Parkinson’s Disease | Biotech Strategy Blog

Using CSF Biomarkers for Differential Diagnosis of Neurological Diseases

Drug development for neurodegenerative brain diseases such as Parkinson’s or dementia, of which Alzheimer’s is the most common form, needs to focus on patients early in the disease, not those where brain damage has already occurred.

Diagnosing and treating patients more effectively earlier will, even if you aren’t able to instigate a cure, offer the ability to modify the disease progression and slow or delay when brain damage occurs. In the case of Alzheimer’s, once the amyloid plaques (tangles of misshapen proteins) have accumulated in nervous tissue, it has so far been impossible to untangle or remove them.

Subscribers can login to read more below:

This content is restricted to subscribers

Last year, I interviewed Dr Todd Sherer, (then the Chief Program Officer) and now the CEO of the Michael J. Fox Foundation, who told me that: “biomarkers are a real focus of the foundation.” Sherer went on to say that:

“Parkinson’s is a difficult disease to diagnose, there is no definitive diagnostic test, so it ends up a clinical diagnosis. Getting a biomarker that could help better confirm the diagnosis would allow people to get the correct treatment earlier in their disease”

Which is why I was interested to see new research published earlier this week in the journal Archives of Neurology (online first, August 27, 2012), by Sara Hall and colleagues at Lund University, University of Gothenburg and Skåne University Hospital in Malmo, Sweden.

Hall and colleagues describe how a panel of five cerebrospinal fluid (CSF) biomarkers allowed the differential diagnosis of common dementia from Parkinsonian disorders:

Beta-amyloid 42
Total tau
Phosphorylated tau
Alpha-synuclein
Neurofilament light chain

Patients with early symptoms of neurodegenerative diseases can be hard to diagnose. Misdiagnosis can occur, which means patients may not respond to treatment or they could be enrolled into a clinical trial, and end up skewing the results.

Ensuring that we have the right patients in clinical trials is important as we seek to alter disease progression. In other words it’s important to see whether new drugs or treatments are impacting the disease course. If you have a wrongly diagnosed patient in a trial, then the drug may show no effect, not because it’s not effective, but that patient’s disease is not responsive.

Multivariate analysis indicated that the panel of 5 CSF biomarkers could accurately differentiate Alzheimer’s disease (AD) from Parkinson disease with dementia (PDD), and dementia with Lewy bodies (DLB). The Neurofilament light chain biomarker alone could differentiate PD from atypical Parkinson disease, Hall and colleagues noted.

Whilst the panel was not able to distinguish all forms of dementia, in an accompanying editorial Richard J. Perrin MD, PhD from the University of Washington, stated that this research “represents a significant step forward.” Perrin concluded that:

“Implementation of CSF biomarker panels such as this one should improve the efficiency of clinical trials and accelerate the evaluation and discovery of new effective treatments for neurological diseases.”

Summary

Developing biomarkers that assist in the ability to diagnose Alzheimer’s, Parkinson and dementia patients correctly, and then be able to monitor their subsequent disease progression, should be a key focus of those biotechnology and pharmaceutical companies that want to do innovative and rational drug development.

References

Sara Hall, MD, Annika Ohrfelt, PhD, Radu Constantinescu, MD, Ulf Andreasson, PhD, Yulia Surova, MD, Fredrik Bostrom, MD, Christer Nilsson, MD, PhD, Hakan Widner, MD, PhD, Hilde Decraemer, Katarina Nagga, MD, PhD, Lennart Minthon, MD, PhD, Elisabet Londos, MD, PhD, Eugeen Vanmechelen, PhD, Bjorn Holmberg, MD, PhD, Henrik Zetterberg, MD, PhD, Kaj Blennow, MD, PhD, & Oskar Hansson, MD, PhD (2012). Accuracy of a Panel of 5 Cerebrospinal Fluid Biomarkers in the Differential Diagnosis of Patients With Dementia and/or Parkinsonian Disorders Arch Neurol. DOI: 10.1001/archneurol.2012.1654

Richard J. Perrin, MD, PhD (2012). Cerebrospinal Fluid Biomarkers for Clinical Trials Arch Neurol. (August 27 Online First) DOI: 10.1001/archneurol.2012.2353

Discovering the cause of Lou Gehrig’s disease

In a letter to the science journal Nature, published online on August 21, 2011, scientists from Northwestern University in Chicago report findings that could help develop drugs for patients with Amyotrophic Lateral Sclerosis (ALS), more commonly known as Lou Gehrig’s disease.

