ProSavin Update for Parkinson's Disease

Another Next Best Hope for PD

Well if I were in the financial world I could probably tell you more about the Prosavin Clinical Trial I/II progress. The word on the Street is that the Oxford Biomedica-Sanofi-Aventis Collaboration has produced enough cash based upon their lentivector program to carry on until 2012. Actually the money comes on the rights give-back of TroVax, a projected cancer treatment with a possible patent lawsuit which may or may not have been settled. But the word is that the trials for ProSavin are going well.

Just when Phase III will actually begin although previously mentioned for a 2009 start year remains to be seen.

As you know, Prosavin is designed to deliver the genes for three enzmes required for dopamine production. ProSavin carries the genes AADC, TH and CH1 which then convert cells which do not normally produce dopamine to become dopamine producing.

Thus far three patients received low doses of ProSavin and all demonstrated improvement in their UPDERS motor scores between 10-50%. Patients apparently continued to take L-Dopa meds. There is also a high dose study in progress.

Things look encouraging.

The key enzymes:
AADC - aromatic l-amino acid dicarboxylase

aka dopa dicarbozylasea deficiency of this enzyme

is associated with autonomic dysfunction

and is extremely rare
TH - tryosine hydroxylase
CH1 - GTP-cyclohydrolase 1

Additional reading:
The GCH1 gene
From Oxford Biomedica: ProSavin

Cogane, a Future Treatment with Hope for a Parkinson's Disease Cure

Cogane Hold Promise for PD, Alzheimer's, ALS, Neuro-Motor and Psychiatric Disoders

It's taken awhile to get this article ready so our apologies to Ken and Hen.

According to Phytopharm, Cogane also known within the company as PYM50028, is a non-peptide orally bioavailable neurotropic factor inducer that crosses the blood-brain barrier. Cogane stimulates the release of neuronal growth factors and increases neurite outgrowth by elevating the levels of GDNF, glial derived neurotrophic factors. Cogane also increases the levels BDNF, brain derived neurotropic factor. Neurotrophic factors can aid the survival of neurons.

GDNF is a protein which has been encoded by the GDNF gene. In its recombitant form it has been shown to promote the survival of dopamine neurons for PD and motorneurons for ALS. GDNF also promotes the survival of serotoninergic and catecholamingeric neurons. The catecholamingeric neurons control a variety of cognitive, motor and endocrine functions. They are associated with many psychiatric and neurodegenerative disorders.

The hope for Cogane is that it lives up to its neuroprotective and neurorestorative potential with safety of use which means that while it might be not only a treatment as a PD progression reducer or even progression reversal, it might also be a cure. It may also become a treatment for Alzheimer's disease.

The largest problem with bringing Cogane to the market is the enormous amounts of money that are needed to bring a drug through the requisite trials and application processes. Phytopharm has done a restructuring to reduce costs and to extend its available cash to September 2010. They are also considering other options and are also seeking grant funding. The Michael J Fox Foundation awarded a $1.16 million grant towards the dosage trials.  The phase 1 trials has been completed and phase 1b is currently recruiting. The Cure Parkinson's Trust partly funded the latest phase and has since committed to ongoing support to develop Cogane.

One important thing to note is that Phytopharm is not the only company working on the GDNF approach to treating Parkinson's disease. During the next few weeks we will provide information of the status of other GDNF research and development as well as clinical trials.

Good news for Phytopharm is that in March the stock tracking of PYM on London Stock Market was 4.25p Footse (down 3 days later to 4.13p) back again to 4.25p by 3/27/09. As of this morning, PYM was at 6.88p (up 1.93) Results of the Phase 1b trial are expected in the last quarter of 2009 and then Phytopharm can move on to Phase II.

Addendum - June 2010
Phase 1b has been completed and Phytopharm recently announced that they have received FDA protocol approval to begin Phase II clinical trials for Cogane.  Enrollment will begin in late 2010.  We'll be posting that information and links to enrollment when it is announced.

