I am not "holding my breath" for this five-year stem cell cure. What was it they said about a cure for PD 10 years ago...oh yes, that we would have a cure for PD in 10-years...that was the statement.

Well, we almost had it a couple of years ago. I think it was called GDNF!!

In a vain attempt to get this Topic back on to a positive footing, how about some good news released yesterday about Gene Therapy research.

Was anyone from here on these trials?


PET scans show gene therapy normalizes brain function in Parkinson's patients
MANHASSET, NY - Brain scans used to track changes in a dozen patients who received an experimental gene therapy show that the treatment normalizes brain function - and the effects are still present a year later.

Andrew Feigin, MD, and David Eidelberg, MD, of The Feinstein Institute for Medical Research collaborated with Michael Kaplitt, MD, of Weill Cornell Medical Center in Manhattan and others to deliver genes for glutamic acid decarboxylase (or GAD) into the subthalamic nucleus of the brain in Parkinson’s patients. The study was designed as a phase I safety study, and the genes were delivered to only one side of the brain to reduce risk and to better assess the treatment.

A recently published study included the clinical results of the novel gene therapy trial, but this new report from the same study focuses on the power of modern brain scans to show that the gene therapy altered brain activity in a favorable way. This latest study is published this week in the Proceedings of the National Academy of Sciences.

The patients only received the viral vector-carrying genes to the side of the brain that controls movement on the side of their body most affected by the disease. It was a so-called open-label study -- everybody received the gene therapy so the scientists knew that there could be a placebo effect. That is why brain scans were so critical to the experiment. Dr. Eidelberg and his colleagues pioneered the technology and used it to identify brain networks in Parkinson’s disease and a number of other neurological disorders.

In Parkinson’s, they identified two discrete brain networks -- one that regulates movement and another that affects cognition. The results from the brain scan study on the gene therapy patients show that only the motor networks were altered by the therapy. “This is good news,” said Dr. Eidelberg, the senior investigator of the study. “You want to be sure that the treatment doesn’t make things worse.” The gene makes an inhibitory chemical called GABA that turns down the activity in a key node of the Parkinson’s motor network. The investigators were not expecting to see changes in cognition, and the scans confirmed that this did not occur.

Position emission tomography (PET) scans were performed before the surgery and repeated six months later and then again one year after the surgery. The motor network on the untreated side of the body got worse, and the treated side got better. The level of improvements in the motor network correlated with increased clinical ratings of patient disability, added Dr. Feigin.

“Having this information from a PET scan allows us to know that what we are seeing is real,” Dr. Eidelberg added. The scans also detected differences in responses between dose groups, with the highest gene therapy dose demonstrating a longer-lasting effect. “This study demonstrates that PET scanning can be a valuable marker in testing novel therapies for Parkinson's disease,” he said.

The gene therapy technique was developed by Neurologix Inc., a New Jersey-based company. Scientists are now working on a design for a phase 2 blinded study that would include a larger number of patients to test the effectiveness of the treatment.

Chris

now if we can just get Penny Thomas herself to post we will have a real "result".

Neil.

Actually I got a reply from the chinese hospital official with e-mail contacts of treated patients including Penny Thomas. After hesitation for many reasons, I sent them e-mails asking them if they may be kind and share their experiences through this forum.

gene therapy success story is starting to receive media coverage previously unheard of. Already three gene therapy stories from different media outlets have found their way to these threads. Faaaantastic.

We have been trumpeting the Proffessor Michael Kapplitt and Proffessor Matt Durring GT trials for over 12 months, and according to their web site Phase 2 trials should be underway.

www.neurologix.net is the web site too book mark. Go there and suck up all the latest knowledge on Gene Therapy progress.

There is nooooo need for me too mention the country of Matt Durring....there is a need to mention another New Zealander Proffessor Richard Faul a neurology scientist of some pedigree, who has just released a research study today on brain cell replication which has far reaching implications for brain disease cures such as PD. It's hard to be humble folks, but for a country of 4.2 million we sure pull above our weight when it comes to science. Rutherford of course will take some beating.

GO HARD>>>> SCIENCE

you may also be interested in the Oxford Biomedica gene therapy trial (Prosavin), due to kick off imminently in France.

Rumour is this is the sh&t or bust product, results in weeks of treatment.

Neil.

http://www.oxfordbiomedica.co.uk/prosavin.htm

http://www.nature.com/nbt/journal/v3.../nbt.2077.html


Nature Biotechnology | News and Views

Dopaminergic neurons for Parkinson's therapy
Olle Lindvall
Nature Biotechnology 30,56–58(2012)doi:10.1038/nbt.2077Published online 09 January 2012



A differentiation protocol guided by developmental principles produces more-authentic dopaminergic neurons for transplantation in patients.