ALS is a progressive, fatal, degenerative motor neurone disease, which results in the inability to walk, get out of bed, move arms, hands, swallow or chew. Unlike Alzheimer’s disease, cognitive functions are not usually impaired, making it a particularly nasty disease when faced with awareness of disease progression.

According to Wikipedia, ALS is one of the most common neuromuscular diseases worldwide, with 1 or 2 people in every 100,000 developing ALS each year.

One of the characteristics of ALS and other neurodegenerative disease is the accumulation of protein aggregates or inclusions. Amyloid-ß plaques and intracellular tau neurofibrillary tangles are common in Alzheimer’s disease, for example.

By contrast, in ALS, a hallmark of the disease pathology is the presence of ubiquitin-positive, protein aggregates in spinal motor neurons.

The new research from Northwestern University shows how a mutation in UBQLN2, the gene that encodes ubiquilin 2, may be the cause of ALS in some patients.

The UBQLN2 mutation results in a failure to properly encode the protein, ubiquilin 2, a member of the ubiquitin-like protein family known as ubiquilins. The result is that normal protein degradation through the ubiquilin pathway is impaired, leading to cellular deposits and abnormal protein aggregation.

How did the team at Northwestern discover this insight?

Using DNA sequencing they looked at a five-generation family with 19 affected by ALS and sought to identify the causative gene in the transmission of this disease. They found that a mutation in UBQLN2, the gene that encodes ubiquilin 2 was the key difference in those family members with or without ALS.

They subsequently tested the hypothesis that UBQLN2 mutations were causative of ALS using clinical data from 40 individuals in 5 families with UBQLN2 mutations. Interestingly in eight patients with the UBQLN2 mutation and ALS, dementia was also present suggesting a possible link between ubquilin 2 inclusions and dementia.

The team explored this correlation by examining brain autopsy samples of 15 cases without UBQLN2 mutations, of which 5 had experienced dementia as well as ALS. They found no ubiquilin 2 pathology in the hippocampus of the 10 ALS patients without dementia, but did find it in the 5 that had experienced both ALS and dementia. They noted:

The correlation of hippocampal ubiquilin 2 pathology to dementia in ALS cases with or without UBQLN2 mutations indicates that ubiquilin 2 is widely involved in ALS-related dementia, even without UBQLN2 mutations.

They also observed that:

We did not observe obvious differences in the distributions of wild-type and mutant ubiquilin2.

The authors concluded:

These data provide robust evidence for an impairment of protein turnover in the pathogenesis of ALS and ALS/dementia, and possibly in other neurodegenerative disorders as well.

These interesting findings by the Northwestern group were reported in Nature, and while promising, must be treated with caution for several reasons:

It is still early-stage preliminary research on a small group of subjects.
The exact function of ubiquilin 2 is not well understood.
Not all ALS patients have the UBQLN2 mutation
If the UBQLN2 mutation is not present in all ALS patients, then this mutation is not the sole means by which ALS develops.
UBQLN2 may not be the only mutation involved in the pathophysiology of ALS.

The data from Northwestern does, however, offer hope that in the future, gene therapy or new treatments could be developed that stop or slow disease progression. Targeting the ubquilin pathway and the UBQLN2 mutation may, for example, prevent the abnormal protein turnover and aggregation that leads to impaired signaling and loss of function seen in ALS.

Further research into pathogenic pathways could lead to new targets for drug development, not only for the treatment of ALS but also dementia, and other neurodegenerative disorders.

Deng, H., Chen, W., Hong, S., Boycott, K., Gorrie, G., Siddique, N., Yang, Y., Fecto, F., Shi, Y., Zhai, H., Jiang, H., Hirano, M., Rampersaud, E., Jansen, G., Donkervoort, S., Bigio, E., Brooks, B., Ajroud, K., Sufit, R., Haines, J., Mugnaini, E., Pericak-Vance, M., & Siddique, T. (2011). Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia Nature DOI: 10.1038/nature10353

Story source: LA Times & Fierce Biotech

Can we halt memory loss as we get older?