You can read the Phytopharm press release here  

The Parkinson's Disease Triangle for Dopamine Cell Death

Or being in the right place at the wrong time
We all know about the Fire Triangle. That group of three elements which need to be present for fire: heat, fuel and an oxidizing agent which is usually oxygen. Yes there are also fire squares and tetrahedrons but lets look at how the basic triangle relates to Parkinson's. When you add the chemical reaction to the triangle you have fire. When Fire Investigators look at what's left after a fire they look for the cause and origin, the way the combination of elements led to the combustion.

In Parkinson's disease researchers know that the death of the dopamine producing neurons in the substantia nigra (SN) cause PD but until now, they have not known what caused the cell death. Although knowing that cause may not provide the all answers to the origin, at least it is a significant area for continued investigation and development.

So what has happened in the last few months? Researchers have learned that an imbalance in the PD triangle of alpha synuclein, calcuim channels and cytosolic dopamine itself can lead to the premature death of the dopamine neurons. Imagine a cell - in this case a neuron or nerve cell which can transmit information by electrochemical signaling - it has assigned places for each task. But what if one team member doesn't want to wait in the correct place?  When things don't work the way they are supposed to work, there can be a serious problem.

What these scientific investigators found was that just as there is good cholesterol and bad colesterol there can be good dopamine and bad dopamine or at least badly behaved dopamine. Although the why is not known yet, what is known in the new study is that it is about location, location, location. Dopamine must be contained within a specific area of the cell and not venture out too early.  Where and when the dopamine is within the neuron will be the deciding toxicity factor because if it moves from the inner part of the cell, the synaptic vesicle, to the outer cytoplasm, where dopamine combines with (calcium and) a-syn to become a toxic gunk. Since the cell cannot properly get rid of this mess...Is it the excess calcium which triggers the premature action potential?

So how to get the dopamine to remain within its inner area of the cell until the right time is the question for researchers. And there is updated information coming in 2010.

Addendum:
The player we didn't mention is DOPAL the MAO metabolite of dopamine. DOPAL is a natural toxin which has recently be found in higher levels in PwPs (people with Parkinson's).
Apparently 3,4-dihydroxyphenylacetaldehyde or DOPAL causes alpha-synuclein to aggregate or clump. This would explain part of the problem. A question raised is the relationship of DOPAL to ROS or reactive oxygen species.
Natural Toxins Implicated in the Development of Parkinson's disease

Resources and related info:
http://www.medicalnewstoday.com/articles/148270.php

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSS-4W5VS0G-3&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=584119172539790fca9149456494469d

The Abstract:
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSS-4W5VS0G-B&_user=10&_coverDate=04%2F30%2F2009&_rdoc=1&_fmt=high&_orig=browse&_cdi=7054&_sort=d&_docanchor=&view=c&_ct=1&_refLink=Y&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=d80d423c21d954c84c93716328fd07dc

Synucleinopathy:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1510951
http://www.nbhope.org/blogs/neuroblastomaresearch/archive/2009/04/21/a-cell-based-model-of-alpha-synucleinopathy-for-screening-compounds-with-therapeutic-potential-of-parkinson-s-disease.aspx

How the brain works:
http://www.aolhealth.com/alzheimers/learn-about-it/how-the-brain-works/a-micro-view-of-the-brain

A glossary of visual links:
How neurotransmitters work:
http://faculty.washington.edu/chudler/chnt1.html

Action potential:
http://faculty.washington.edu/chudler/chmodel.html

Nerve cell transmission:
http://teens.drugabuse.gov/mom/tg_nerves.php

Neurons, synapses, action potentials and transmission of impulses:
http://www.mind.ilstu.edu/curriculum/neurons_intro/neurons_intro.php

Cells, Genes, Functional Genomics and Microarrays
http://www.ebi.ac.uk/microarray/biology_intro.html

New Theory Of Parkinson's Disease Gives Researchers Fresh Ideas For Treatments