Posted on November 12th, 2013
by John Commissiong
Neurotrophic factors don’t come around every day. Since the first neurotrophic factor (NGF) was discovered in 1950’s by Rita Levi-Montalcini’s group, the feat of discovery has been repeated well under 30 times. Moreover, never has the discovery process been meticulously engineered to yield a molecule with an activity profile to treat a specific indication; except in the case of MANF which was discovered for the treatment of Parkinson’s disease. The fact that MANF has been shown to be effective in treating various models of disease in animals gives us a glimpse of what might be possible if we discover more growth factors with the purpose of treating other neurodegenerative diseases.
When I was leading the Neurotrophic Factors Group at the National Institutes of Health in the 1990s, I had a very keen interest in astrocytes because they dramatically outnumber neurons in terms of number of cells and morphological complexity.
After years of research, our team was the first to demonstrate that astrocytes from one region of the brain (substantia nigra) secreted molecules that protected neurons from that region of the brain (dopaminergic neurons of the substantia nigra) better than astrocytes from any other brain region could. Shortly after we published our findings, another group published an almost identical set of results, giving us the confidence that we were on the right track.
From there, another important issue needed to be resolved: In order to use astrocytes as a tool for discovering the neurotrophic factors responsible for the protection we were seeing, we needed a stable source of astrocytes capable of being used in a systematic screening process over and over again. It was here that I reached into some of my early research experience to engineer some proprietary methods to immortalize the astrocytes we were using to generate the initial results in order to turn them into stable cell lines that could be used for neurotrophic factor discovery. We achieved success at 2am one Thursday morning in 1997, the first PhenoGuard cell line (VMCL1) was created, and from there on in my mind it became only a matter of time until multiple neurotrophic factors would be discovered from this methodology. We began using our cell culture to assist companies in drug discovery efforts in 1998, helping Teva Pharmaceuticals in their screening process and ultimately advising them to select Rasagiline from a group of candidates they were evaluating. Rasagiline was approved in 2006, and was the first proof of principle that our cell culture had validity in identifying approvable drug candidates.
Fast forward to 2002, my team discovered and patented MANF using the same cell culture alongside our PhenoGuard cell lines as the biological approach to our neurotrophic discovery program, with MANF ultimately having the signature of protecting dopaminergic neurons that we saw in the cell lines. Shortly after MANF’s sequence was first made public at Dr. Levi-Montalcini’s neurotrophic factors conference in Modena, Italy, the homologue of MANF, CDNF (previously known as MANF2) was discovered by a group at the University of Helsinki using a bioinformatics approach based on MANF. Taken together, MANF and CDNF represent a new neurotrophic factor family discovered as a result of our PhenoGuard discovery platform.
With proof of principle established in various animal models for MANF, the addition of a seasoned drug development organization to the Amarantus team, and the recent move of the Company to a facility where we will have access to all the necessary equipment to restart the PhenoGuard program, I am eager to set about the business of discovering a new neurotrophic factor family. The scientific methods have advanced tremendously in the last decade, which gives me confidence that we will be able to achieve results while deploying significantly fewer resources than we did while discovering MANF. Coupled with our partnering business model, we believe we will be able to find the appropriate partner for PhenoGuard to fully exploit the true value of this technology.
Proving that the discovery of MANF was not serendipitous would represent a massive scientific achievement for the Company in this era of outsourced drug discovery in the pharmaceutical industry. We expect to be in a position to start collaborating on this project in early 2014 having expanded our PhenoGuard cell line library to 88 cell lines from four distinct brain regions associated with Parkinson’s, Alzheimer’s, Clinical Depression and Huntington’s disease.
Science can sometimes be an uncertain endeavor, however with proper parameters established, it has the potential to yield groundbreaking advances in medicine. We believe PhenoGuard could be one such engine in the emerging era of neurotrophic factor development.
John W. Commissiong, PhD
Forward Looking Statements
Certain statements, other than purely historical information, including estimates, projections, statements relating to our business plans, objectives, and expected operating results, and the assumptions upon which those statements are based, are forward-looking statements." These forward-looking statements generally are identified by the words believes," project," expects," anticipates," estimates," intends," strategy," plan," may," will," would," will be," will continue," will likely result," and similar expressions. Forward-looking statements are based on current expectations and assumptions that are subject to risks and uncertainties which may cause actual results to differ materially from the forward-looking statements. Our ability to predict results or the actual effect of future plans or strategies is inherently uncertain. Factors which could have a material adverse effect on our operations and future prospects on a consolidated basis include, but are not limited to: changes in economic conditions, legislative/regulatory changes, availability of capital, interest rates, competition, and generally accepted accounting principles. These risks and uncertainties should also be considered in evaluating forward-looking statements and undue reliance should not be placed on such statements.