It’s a fact of human life that we lose physical and mental function as we get older. In the information age that we currently live in, this translates into a decline in our ability to function and perform the activities of daily living. Can we halt or delay age-related memory loss?

Min Wang and colleagues from Yale University School of Medicine in the August 11 issue of Nature, have published some elegant research that suggests we may be able to, at some point in the future.

It’s important to distinguish the cognitive loss associated with normal ageing from that associated with dementias such as Alzheimer’s disease where major changes to the brain structure and function occur. The Yale researchers accomplished this by using aged monkeys that have a highly developed prefrontal cortex (PFC), the part of the brain associated with working memory. Monkeys, unlike humans, do not develop age-related dementias!

Working memory that allows you to keep things “in mind” e.g. where you put the car keys down, relies on a network of pyramidal neurons in the dorsolateral PFC that excite each other.

The strength of this excitatory network depends on the neurochemical environment e.g. elevated cAMP signaling reduces nerve firing. Wang and colleagues reversed the age-related decline in PFC activity by restoring an optimal neurochemical environment. Through a series of experiments they found that:

The memory-related firing of aged DELAY neurons was partially restored to more youthful levels by inhibiting cAMP signalling, or by blocking HCN or KCNQ channels.

These findings reveal the cellular basis of age-related cognitive decline in dorsolateral PFC, and demonstrate that physiological integrity can be rescued by addressing the molecular needs of PFC circuits.

This research, although preliminary and based on animal models, is promising. It offers the hope that in the future we may be able to reverse or slow-down the age-related memory loss and cognitive defects we would otherwise experience.

Many biotechnology and pharmaceutical companies are focusing on Alzheimer’s disease as a target. What this research suggests is that developing therapies that may delay or slow-down age-related memory decline could also be a valid target for drug development, with a significant market opportunity.

Wang, M., Gamo, N., Yang, Y., Jin, L., Wang, X., Laubach, M., Mazer, J., Lee, D., & Arnsten, A. (2011). Neuronal basis of age-related working memory decline Nature, 476 (7359), 210-213 DOI: 10.1038/nature10243

ARVO 2011 Using the eye as a window into the brain

By Pieter Droppert on May 4, 2011

Due to the pressure of other commitments, I only had the pleasure of attending the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) for two days, but one of my key take home messages from the meeting is how we can use the eye as a window into the brain. This is particularly relevant to Alzheimer’s research.

ARVO researchers at a lunchtime workshop that I attended asked the question of what can we learn from shared disease mechanisms in age-related macular degeneration (AMD), Alzheimer’s Disease (AD) and Glaucoma to devise therapies of the future?

What I learnt in the introduction by Nicholas Bazan from LSU Health Sciences is that both AD and AMD are both multifactorial, genetically complex, progressive, late-onset neurodegenerative conditions. Common features include:

Age-related neurodegeneration
Amyloid precursor protein mis-processing
Non-resolving inflammatory response
Selective apoptotic cell death

Researchers in the workshop presented early experimental findings.

Catherine Bowes Rickman from Duke presented data that showed anti-amyloid immunotherapy blocks retinal pigment epithelium (RPE) damage and visual function defects in an AMD-like mouse model. Interesting questions were raised as to whether mouse Aß aggregates differently to human, so is this a good model?

Adriana Di Polo from the University of Montreal discussed Glaucoma and AD: common neurodegenerative pathways and therapeutic targets. It was interesting to note that high rates of visual abnormalities, including glaucoma, have been reported in AD patients, but causality has not been established. Neuronal loss in both glaucoma and alzheimer’s disease occurs via common cell death processes including altered metabolism of Amyloid Precursor Protein (APP) and Aß.

What Di Polo highlighted in her talk was the potential to use therapies effective in one disease to treat the other e.g. galantamine is approved for treatment of mild to moderate AD symptoms. Because it crosses the retinal-brain barrier and has high bioavailability, she presented results using this in an animal model of glaucoma.

