Hot Topics@PD Therapeutics 2009

A more detailed report of the Q&A sessions around these talks will follow over the next several days - in the mean time, here are some highlights:

• First up was Mattias Baehr, who talked about the promise of Granulocyte-colony stimulating factor (G-CSF) as possible neutoprotective therapy for PD.  After the talk a number of questions were discussed regarding interactions with the blood brain barrier, possible effects of the protein on signaling and microglia. Though this potential therapy is in very early stages of develoment, Bill Langston asked Mattias to speculate on how this might be actually delivered therapeutically to patients, if it were to ultimately get through all the necessary clinical trials and approvals.  Dr. Baehr said that a single weekly subcutaneous injection could be feasible, and is in line with their current pre-clinical use.

• Next was Jeff Conn, who presented some exiting progress in his approach to develop a pharmaceutical bullet that can reduce the pathological hyper-activity in PD neural circuits -- going for the same kind of therapeutic effect that is currently achieved through surgically invasive lesion and deep-brain-stimulation therapies. Jeff and his colleagues have identified two molecules with promising drugability profiles that target the mGluR4 receptor and provide symptomatic benefit in a pre-clincial model of PD.  The Q & A session following the talk addressed details of selectivity of the compounds for mGlur4 vs. mGlur5, mGlur4 distribution in the CNS, and speculation on the manner of potential therapeutic administration, either as monotherapy or in combination with other drugs.

• David Bumcrot reported on his siRNA strategy for reducing alpha-synuclein expression in rodent and primate brain.  He presented data showing that direct intraparenchymal infusion of siRNA reduced gene and protein expression.  There was a particularly lively Q & A session after this talk, including discussion of the ever-popular questions around what exactly alpha-synuclein has to do with PD anyway.  Other issues discussed included: What is the optimal level of synuclein reduction you want to achieve? Is 100% too much?; Does the infused siRNA itself accumulate or degrade?  This couldn't possilby work against already-formed synuclein aggregates, right? Bill Langston concluded with a reminder that Braak, in his analysis of the distribution of alpha-synuclein throughout the body, does not look at Lewy bodies at all: he looks at evidence of widespread synuclein-associated neuropathology.

How do you decide which patients are the best population to study novel disease-modifying or preventative therapeutic strategies for Parkinson's disease? This is an issue arising again and again among PD researchers and clinicians, without an easy answer. Parkinson's disease pathogenesis is thought to rely on a triggering event causing the progressive disease. Reinforced by the recent findings of alpha-synuclein transmission between neurons and the pathological protein accumulation in Lewy bodies over time, the silver bullet of Parkinson's treatment is a method of halting those initial events and preventing the progressive loss of dopaminergic neurons. Yet, can we develop a therapeutic that will prevent or diffuse that initial trigger?

From a development perspective, possibly. Numerous strategies are being developed, including a few discussed at the PD Therapeutics Conference: preventing cell death with G-CSF, siRNA against alpha-synuclein, gene therapy using neurotrophic factors (GDNF), and targeting protein handling mechanisms (VPS41). Each of these methods has the potential to prevent the accumulation of protein aggregates or nurture already stressed cells back to health. But, practical concerns may prevent these therapies from ever getting to the right patients, early enough to impact disease progession. For example, David Bumcrot was asked during the Q&A session when he thought alpha-synuclein siRNA should be administered to patients. This is a prime candidate to prevent the initial accumulation of this long-lived protein, but the method of delivery is quite invasive (as with gene therapy): surgical implantation of a catheter and pump directly into the brain. Though it would likely be more effective as a disease-modifying or preventative treatment, in a clinical situation only advanced patients would undergo such an invasive procedure. But, would silencing expression of alpha-synuclein help patients who already have a large amount of protein inclusions? Would neurotrophic factors aid survival if there are few neurons left to survive? The same questions were raised following the disappointing results of the Ceregene trial for GDNF.

It's an issue without an easy answer and is raised again and again when scientists and drug developers convene.  How do we address this problem? Can you evaluate a preventative or disease-modifying therapy in advanced patients? If an approach fails to meet expectations in advanced patients, is it because the therapeutic strategy failed or because you didn't test in the right population? Do we need to change how we approach clinical trials from development, clinical and regulatory perspectives? How do you design such a trial?

• David Standaert described a fascinating path taken from discovery in worms to mammalian PD models by VPS41, a protein involved in lysosomal trafficking that is emerging as a useful target for the development of PD therapeutics.  In acknowledgement of the lack of a definitive PD model, David and colleagues have profiled this protein in a variety of the commonly used PD models including rotenone and 6-OHDA.  There was a very informative Q & A session following, which we will report on in greater detail over the next several days.  Questions discussed included:  How many PD models do you need to test?  Are there binding partners for the 2 implicated domains?  Might this be a target for other proteinopathies?  Along the way David described an elegant structure-function analysis of this protein, which has inspired me to plan a new PD Online Research Question about the how’s, why’s and best practices of this kind of analysis – stay tuned for that.