In Parkinson's disease, impaired control of movement stems from the degeneration of dopaminergic neurons in the substantia nigra and the resulting loss of dopamine in the striatum. Clinical studies in which human fetal mesencephalic tissue, rich in dopaminergic neuroblasts, was transplanted into the striatum of individuals with Parkinson's disease have shown in principle that dopaminergic neurons can be replaced and symptoms reduced in some cases1. But the functional outcome of this treatment has proved highly variable, and human fetal tissue is scarce, suggesting that other sources of dopaminergic neurons are needed to develop a clinically useful cell therapy. A recent report in Nature by Studer and colleagues2 describes the conversion of human embryonic stem cells (hESCs) into substantia nigra dopaminergic neurons that ameliorate Parkinson's disease symptoms in animal models without forming tumors. From the clinical perspective, this new differentiation protocol, which generates large numbers of transplantable dopaminergic neurons of the correct phenotype, represents a major advance toward the first application of hESC-derived dopaminergic neurons for grafting in patients.

Previous studies by my group and others have shown that dopaminergic neurons in fetal grafts can reinnervate the striatum and restore dopamine release in the brain of Parkinson's disease patients1. Some of our patients improved to the extent that they have managed for several years without treatment with L-dopa (a chemical that crosses the blood-brain barrier and after decarboxylation increases brain dopamine levels)3. These clinical programs came to an end after troublesome graft-induced involuntary movements, or dyskinesias, developed in ~15% of patients1. This problem now seems to be solved as the graft-induced dyskinesias in three of our patients were found to be caused by graft-derived serotonergic hyperinnervation of the striatum and could be abolished by pharmacological blockade of serotonin signaling3. In other studies, a small fraction of fetal graft–derived dopaminergic neurons was shown to contain Lewy bodies (the hallmark of Parkinson's disease) many years after transplantation1, 4. However, the progression of pathology to grafted neurons was slow, and they were still functional after a decade, with patients showing long-term improvement.

Stem cells could become a source of virtually unlimited numbers of dopaminergic neuroblasts for transplantation. To induce substantial clinical benefit, stem cell–derived dopaminergic neurons must be of human origin and must exhibit the specific properties of substantia nigra neurons. Promising results have been obtained using hESCs5, 6, 7, but several problems of fundamental importance for clinical translation remain8. The identity of the cells as substantia nigra dopaminergic neurons, their ability to extensively reinnervate the striatum in a larger brain and their capacity to markedly improve deficits resembling the symptoms experienced by Parkinson's disease patients—none of these prerequisites has been convincingly demonstrated yet. Moreover, hESC-derived grafts are associated with a risk of tumor formation5, and some protocols for generating dopaminergic neurons involve ex vivo gene delivery7, which may hinder clinical application.

Studer and colleagues2 provide solutions to several of these problems (Fig. 1). Compared to previous protocols for generating dopaminergic neurons from hESCs, the most important change in the new method is that the cells are passed through a developmental stage at which they exhibit the characteristics of floor plate tissue. The floor plate is a signaling center during neural development, located along the ventral midline of the neural tube, and the midbrain floor plate is neurogenic and a source of dopaminergic neurons. Studer and colleagues2 derived floor plate cells from hESCs in vitro using dual inhibition of SMAD signaling and high levels of sonic hedgehog9, 10. Midbrain floor plate identity was induced by activation of WNT signaling, and cells were exposed to BDNF, ascorbic acid, GDNF, cAMP, TGFβ3 and DAPT. Differentiation to dopaminergic neurons with extensive fiber outgrowth occurred with high efficiency. The cells expressed phenotypic markers typical for substantia nigra dopaminergic neurons and expressed genes that define these neurons during development. They also exhibited electrophysiological properties of nigral neurons and released large amounts of dopamine in vitro.

Figure 1: Generation of functional dopaminergic substantia nigra neurons for transplantation in Parkinson's disease.


Floor plate cells are derived in vitro from hESCs by dual inhibition of SMAD signaling and high levels of sonic hedgehog. Midbrain floor plate identity is induced by activation of WNT signaling, and dopaminergic neuron precursors are generated in the presence of trophic factors, ascorbic acid, cAMP and DAPT. After intrastriatal transplantation in mice, rats or non-human primates, these cells give rise to large numbers of dopaminergic neurons with a substantia nigra phenotype, which reinnervate the striatum and ameliorate behavioral deficits resembling the symptoms in Parkinson's disease patients.
Full size image (242 KB)