Her conclusion was that “therapeutic modalities that promote neuroprotection in AD may be useful in glaucoma and vice versa.”

The third speaker of this fascinating workshop was Ian Trounce from Melbourne, who challenged the Amyloid theory of AD. His hypothesis was that sAPPα may trigger oxidative stress in mitochondria and be the problem. He discussed the increasing acceptance/overlap in pathologies between Parkinson’s and AD. He presented data that sAPPα overexpression protects retinal ganglion cells (RGC) from rotenone via PI3K-AKT activation.

Critical feedback on the three presentations was provided by Guy Eakin of the American Health Assistance Foundation (AHAF) and Imre Lengyel from UCL.

As Dr Lengyel succinctly notes in his UCL Institute of Ophthalmology bio:

“It appears that the development of age related macular degeneration (AMD) and Alzheimer’s disease (AD) share similar histopathology, vascular risk factors and genetic predisposition. In addition, the development of AMD appears to use similar or identical steps on the cellular and molecular levels to AD: vascular damage, oxidative stress, inflammation, extracellular protein and peptide degradation or deposition, and the role for lipids and trace elements (especially zinc) in the degenerative process are amongst the many common features. Furthermore, amyloid beta peptides are an integral part of drusen (the hallmark lesion in AMD) and their formation might be similar to plaque formation in AD.”

I applaud ARVO for looking at how the eye can be used as a window into the brain. It raises the intriguing prospect that research on AMD may not only help understand the cause of AD, but that the eye may serve as an experimental model for future new treatments. Collaboration between Opthalmology and Alzheimer’s researchers is something I expect and hope we will see more of.

Making a difference to Parkinson’s Disease Research, an interview with Dr Todd Sherer, Michael J Fox Foundation

Biotech Strategy blog recently had the privilege to do a phone interview with Dr Todd Sherer, the Chief Program Officer of the Michael J Fox Foundation. In this two- part interview, Pieter Droppert asks what the MJFF approach to research funding is and what the future holds for Parkinson’s disease research?

Part 1: Research Funding

Research funding is key to science. Without it there would be no translational medicine that takes basic research and turns it into clinical applications that benefit humans. One organization that is making a difference and bridging the gap between patients and research is the Michael J Fox Foundation (MJFF).

Biotech Strategy Blog: What does a Chief Program Officer do?

Dr Sherer: My role as Chief Program officer is to lead the research efforts at the Michael J Fox Foundation. My background is as a neuroscientist so I have a PhD in neuroscience, and my lab work was in Parkinson’s disease before I joined the foundation. At the foundation we have a number of additional scientists, seven in total. They work closely with people with business backgrounds in a collaborative way. What we are trying to do is apply business principles to scientific research. So, select the best scientific projects and then design them in a way where there are deliverables, milestones and goal directed research with the ultimate aim to improve treatment for Parkinson’s patients.

Biotech Strategy Blog: MJFF receives 800 grant applications a year, what is your approval process, is it similar to the National Institutes of Health?

Dr Sherer: It is modeled after the NIH process with the one main difference being that our internal scientific staff has a proactive role in making the final funding decisions. We take the peer review panel to help us evaluate, but the ultimate decision lies with our internal staff. We do a rapid turn around of those reviews so from receiving an application to funding is usually for us 3 to 4 months total.

Biotech Strategy Blog: What business principles do you use in managing the research that you fund?

Dr Sherer: One of the main things we do with every grant we make is laying out from the beginning: what is actually the goal of that grant. This probably seems logical, but actually a lot of scientific research is very open ended – it is kind of “let me see what I discover”. But we are really trying to define from the beginning: what are we trying to accomplish? Then what we can do is set milestones along the way to that goal to make sure during the course of the project, we are making the progress we need to achieve that goal.

Biotech Strategy Blog: Are grant payments linked to performance?

Dr Sherer: The payments for the grants are all tied to the milestones, and I would say that we are realistic in that we are experienced in how research works. This is not manufacturing, and we know that you can have the best plan, but it is all based on a hypothesis and things can come up in the course of the research. Our scientific staff here will always work closely with those grantees to make the rational adjustments in the plan based on what we are learning along the way.

