[olsen]

Oxford Biomedica Presents Encouraging Preclinical Efficacy Data with Prosavin in Parkinson's Disease



- Presentation at the 14th Annual Congress of the European Society of Gene Therapy, 9-12 November 2006, in Athens, Greece -



OXFORD, England, November 13, 2006 - Oxford BioMedica (LSE: OXB), a leading gene therapy company, announced today that new preclinical efficacy results with its gene-based product for Parkinson's disease, ProSavin, were presented at the 14th Annual Congress of the European Society of Gene Therapy (ESGT) in Athens, Greece, which was held on 9-12 November 2006 (http://www.esgt.org <http://www.esgt.org/> ). The data showed, for the first time, that ProSavin outperformed the standard treatment for Parkinson's disease, L-DOPA, in terms of efficacy without inducing any of the disabling dyskinesias (movement disorders) that occur following prolonged treatment with L-DOPA. Also, long-term data showed that ProSavin's therapeutic benefit was maintained for at least 15 months, the most recent time point, without any loss of effect.


ProSavin is administered locally to the region of the brain called the striatum, delivering the genes for three enzymes that are required for the synthesis of dopamine. These genes are able to reprogram the cells that they enter, enabling these cells to manufacture and secrete dopamine. The treated brain region becomes a new endogenous source of dopamine, replacing the patient's own lost source of the neurotransmitter. Sustained expression of the genes is a key requirement for the product to be clinically successful.


Dr Palfi, Head of Neurosurgery at Henri Mondor Hospital, Creteil is the principal researcher conducting the preclinical in vivo evaluation of ProSavin. At the ESGT meeting, Dr Palfi presented a comparison of ProSavin with L-DOPA in an industry standard model of Parkinson's disease. In the early stages of treatment, ProSavin gave high levels of efficacy when evaluated by a series of clinically relevant parameters. In addition, the benefit of a single administration of ProSavin was maintained after a prolonged period, whereas the benefit of continuous L-DOPA therapy waned significantly. Dr. Palfi reported that ProSavin has been effective to the most recent time point of 15 months.


The higher efficacy of ProSavin combined with the absence of side effects suggest that ProSavin could be used to replace current standard therapy with L-DOPA in late-stage Parkinson's disease. These new data add to the extensive preclinical data package that supports advancement of the product into human trials.


Oxford BioMedica is planning to start a European Phase I/II trial of ProSavin in 2007 in patients with late-stage Parkinson's disease and has proposed a clinical plan to progress to a Phase III trial following success in the Phase I/II trial. The Phase III trial, which is designed to support product registration, could commence in 2009. Discussions with relevant regulatory agencies are ongoing.


Commenting on the ProSavin data, Oxford BioMedica's CEO, Professor Alan Kingsman, said: "These new results substantially strengthen the already impressive preclinical data set for ProSavin and confirm its potential as a treatment for Parkinson's disease, particularly when other therapies fail. Its duration of action and lack of side effects are particularly promising. We are now working towards the start of human trials and have been encouraged by discussions with the regulatory agencies."


http://www.pharmalive.com/News/index...&categoryid=40

[Daffy Duck]

1. There is no evidence that people with Parkinson's Disease lack the genes required for the formation of dopamine. Therefore, supplying the genes as a means of treating Parkinson's Disease lacks any scientific basis.

2. There are only two enzymes involved in the formation of dopamine. By claiming that there are three (none of which they name) suggests that they don't even know how dopamine is formed.

3. The formation of dopamine also requires a precusor, cofactor and coenzymes, none of which they account for.

4. They claim that it was shown to be more effective in Parkinson's Disease than L-dopa, but nobody has ever used it.

[aftermathman]

this is not my field so I am interested in your views here.

Oxford Bio claim :

"ProSavin delivers to the patient’s brain three genes required to convert cells that normally do not produce dopamine into cells that do, thereby replacing the dopamine synthesising cells lost during the course of the disease. ProSavin is based on a novel LentiVector system carrying the genes AADC (aromatic amino acid dopa decarboxylase), TH (tyrosine hydroxylase) and CH1 (GTP-cyclohydrolase 1). These genes are able to reprogramme transduced cells to manufacture and secrete dopamine".

Accepting your point re. lack of proof of the claim of efficacy vs L-dopa, I am interested in your views as to the potential of this product.

I am also interested in why Oxford and others would view this as worth the cost of testing.

Please try to keep the explanation simple, I am a mere techie and the world of gene therapy can easily go over my head.

Thanks for your help,
Aftermathman.

