minocycline (tetracycline class of drugs, as is doxycycline)in neurodegenerative diseases for its interference with microglia activation... I remember minocycline crosses the BBB. Confusing. )

MrsD, any insight, or am I over-reading/mis- associating this stuff again?


http://blog.taragana.com/health/2009...therapy-10952/
Mandel’s research group has concentrated on using an adeno-associated virus to engineer brain cells in animal models with genes that can protect dopamine-producing cells, which then do the vital work of producing glial cell line-derived neurotrophic factor (GDNF).

The naturally occurring protein(GDNF) is important for the survival of dopamine-producing neurons during brain development, and a survival factor when given to adults.


...For the current study, the researchers engineered the virus with two genes that must act in concert to produce the protein (GDNF).

But this precise interaction can be inhibited with dietary doxycycline, an antibiotic..

Depending on the amount of the antibiotic, protein production can be reduced or stopped, which would for the first time give medical investigators the ability to regulate gene therapy after the treatment was delivered.

“With this technique, you could adjust the therapy in the patient. That would be extremely helpful because no one is really certain yet what dosage is required for a protective effect in humans. The process is also much more sensitive than we had imagined it would be. GDNF production can be shut down completely with a dose of doxycycline that is much smaller than what is commonly prescribed,” said Fredric P. Manfredsson...

The researchers used a number of methods to gauge GDNF production, but one was uncommon and involved the novel observation of the rats’ weight.

The scientists found that they could control the rate of weight gain in the rats with dietary doxycycline, which essentially verified they were controlling the GDNF therapy...

(Abstract of study to which the above report refers: [had I first read this abstract, I would NEVER have known the study involved using doxycycline to decrease the production of GDNF}:)


http://www.nature.com/mt/journal/v17...t2009196a.html
Molecular Therapy 17, 1857–1867 (1 November 2009) | doi:10.1038/mt.2009.196



Tight Long-term Dynamic Doxycycline Responsive Nigrostriatal GDNF Using a Single rAAV Vector
Fredric P Manfredsson , Corinna Burger , Aaron C Rising , Kheir Zuobi-Hasona , Layla F Sullivan , Alfred S Lewin , Julia Huang , Emily Piercefield , Nicholas Muzyczka & Ronald J Mandel

Glial cell line-derived neurotrophic factor (GDNF) gene transfer is being developed as a treatment for Parkinson's disease (PD). Due to the potential for side effects, external transgene regulation should enhance this strategy's safety profile. Here, we demonstrate dynamic control during long-term expression of GDNF using a recombinant adeno-associated virus (rAAV)-based bicistronic tetracycline (tet)-off construct... Molecular Therapy (2009) 17 11, 1857–1867. doi:10.1038/mt.2009.196

minocycline protects dopa neurons against rotenone toxicity
 

Minocycline Protects Dopaminergic Neurons Against Long-Term Rotenone Toxicity
Canadian Journal of Neurological Sciences, 12/21/09

Radad K et al. – Minocycline has neuroprotective potential against the progressive loss of tyrosine hydroxylase immunoreactive neurons induced by long–term rotenone toxicity in primary dopaminergic cultures.
http://cjns.metapress.com/app/home/c...lts,1:300307,1

GDNF potential agent for PD (2006 article)
 

http://ejournal.vudat.msu.edu/index....ewFile/164/140

Glial cell line-derived neurotrophic factors (GDNF), a
potential therapeutic agent for Parkinson’s Disease.
Michelle Ye

Doxycycline as a "transgene switch"
 

Madeline,

The use of doxycycline in the research you cited is a recently discovered laboratory "molecular trick" designed to allow control of the production of a protein from an introduced theraputic transgene, GDNF in this case.

In these systems, an on-off switch is built into a theraputic gene to be administered by way of a virus vector. These vectors are constructed by inserting a special sequence of DNA ahead of the coding sequence for the desired product. That inserted sequence responds to the presence of doxycycline by interrupting the expression of the downstream gene.

The idea is to allow regulation of the amount of the GDNF protein produced by giving the patient an easily administered, safe substance, since the regulatory sequence responds to levels of doxycycline far below those needed for its function as an antibiotic.

Robert

doxycycline
 

Thank you, Robert. How ingenious. madelyn

Doxycycline
 

This article caught my eye in early September when Dr, Mandel's group published their results. In our ongoing quest to discover how we contracted PD, doxycycline appears to be a prominent factor in my specific history.

Onset of symptoms 1996. Contracted a respiratory virus. Significant cough developed resulting with 7 fractured ribs over a 2 month period. Cultures and all tests failed to idenitfy any organism etiology. I was treated with doxycycline orally. Within a week or two I began to lose weight rapidly and watched my liver enzymes elevate off the page. Doctors were mystified and told me that I had a "Toxic Hepatitis", probably contributed to the doxycycline. Recovery was slow and I never regained full strength. Three years later the early symptoms and signs of Parkinson's Disease were apparent. Most of you can probably relate to the rest of the story.

Was Doxycycline responsible for the release of a neurotoxin?
Was the toxin carried and introduced by the virus?
What role did the protein play?
What was the role of DNA? (DNA analysis negative fpr Parkin or LRRK2)

I have written to Dr Mandel's group but have not has a response.
Thanks for the explanations and info above.

Gary

Gary,

When i read the words "a simple antibiotic" to switch off the gene the word oxymoron comes to mind.

paula