Biotech Strategy Blog: In addition to the grant applications that you receive, does the Michael J Fox Foundation initiate its own projects?

Dr Sherer: Yes. We have identified specific priority topics within Parkinson’s disease, whether they be specific therapeutic targets, or something like a biomarker, where we are more proactively working with the research community to develop projects to address critical challenges in those areas. We also do conduct some research using a virtual research model where the scientists here may outsource some work with contract research organizations. We have been particularly doing that around research tools so that we can make those tools widely available to our researchers — things like antibodies, plasmids, vectors — we want to quickly get these made without any licensing or intellectual property restrictions and then make them broadly available to the research community.

Biotech Strategy Blog: Why does MJFF fund research by commercial entities e.g. biotechnology & biopharmaceutical companies?

Dr Sherer: The goal of the foundation, the goal of all the research that we are supporting is to develop new therapies for Parkinson’s disease patients. We understand that will involve all players in the research space, so it involves academic researchers. But really to convert those discoveries into therapies for people, we want to proactively engage and interact with the biotech and biopharma community because they are the ones who in the end make the therapies for patients. About 5 or 6 years ago we decided to more proactively outreach to the biopharma community to determine: if we provided funding, could we induce more companies to work in Parkinson’s disease or accelerate their work in Parkinson’s disease.

Biotech Strategy Blog: What types of biotech & biopharma companies do you fund?

Dr Sherer: There are some companies that have worked in related diseases, like another neurodegenerative disease, and our funding allows them to apply that technology to Parkinson’s disease. Another category would be a platform type of company that we have supported, where they could really go to any disease, but the Fox funding allows creates a rationale to choose Parkinson’s. Then we have funded some companies who are interested in Parkinson’s but for budgetary reasons have made some trade-offs in the design of that study. With additional funding from the foundation they can increase the sample size, hone the end points or what have you, to really make that study more robust. We have seen a lot more companies working in Parkinson’s as a result of this outreach.

Biotech Strategy Blog: Do you take any rights in any commercial research you fund?

Dr Sherer: In most of our projects we do not have any stipulation like that, particularly in the case where we are funding some preclinical testing. That said, in our largest, multi-million dollar grants, particularly those in late-stage clinical development, we usually have an agreement that there is a return payment after some amount of sales. That is more the exception than the rule.

Biotech Strategy Blog: Thank you

Part 2 of this interview with Dr. Todd Sherer, Chief Program Officer of the Michael J. Fox Foundation, will provide insight on the current status of research into Parkinson’s disease, and what we can expect the future to hold?

Patients with Spinal Cord Injury may benefit from treatment with Taxanes

Taxanes are a class of drug that are used in breast, lung and ovarian cancer chemotherapy to disrupt the function of microtubules that are essential to cell division. They include paclitaxel (Taxol®) and docetaxel (Taxotere®).

Paclitaxel is also used to prevent the narrowing (restenosis) that occurs with coronary artery stents that are used to open blocked coronary arteries. Drug coated stents (a.k.a. “drug-eluting stents) reduce scar tissue.

Research published in the February 18, 2011 edition of Science, by Farida Hellal and colleagues has now shown that treatment with paclitaxel reduces the scarring associated with spinal cord injury (SCI) and promotes nerve regeneration.

The paper in Science is well worth reading and takes the reader through a logical thought process as the researchers tested their hypothesis that paclitaxel might stabilize microtubules around the site of SCI.

One of the cellular events that occurs after SCI is the activation of transforming growth factor-ß signaling (TGF-ß).

Increased TGF-ß leads to fibrosis or scarring. TGF-ß acts on Smad2 to bind to microtubules through kinesin-1. Hellal and colleagues asked if treatment with paclitaxel would impair Smad-dependent TGF-ß signaling? The answer from their elegant series of experiments is that yes it does.

Not only that, but TGF-ß also regulates the axon growth inhibitor, chondroitin sulfate proteoglycans (CSPGs). The researchers asked whether pacllitaxel decreased CSPGs after SCI? They found that cultured meningeal cells and astrocytes treated with 10 nM paclitaxel showed a 35% and 32% decrease of glycosaminoglycan (GAG) levels.

