It is our philosophy at ALS TDI to provide the ALS community with timely updates on, and access to, its research efforts AND findings from other ALS research labs around the world. In this vein, a number of researchers and staff members from the Institute attended the Annual Meeting of the International Alliance and the International ALS/MND Research Symposium, in Birmingham, UK, October 30th - November 5th, 2008. Below you'll find two reports, written by Directors working at ALS TDI, recounting the highlights, findings, discussion topics and controversial subjects from each aspect of the conference.
Report from the 16th Annual Meeting of the International Alliance
Robert A. Goldstein, Director of Communications
This year, ALS TDI was represented at the 16th Annual Meeting of the International Alliance of MND/ALS Organizations. The Alliance consists of several dozen member organizations which focus on furthering research, conducting clinical trials, and/or providing support to patients and their families. The meeting featured several days of presentations from all of the worldwide participants, including new participation by Slovakia and Taiwan and updates on recent success in Spain and Israel.
In accordance with my communications background, I will highlight a number of presentations and topics from the Annual Meeting that were particularly interesting, Most notably were a group of awareness videos that may not be acceptable in the United States, based on FCC guidelines. Two videos in particular were memorable and thought provoking. I've included a link to the video from a Canada-based organization (http://www.coloribus.com/paedia/reels/2008/11/10/514264/) for your viewing pleasure. The second video, from a UK-based organization, was designed for a full theatrical release. Upon completing the video, they will provide a link to it on Youtube.com for distribution. In both films, the audience is shown the progression of an ALS patient, from diagnosis to paralysis. Poignant and meaningful discussions followed the screenings, content of which were mainly devoted to 'waking people up' to the disease. We will optimistically follow the progress of these promotional videos and keep you aware of their progress.
Beyond promoting the awareness of the disease, several Alliance members made presentations on improvements to patient services. Among the various countries that spoke, some had no services at all at this time last year. One presentation in particular stood out, Spain's Adela (http://www.adelaweb.com/). In a rather short time, this group has done a tremendous job organizing its community and raising funding for a rather extensive array of support services being conducted at a clinic outside of Madrid.
Two additional items of note; Rodney Harris, long time Chairman of the Alliance, stepped down at this year's meeting and handed the gavel over to Gudjon Sigurdsson (pictured to the left) from Iceland. Gudjon, a PLS patient, led the meeting with humor and has long term goals for the Alliance: to continue growing its membership,and continuing providing support to organizations and patients in the global MND/ALS community. The most enthusiastic, spirited, and contentious conversation took place in response to Nir Tsorsan's (IsreALS) call for the Alliance to organize a $100 million fundraising mission for research. A small group of the Alliance's members, including ALS TDI, have committed to discussing this potential international fundraising collaborative.
The Annual Meeting takes place prior to the Research Symposium each year and is a place for the exchange of ideas among representatives of ALS organization all over the world. Next year's Alliance Meeting and Research Symposium takes place in Berlin, Germany. We expect that ALS TDI representatives will attend and present at both the Annual Meeting and Research Symposium. The website for the Alliance is http://www.alsmndalliance.org/.
Report from the 2008 Birmingham, UK, International ALS/MND Research Symposium
John McCarty, Ph.D., Director of Therapeutic Investigations
Each year, the ALS/MND Alliance hosts an international symposium emphasizing emerging topics from the clinical and research fields with relevance for ALS. As has been our custom, ALS TDI sent a team of researchers to Birmingham, UK, to meet with our international colleagues, participate in the discussions and presentations and report on our progress towards therapeutic development in ALS. This short report will highlight some of the noteworthy progress that has been made in the last year.
A highlight of the meeting, from a therapeutic-development perspective, was the session on the appropriate use of the animal model. This was also the only session of the meeting that included a panel discussion in which the presenters openly responded to audience questions. ALS TDI Chief Scientific Officer Steve Perrin presented an overview of the Institute's work and results with the animal model, recapping the efforts published a year ago (Scott, S., et al., 2008). Expanding on that theme, Richard Mead (Sheffield, UK) provided some new information on efforts to increase the range of 'read-outs' that measure the potential of a drug to show efficacy. In addition, Dr. Mead discussed how the use of a more genetically 'clean' version of the SOD1 mouse model minimizes noise and thus increases experimental power or, alternatively, allows a reduced number of mice necessary for conclusive efficacy evaluation experiments. Generally, the discussions on the mouse model focused on how to use the model better and with more reliably.
In much the same vein, the work presented by Dr. Perrin, on behalf of Sean Scott and other researchers at ALS TDI, was well received and formed the basis for discussions on how to incorporate the Institute's methodologies and experimental design into research facilities worldwide. While the panel discussion did address whether it might be appropriate to avoid testing in the animal model prior to human clinical trials, the prevailing conclusion was that the animal model provides the most rigorous and reliable justification for human testing. The panel concluded by recommending the development of a specialized, international conference to establish guidelines for the implementation of recommended pre-clinical animal model evaluation protocols for ALS.