[ol'cs]

Is that the "plasmid" organelles of a striatal cell have been "transfected" with a gene construct that is incorporated in the plasmid DNA and then expressed as the ability to do three things. The first would be to enzymatically transform phenylalanine into tyrosine, next tyrosine into dopa, then dopa, decarboxylated to dopamine. All needed co-factors for the enzymatic transformations should already be a part of the cellular machinery for similar enzymatic manipulations, albeit, maybe these too need a boost.
My question is, since dopamine production and release from the substantia nigra is the source of striatal dopamine higher in the midbrain, and midbrain dopamine is involved with mood function, not motor function (this is the job of basal ganglia neurons, lower in the brainstem), than what have they accomplished specifically for helping PD?
Since the "dopamine transporter is "compartmentalized" as such, wouldn't the transfection of cells closer to the substantia nigra be the real intent to provide endogenous dopamine that the cells left in the nigral area can exploit?

[Daffy Duck]

Originally Posted by aftermathman

this is not my field so I am interested in your views here.

Oxford Bio claim :

"ProSavin delivers to the patient’s brain three genes required to convert cells that normally do not produce dopamine into cells that do, thereby replacing the dopamine synthesising cells lost during the course of the disease. ProSavin is based on a novel LentiVector system carrying the genes AADC (aromatic amino acid dopa decarboxylase), TH (tyrosine hydroxylase) and CH1 (GTP-cyclohydrolase 1). These genes are able to reprogramme transduced cells to manufacture and secrete dopamine".

Accepting your point re. lack of proof of the claim of efficacy vs L-dopa, I am interested in your views as to the potential of this product.

I am also interested in why Oxford and others would view this as worth the cost of testing.

Please try to keep the explanation simple, I am a mere techie and the world of gene therapy can easily go over my head.

Thanks for your help,
Aftermathman.

At first I thought this was very interesting because it was doing something very new and claiming proven efficacy for it. However, after checking further details elsewhere it is not all it seems.

I'll try to explain what it is attempting to do in English rather than biochemical gobbledeegook. If I don't succeed please let me know.


DOPAMINE

Parkinson's Disease is primarily due to a lack of dopamine.

Dopamine is produced naturally in the brain in the dopamine producing cells (called the dopaminergic neurons).

They have claimed that the lack of dopamine is due to a lack of these cells, yet no research has ever shown this.

Dopamine is naturally produced in the brain by the following means :

L-tyrosine >>> L-dopa >>> dopamine

So the brain is taking L-tyrosine, turning it in to L-dopa and then turning it in to dopamine.


ENZYMES

An enzyme is a chemical substance turns one substance in to another substance in the body.

So one enzyme turns L-tyrosine in to L-dopa. This is the enzyme they refer to as TH (tyrosine hydroxylase). Incidentally, that name is forty years out of date !

A secoond enzyme turns L-dopa in to dopamine. This is the enzyme they refer to as aromatic amino acid dopa decarboxylase. Incidentally that name is an incorrect mixture of the old name and the present name.

There is no third enzyme involved in dopamine formation as they have suggested.


GENES

Enzymes are made from genes. Each enzyme has a specific gene that makes it. A gene is chemical substance that normally naturally occurs, and is in the body from birth.

So as they claim that there are three enzymes needed to make dopamine, they are providing, by injection in to the brain, three genes to make those enzymes. By this means they hope that those enzymes will make more dopamine.


FLAWS

There are several flaws in their facts and their theory :

Parkinson's Disease isn't due to a massive lack of dopamine producing cells.

Parkinson's Disease isn't (usually) a genetic disorder. So replacing the genes has no rational basis, as there is no deficincy to begin with. People with PD have plenty of these genes already.

They've got the enzyme names and number completely wrong.

By artificially stimulating the activity of these enzymes will result in an opposite after effect.

They take no account of all the other substances that the brain needs in order to produce dopamine.

Their supposedly successful clinical trials have not even begun. They are still applying for permission to carry out the clinical trials. I checked their web site, that soon makes it obvious that nobody has even used, let alone improved using their method. They really are stretching the facts concerning this.


VERDICT

"I am also interested in why Oxford and others would view this as worth the cost of testing."

A huge range of methods and substances are under investigation for use in Parkinson's Disease. Most of them, this one included, could be correct except that the theory they have based it on contains fundamental errors. Also in medicine what may work in the short term is often counterproductive in the long term. What many researchers unfortunately do is to concentrate on the initial beneficial effects and completely disregard what will happen over time - which is usually the opposite effect ! Also, contrary to common belief, most research is arranged by people who have never studied human biochemistry, or whose knowledge of it you could write on one piece of paper (or a lot less). This causes them to make obviousy false assumptions. I have been in discussions with supposed "world experts" in Parkinson's Disease only to find that they didn't even know basics. The errors that have been made with this product make it obvious to me that they do not even know the bicohemistry involved.

