Alzheimer’s disease, a neurodegenerative disorder often characterized by the accumulation of amyloid plaques in the brain, affects over 30 million people worldwide – a figure predicted to double by 2030, according to the World Health Organization. The greatest risk factor for this disease is age. It has therefore been suggested that compounds targeting age-associated pathologies of the brain, as well as amyloid metabolism, may be beneficial in the treatment of Alzheimer’s disease. Marguerite Prior and colleagues at the Salk Institute, California investigated the cognitive effects of the neurotrophic molecule J147 on disease progression in a mouse model of late stage Alzheimer’s disease, as published in a recent study in Alzheimer’s Research & Therapy. This article is part of a thematic series titled ‘Cognitive enhancers for ageing and Alzheimer’s disease’, which presents new approaches to drug discovery and development for cognitive aging therapeutics. Prior told us more about the significance of the recent study into J147 and its potential in treating Alzheimer’s disease.
You previously showed neurotrophic molecule J147 is able to prevent or delay the onset of Alzheimer’s disease-like symptoms in young mice. How does your latest study further this investigation?
In our previous studies we tested J147 in Alzheimer’s disease mice by treating them before pathology is present. This is the preventative treatment strategy that is typically used to screen compounds for an effect in Alzheimer’s disease. The aim of our latest research was to test J147 in a more rigorous pre-clinical model that would more accurately reflect what happens in humans when pathology is advanced at the time of diagnosis and treatment begins. The therapeutic strategy employed in this study involved aging Alzheimer’s mice to 20 months old before treating them. The results add to the range of biological activities of J147 relevant to Alzheimer’s disease in humans.
What are the main findings of your study?
We showed that when J147 was administered in food at a stage when pathology is advanced in 20-month-old transgenic Alzheimer’s disease mice, it rescued the severe loss of memory, reduced soluble levels of amyloid and increased neurotrophic factors essential for memory. When compared to Aricept, currently the most widely prescribed Alzheimer’s disease drug, J147 performed equally well or superior in memory tests, and even showed synergistic effects in one memory test. This particular result is itself very important because when recruiting for clinical trials most patients will likely already be receiving Aricept.
Aricept only manages disease symptoms and does not modify the disease at all, it only works for a short time and does not work for everybody. It is also quite toxic at just 45mg/kg, whereas J147 showed no toxicity at 2g per kg. Our study also details some of the pharmacology and safety data we have collected to date showing that J147 gets into the brain rapidly, has good medicinal, chemical and pharmacological properties for a central nervous system (CNS) drug, has few off-target effects, and is orally active. Our findings also further support the hypothesis that the mechanism of action of J147 is related to its ability to increase levels of neurotrophic factors that are important for memory. Studies are now being conducted to identify its molecular target.
What excited you when you started looking at the data?
The most exciting thing when we started looking at the data was finding that a compound could reverse severe memory deficits in the Alzheimer’s disease mice even when given at a really late stage in disease progression. Testing of Alzheimer’s drugs in mice is usually done before pathology is present because the alternative strategy of waiting until pathology is present or advanced is often viewed as too difficult to achieve positive results. The fact that J147 was able to reverse memory deficits following a short term treatment of three months and that this effect on memory was supported by our biochemical data was very exciting to us. All of our data to date suggests that J147 has great potential to be a disease modifying drug for Alzheimer’s disease. This is significant because currently all of the FDA [US Food and Drug Administration] approved drugs for Alzheimer’s disease just manage the symptoms and don’t do anything to halt disease progression.
What are the implications of the findings?
Alzheimer’s disease research has traditionally focused on a single target, the amyloid pathway, but unfortunately drugs that have been developed through this pathway have not been successful in clinical trials. It is definitely time for a new approach and a new kind of drug. Age is the greatest risk factor for Alzheimer’s disease and we believe that normal aging and age-associated neurodegenerative disease are caused by a combination of several toxicities, not just one. So cells in the aging brain are likely to be compromised from the convergence of multiple insults. An alternative approach therefore is to use a drug discovery paradigm based upon screening procedures that reflect the biology of aging and the disease pathology without preselecting a molecular target.
The drug screening procedure that we used to identify J147 is based on old age associated pathologies using cell culture assays that mimic multiple pathways of CNS nerve cell damage. These assays include proteins that keep cells alive that are lost in old brains, oxidative stress, reduction of energy metabolism and toxicity from damaged proteins. Age associated parameters have not been employed as a group for targeting pathways in Alzheimer’s disease drug discovery. Multi-target lead compounds such as J147 offer the best chance for success at treating what is a very complex disease. J147 is a particularly exciting new compound because it both slows disease progression through the protection of neurons as well as providing rapid benefits to memory by reversing memory deficits following short-term treatment. These dual attributes improve the chances for success in clinical trials as a disease modifying drug.
How useful are rodent models for studying Alzheimer’s disease?
The therapeutic strategy employed in our study is rarely used to screen compounds for Alzheimer’s disease even though in humans, pathology is usually quite advanced at diagnosis and treatment. Instead, the typical preventative strategy of treating Alzheimer’s mice before pathology is present is used. Over 200 compounds appear to alter amyloid metabolism or behavioral deficits in Alzheimer’s disease transgenic mice but none have translated into Alzheimer’s disease therapeutics. The reason for the lack of translation may be that many of these compounds are only effective when administered before pathology is present. Our chosen therapeutic strategy more closely resembles what happens in humans where they have advanced pathology when treatment begins. We believe that while this therapeutic strategy might be perceived to be difficult to employ, it is a more viable and certainly more rigorous model for testing potential Alzheimer’s drugs and it will likely be more accurate at predicting disease modifying drugs in humans.
The rodent models for Alzheimer’s disease also have another limitation; they are all based on gene mutations that are found in only five percent of human cases of Alzheimer’s disease – those that are genetically based. The remaining 95 percent of cases are sporadic in nature, meaning we don’t know what causes them. This could also explain the lack of translation of drugs into the clinic, as the compounds were screened against the genetic form of the disease that is different from the sporadic form.
What’s next for your research and the J147 project?
Our research group has done as much as we can possibly do with J147, including a lot of the pharmacology and toxicology. We would love to get J147 into clinical trials because we believe that this compound, with its memory enhancing and neuroprotective properties alongside its safety and oral activity, is an ideal candidate for Alzheimer’s clinical trials. We are ready to file an Investigational New Drug (IND) application with the FDA here in the US but that requires a certain amount of pre-clinical work outside our lab first. Based on quotes from contract research organizations that carry out this type of work, the required pre-clinical work will cost around $1.5 million dollars and take six months to a year to complete. We are in the process of raising the funds to do the work, file the IND with the FDA and get J147 into human clinical trials as soon as we can.
How important are public outreach programmes to highlight research such as yours?
It is important for a number of reasons. Firstly, it demonstrates that people are still working very hard to cure Alzheimer’s disease despite the fact that all of the clinical trials from the pharmaceutical industry have failed. It also shows that places other than the pharmaceutical and biotechnology industries are working on the problem. Public outreach additionally highlights how big the problem is and how little funding for Alzheimer’s disease drug discovery there really is. Lastly it gives research organizations and individuals involved in drug discovery the chance to promote their work and so potentially secure funding.
Listen to more from Marguerite Prior on J147 and it’s potential for treating Alzheimer’s here.
Alzheimer's Research & Therapy 2013, 5:25
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