The next logical question is whether the reduction of scar formation by paclitaxel results in any benefits for new nerve formation? The regeneration of dorsal root ganglions (DRG) were evaluated. In what to me was a finding of great significance, the researchers found (references to figures omitted) that:

“Taxol-treated animals had regenerative fibers growing along the edge of the lesion cavity into the injury site and beyond. The longest axons per animal grew 1199 T 250 mm in the Taxol-treated group versus 176 T 225 mm in the vehicle-treated an- imals (n = 13 animals per group; P = 0.002; two- tailed t-test). The Taxol-treated lesion site thus becomes favorable for regeneration of growth-competent axons.”

The final part of this research asked whether treatment with paclitaxel led to any functional improvement after the test animals received a spinal cord injury? They found that those rats that received paclitaxel after injury, had greater improvement in their locomotor function. The conclusion being that “Taxol-induced functional recovery correlates with its axon growth–inducing effect.”

The results from any animal study must be viewed with caution, since they don’t necessarily translate to humans. However, this animal research, if supported by data from human clinical trials, suggests that treatment with taxanes may be of benefit to those with spinal cord injuries.

Given the debilitating effect of any spinal cord injury, this is an important finding.

Hellal, F., Hurtado, A., Ruschel, J., Flynn, K., Laskowski, C., Umlauf, M., Kapitein, L., Strikis, D., Lemmon, V., Bixby, J., Hoogenraad, C., & Bradke, F. (2011). Microtubule Stabilization Reduces Scarring and Causes Axon Regeneration After Spinal Cord Injury Science, 331 (6019), 928-931 DOI: 10.1126/science.1201148

Allon Therapeutics announces promising preclinical results for davunetide in Parkinson’s Disease

By Pieter Droppert on February 24, 2011

Earlier this month the Michael J Fox Foundation (MJFF) announced that Vancouver based Allon Therapeutics had been able to improve motor function and brain pathology in a mouse model of Parkinson’s disease (PD).

MJFF funded this research with Allon Therapeutics. The preclinical study results are published in the Journal of Molecular and Cellular Neuroscience.

What makes this data interesting is that it adds further support to the potential efficacy of the company’s lead product, davunetide, in a wide range of neurodegenerative disorders.

Davunetide (AL-108) is a microtubule-interacting peptide based on an eight amino acid sequence, Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln, single letter code NAPVSIPQ (NAP) derived from activity-dependent neuroprotective protein (ADNP). It has been shown to have neuroprotective properties.

Davunetide can be administered by IV or intranasally and crosses the blood/brain barrier. It is effective at promoting neurite growth, restoring transmission between nerve cells and untangling some of the damage seen in neurodegenerative disorders such as Alzheimer’s disease. References to the scientific publications and mechanism of action can be found on the Allon Therapeutics website.

Currently it is being developed for Alzheimer’s disease (AD), schizophrenia cognitive impairment and frontotemporal dementia (FTD). Davunetide is in a phase 3 clinical trial for progressive supranuclear palsy (PSP), a subtype of FTD.

The company’s strategy is to pursue a fast-track to market in a small indication such as PSP. This is makes a lot of sense for a small biotechnology company with limited funding. Successful approval in PSP will significantly increase the value of the company and improve the terms of any future licensing/partnering deals.

The hope for davunetide is that it will prevent disease progression in disorders such as AD and provide neuroprotective prophylaxisis prior to surgery that carries a high risk of memory loss e.g. heart bypass and coronary artery graft surgery (CABG).

While davunetide may not be a cure for AD, being able to slow down disease progression is something that has considerable value. Given that new imaging biomarkers are likely to provide the opportunity to detect AD much earlier, the market opportunity for early treatment is set to increase.

Many families and caregivers would welcome a drug that delays further cognitive decline and memory loss in their loved ones.

On the basis of the promising preclinical results, I think we can expect to see further clinical research on davenutide in Parkinson’s Disease.

Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Immunotherapy

Posts from the ‘Parkinson’s Disease’ category