I suspect that we will continue to hear more about this but that it will gradually fade away because in practice they will find that any beneficial effects will not be long term and will end up being counterproductive.

[aftermathman]

Daffy, you say "Parkinson's Disease isn't due to a massive lack of dopamine producing cells".

However a large part of my diagnosis was via a DAT scan which (I thought) positively showed up the absence of dopamine producing cells. Is this correct ?

Aftermathman.

[aftermathman]

what makes you say PD isn't a genetic disorder, do we know this for sure ??

Thanks for your patience,

Aftermathman.

(Hopefully this is diverting Howardh from the NZ vs France massacre).

[Daffy Duck]

Originally Posted by aftermathman

Daffy, you say "Parkinson's Disease isn't due to a massive lack of dopamine producing cells".

However a large part of my diagnosis was via a DAT scan which (I thought) positively showed up the absence of dopamine producing cells. Is this correct ?

Aftermathman.

Although DAT scans are often claimed to show a loss of dopamine producing cells, DAT scans can instead show a reduced activity of the dopamine producing cells. Most of the cells are there. They just aren't as active as they should be. In typical PD the activity is about 25%. In severe PD the activity can be less than 10%.The level of activity is constantly changing, which is why symptoms can fluctuate.

[Daffy Duck]

Originally Posted by aftermathman

what makes you say PD isn't a genetic disorder, do we know this for sure ??

Thanks for your patience,

Aftermathman.

(Hopefully this is diverting Howardh from the NZ vs France massacre).

There are a number of known genetic mutations that can cause Parkinson's Disease. Somebody can inherit them or acquire them later in life. However, few people have PD that is genetically caused, and in most cases genetic PD appears to incline somebody to developing PD rather than making it inevitable.

You'd better hope that this distracts Howardh from the result of the England Argentina game as well.

[ol'cs]

Now I've never performed histopathology on human nigral or locus ceruleus tissue, but when one looks for causes of PD, one gets something like this.

"Dopamine is a neurotransmitter that stimulates motor neurons (nerve cells), and is necessary for organized, coordinated movement and maintenance of normal muscle tone. Parkinson's is caused by degeneration of nerve cells in the substantia nigra ("black substance") and the locus ceruleus ("blue location") where dopamine is produced and stored. Loss of dopamine causes neurons (cells in the brain) to fire out of control, leaving people unable to direct or control movement normally."

But Daffy says that the cells themselves are not lost, just their ability to produce, store and release dopamine is compromised. It could be a biosynthesis problem (and just as an aside Keith, I was looking today and found that 3-hydroxy phenylalanine, can be 4-hydroxylated to give dopa, which infers yet another enzyme catalysed process, as I wouldn't expect phenylalanine 3-hydroxylase to be the same entity as tyrosine hydroxylase, you know how specific enzymes are). It could be intracellular damage caused by either an endogenous (gene expression) or exogenous (toxic agent). If it's gene expression it could be something turned on by some mistake which could be initiated by lack of cofactors or rampant free-radical oxidative damage to certain organelles, that result in either the stopping of some part of the dopamine cycle due to cell damage, or outright "kicking in of apoptosis to completely kill the cell instead of just leaving it in a damaged, weakened, reversable (or not), non-dopamine producing cell. I don't know becuase i've never seen a "dead" substantia nigra, but only go by what ive read, that is, that the cells are actually dead.
All this is pertinent here because the stated "gene therpapy" work was done on the wrong cells to affect any reversal of PD. If what you say is true (that most nigral cells are not dead, but just in an inoperative (as far as dopamine production and transmission goes) state, then they should try transfecting enzymatic constructs into nigral or LC neurons?
Of course they would have to know exactly what the "problem" is whether it's a dearth of a critical dopamine producing enzyme, or whether it's primarily a "cell damaging" factor, one which prevents the cell from acting as a dopaminergic neuron. So maybe, most of what the causal process leading to PD could be DNA damage, since DNA is the ultimate blueprint for production of RNA which holds the enzymatic code necessary to actually go out of the cell nucleus and assemble the chains of amino acids that constitute an "enzyme".
It's all so complicated to us, but to a trained biochemist, with all their expensive tools, wouldn't you think that they would have figured some "truths" about all this by now? cs