The session that focused on the use of animal models was, however, not without controversy. Notably, John Crow (Arkansas, US) closed the presentation by reporting on his studies in the ALS mouse. Dr. Crow emphasizes drug initiation after disease onset (and, presumably, sets a higher hurdle for efficacy, compared to the earlier drug administration strategy used by most researchers). He also used a protocol for filling study and control groups that was not based on randomization and animal matching, also rarely used by other international researchers. Using this non-canonical experimental design, he reported large effects for a diverse collection of drugs/supplements. Furthermore, he generally saw very similar effects despite instances when drugs with independent mechanism of actions were administered together. Some of these drugs, such as minocycline, have been tested in human clinical studies with no indication of efficacy and were not reported by ALS TDI as having indicated any benefit in the mouse. The consistency of Dr. Crow's observations, across a wide variety of compounds or combinations, could suggest that there is a systematic error in experimental design that is leading to the misinterpretation of therapeutic efficacy.
The meeting's closing session, reserved for the day's featured presentations, addressed two stories directly relevant to therapeutic development. The talks referenced two of the more interesting topics from 2008. The latter of these presentations was by Jean Pierre Julien (Laval, Quebec) who spoke on the development of immunotherapy for ALS, directed at SOD1. Dr. Julien had presented a similar presentation a few weeks earlier at the ALS Therapy Development Institute's Leadership Summit & Research Symposium. Jean Pierre's project is advancing and aims to utilize various monoclonal antibodies that would specifically recognize unfolded SOD1. While the general applicability of this potential therapeutic to sporadic ALS needs to be established, there is hope that this novel approach will fill the existing void at ALS clinics in need of compelling therapeutic options.
The other presenter in the closing section was Clive Svendsen (Madison, WI). Dr. Svendsen reported on his efforts to use stem-cells as delivery platforms for therapeutically relevant neurotrophic factors in the rat version of the SOD1 animal model. While little new information was presented regarding muscle implants expressing GDNF(beyond his recently published paper), it was interesting to hear Dr. Svendsen present his work as a continuous story, including results published a year ago, in which no direct survival benefit was shown following GDNF transplants in the spine. Clive's work, while it presumably faces some significant hurdles in translating to clinical studies and eventually human use, represents one of the more substantial and encouraging advances in the field of ALS research. Without doubt, his data will be useful for understanding ALS and how various therapeutics may ultimately be shown to be beneficial. It is important to indicate that ALS TDI researchers have been similarly focused on, and committed to analyzing, the muscle as a prominent potential therapeutic target tissue.
Several relatively small reports were worthy of note and I'll mention those in the remainder of my report. The first study was an analysis of the SOD1 characterization of the commonly-observed neurological defects that mimic ALS in Welsh Corgi dogs. Such identification reinforces the importance of the SOD1 gene in ALS causation and represented the culmination of many years of patient, observant research with these afflicted animals. However, the direct implications of this model for drug development remain to be seen, given the obvious complexities of doing any substantial experimentation with such a relatively slow-developing animal model.
Another very interesting observation was reported by Lizzie Fisher (London, UK) on mice harboring both the SOD1 mutation and mutations in the gene associated with Charcot-Marie-Tooth disease. (Charcot-Marie-Tooth disease is a neurodegenerative disorder afflicting both sensory and motor neurons, the particular mutation in GARS, a glycyl-tRNA synthetase gene.) These double mutant mice showed significantly increased survival, relative to mice carrying only the mutation in SOD1. This report reflects very similar observations in other double mutants of SOD1 with genes that would alter axonal transport such as the LOA gene. While intriguing, the direct implications of these observations for deciphering ALS pathology remains elusive.
A third report of interest was the presentation on a small clinical trial in Russia, using viral gene delivery to administer neurotrophic factors to ALS patients. This ground-breaking, small-scale study was unable to find evidence of efficacy and there were substantial indications that the body's immune system would respond in a manner that would inhibit viral propagation. While the failure to establish efficacy is disappointing, I believe this report will be a harbinger of significant research that will be forthcoming in gene therapy approaches to ALS.
As scientists it is important to listen to what is said, but equally as important to consider what was not said, or was not claimed to be beneficial. In this category, I'd be remiss not to mention the silence that surrounded the very controversial use of lithium as a potential therapeutic; lithium has been a hot topic since 2007's meeting in Toronto. ALS TDI has repeatedly shown no signs of efficacy in the preclinical animal model, based on the claims of an Italian report released in February of this year. The Institute is in the process of submitting the results of these tests for publication. The results from a recently concluded, major IGF-1 study were also discussed, in which the speaker verified that no efficacy in humans was observed.
Finally, though there was an entire session devoted to TDP-43, the gene recently linked to some familial ALS, no new information was forthcoming. It is also important to note that there were no reports that any research design was validating the development of ALS symptoms, a pre-requisite for use as an animal model for the disease. We will continue to listen to the data in the hopes that TDP-43 research will demonstrate the gene as another tool for researchers to use in the development of a therapeutic for ALS.
For more information of the International Meeting, please contact marketing@als.net or by calling 617-441-7200.