Notably, high numbers of dopaminergic neurons with a substantia nigra phenotype survived for a long time after intrastriatal transplantation of the hESC-derived dopaminergic precursors both in mice (~5,000 cells per graft at 4.5 months) and rats (~15,000 cells per graft at 5 months)2. These quantitative data suggest that the cells could be clinically useful because successful fetal transplants in Parkinson's disease patients require ≥100,000 dopaminergic neurons per putamen. In a nonhuman primate model, the grafted dopaminergic neurons extended their axons up to 3 mm into the striatum already at 1 month2. This is important because the axonal outgrowth from human stem cell–derived dopaminergic neurons generated so far has been poor8. The new hESC-derived dopaminergic neurons seemed to be able to reinnervate a major portion of the denervated striatum also in a larger brain, which will be necessary for clinical efficacy. Finally, the dopaminergic cell grafts not only completely reversed drug-induced rotational asymmetry but also improved clinically relevant behavioral deficits resembling symptoms in Parkinson's disease patients.

These findings are supportive of a future hESC-based therapy for Parkinson's disease, but several issues remain to be addressed. A critical issue for clinical translation is safety. The protocol for generating dopaminergic neurons should be fully chemically defined, and the components of animal origin eliminated. The potential for graft-induced dyskinesias after transplantation should be assessed in appropriate animal models. Notably, serotonergic neurons were rare in the grafts in rodents2, suggesting that the risk of dyskinesias in the clinical setting is probably low. The authors observed no tumors after transplantation, and the percentage of proliferating cells was low. However, before the cells are used clinically, their tumorigenicity must be assessed more rigorously. As part of this evaluation, it will be important to determine the identity of all cell types in the implants. Use of cell sorting to eliminate tumor-forming cells or of regulatable suicide genes may be necessary to improve safety.



Another question concerns the functional efficacy of the hESC-derived dopaminergic neurons. To be competitive with alternative therapies, grafts must bring about major recovery of motor function. Motor symptoms in Parkinson's disease patients can already be treated rather well with L-dopa, dopamine agonists, enzyme inhibitors and deep brain stimulation. Studer and colleagues2 found that the hESC-derived grafts contained large numbers of dopaminergic neurons and were efficacious in rodents. A cell potency assay comparing hESC-derived neurons with fetal dopaminergic neurons would be useful to estimate the number of cells needed for humans. Also, the growth capacity of the dopaminergic cells must be carefully analyzed to determine the number and distribution of implants required to reinnervate most of the human striatum. Finally, it should be noted that restoration of striatal dopamine transmission by cell therapy is unlikely to improve nonmotor problems in Parkinson's disease, which are due to the degeneration of other dopaminergic and nondopaminergic neuron systems.

Although several challenges lie ahead for stem cell therapy in Parkinson's disease, the findings of Studer and colleagues2 are cause for optimism. If implantation of their dopaminergic cells is found to enable robust, long-lasting improvement of motor function and to allow withdrawal of dopaminergic medication, as observed in some patients with fetal grafts3, this study would represent a breakthrough in the field that could make cell therapy available to large numbers of patients.

Another important study, by Olle Lindvall:

"Clinical application of stem cell therapy in Parkinson's disease"

http://www.biomedcentral.com/1741-7015/10/1

Gene therapy has proved less than stellar, Prosavin (described as sh%t or bust in 2007), looks like a bust.

Neurologix seems a bit of a mystery, it passed blinded trial but lack of money or real humdinger results are stalling it.

Stem cells are still in the office, Brainstorm are trialling stem cells for ALS, heaven only knows what the self proclaimed "world leading" Brits are doing, (don't mention bloody Dolly the sheep). Probably the usual testing to destruction in the offices with no idea or inclination of how to send it out to the real world. Still good for the sheep of this world to know there is a kidney out there for them if they need it.

The worlds only super power to me, an outsider, still seems paralysed by the hangover of the Bush administration where stem cells are concerned. Where Arnies billions of California taxes went on this subject is best left unmentioned.

Korea, still lacking credibility following the debacle.

Ho hum, still we may have a cure in 5 years, say that every year and one year we will get it right.

Neil.

Hi Neil, I completely agree with you. In any case, I feel hopeful and confident, for example, about the last great works, made ​​by Dr. Lorenz Studer and his international colleagues (www.neurostemcell.org), as well as on the work are leading in Sweden, Drs Olle Lindvall and Anders Bjorklund. Maybe not tomorrow, but I think very soon begin to test even in humans with PD.
Furthermore, what else could we ever do, except hope?

Paging Dr. Bin Hu. Paging Dr.Hu. (neuro-scientist at University of Calgary and a hospital in Shanghai; has been going around China setting up PD clinics); some estimate there will be 30 million PWP in China as population ages; Chinese government said to be pushing PD research with military determination.