• Gretchen Snyder described the strategy she and her company are taking to develop compounds that mimic and potentiate the normal actions of dopamine, with the goal of making it possible to refine and maximize the therapeutic benefits of l-DOPA.  She described phosphodiesterase inhibitor PDE1B, which activates cAMP and cGMP and has a therapeutic effect on several assays of motor function and dyskinesia in PD models, as well as effects on measures of normal cognitive functions.   Questions again were lively, about the expression patterns and specificity of PDE1A as well as the PDE1B and PDB1C isozymes, details of the drug-induced catalepsy model, and possible interactions with D1 andD2 agonists.

More detailed coverage of the Q&A sessions from these talks will come over the next several days: stay tuned!

• Krystof Bankiewicz described efforts by his lab and colleagues in improving the effectiveness of intraparenchymal delivery of AAV vectors using concurrent imaging and convection enhanced infusion techniques.  Krystof discussed the weight-loss effects seen with substantia nigra infusion of AAV2-GDNF in his hands, and recommends that axonal transport to the nigra from putaminal infusion sites is the way to get GDNF action in the nigra.  Questions included details about exactly how and where axonal transport of GDNF takes place in these experiments, and why there is no weight loss in animals with axonally transported nigral GDNF compared with nigrally infused AAV2-GNDF.

• Susan Bressman described her work about LRRK2 in Ashkenazi Jews and her participation in the rowing consortia being assembled to better investigate this most common genetic cause of typical PD.  Susan addressed the classic issues of penetrance with regard to LRRK2 and how these issues affect the design of her studies: are ‘non manifesting carriers’ really normal? Questions from the audience concerned dosage effects, lessons that could be learned from Huntington’s, plans for development of iPS cell resources, and the desire for longitudinal studies of such cohorts. 

The next 2 talks focused on alpha synuclein:

• Robert Nussbaum described his recent work with artificial chromosome transgenic manipulation of human and murine alpha-synuclein. Robert and colleagues have developed two new transgenic mouse line, each expressing one of two mutant forms of a-synuclein (A53T and A30P), and characterized them with a broad range of assays for motor, gastrointestinal, autonomic and olfactory function.  Of particular interest was the extensive testing of enteric nervous system function and discovery of gastrointestinal disorders in mutant mice that are also observed in humans in early PD.  Questions and comments focused on the enteric nervous system results, and included a statement by Bill Langston that PD research has not benefited from the brain-centric view of the disease.  It was also pointed out that these mice show motor defects but no neurodegeneration: Dr. Nussbaum responded by saying that his results point to an interference with synaptic function that manifests without the actual death of neurons.

• Michael Schlossmacher talked about his progress in developing PD-diagnostic algorithms of protein levels in blood and cerebral-spinal fluid.  This work focuses on alpha synuclein and compares expression patterns in different diseases including PD, DLB, MSA, and Alzheimer disease.  Questions and comments included possible explanations for contradictory findings in the scientific literature,  testing such algorithms, and methodological standards for handling biosamples for precise analysis.

More detailed coverage of the Q&A sessions from these talks will come over the next several days: stay tuned!

In response to the presentation from David Bumcrot regarding an siRNA approach to reducing alpha-synuclein levels, there was an interesting discussion about the relevance to this type of approach in Parkinson's disease. The crux of the debate came down to one question: What is the evidence that reducing alpha-synuclein expression levels is actually beneficial? Obviously this has not been demonstrated in humans but the audience was not able to cite any published data supporting this hypothesis.

The conference ended with 2 talks on challenging topics assigned by MJFF – Franz Hefti and Andrew Singleton took up the challenge.

• Franz Hefti stepped up to the plate and told us all how to design ‘The First Alpha-Synuclein Efficacy Trial’.  He began by comparing approaches taken to deal with a-beta in AD with those taken regarding alpha-synuclein and PD, and discussed many of the realities faced by industry in deciding what treatments to invest in.  Questions included a very cogent one from Bill Langston, who asked what Franz considered to be the minimum requirements that Industry wants before going to clinical trials with a treatment: Franz replied: 
  • A compound with reasonable drug-like properties that works in a reasonably well justified transgenic animal model that replicates the disease process.
  • An endpoint in the animal model experiments that is the same as that proposed for the clinical trial.
  • A duration of treatment of 1 year or less.

• Andrew Singleton gave the last talk, about how genome-wide association studies (GWAS) can help drug developers.  He began with what GWAS are good for and not good for – for example, they are not good for finding rare mutations, though occasionally they do so.  Questions probed distinctions that Andy reported about differential  GWAS results for PD and multiple systems atrophy (the SNPs are largely the same between PD and MSA, but the underlying haplotype structure is subtly different).  Also the prominence of both SNCA and GBA in GWAS for PD was emphasized.

More detailed coverage of the Q&A sessions from these talks will come over the next several days: stay tuned!  

An interesting point raised by Jeff Conn during his presentation on mGlur4 allosteric modulators that could be applied to any small molecule program: Often when groups explore the selectivity profile of their molecules and screen against other neurotransmitter/GPCR receptors, the profile typically involves binding of the molecule to the receptors; however a more informative screen is to use a functional screen to not only determine whether the molecule binds to other receptors but also whether it elicits a functional response that may more accurately predict off-target effects.