Core facilities for the ALS community worldwide
Despite the recent outpouring of new data on ALS disease mechanisms and targets, many studies stop short of constituting the complete portfolio that would be necessary to justify investment in a high-level drug discovery program. There are good reasons for this: many of the missing links require resources that are rare, or are hard to set up in individual laboratories. For this reason, Target ALS has established an unprecedented series of core facilities :
- Target ALS human postmortem tissue core
- In vivo target validation core
- Target ALS viral vector core
- Target ALS stem cell core
These will allow ALS researchers worldwide to answer some simple but critical questions about candidate targets they have discovered:
1) Is my target expressed in ALS patient spinal cord or brain?
This is an essential question for any company envisaging an ALS drug development program. Access to high-quality post mortem tissue samples from defined CNS regions of ALS patients and controls has been a major limiting factor in establishing disease relevance. The Target ALS Post-mortem Tissue Core centralizes tissues from 5 leading academic centers that are well-characterized in terms of their genetic status and clinical history.
2) My target is expressed in ALS tissue but does it contribute to the disease process?
This is the central question in validating a potential therapeutic target, yet for many of the most interesting potential candidates remains unanswered. Target ALS provides investigators worldwide with the opportunity to address this question in two complementary manners:
- a) In ALS model mice. Tell us the name of your candidate target and provide the rationale for thinking it may be a target in ALS. Its functional involvement in vivo can be tested by knockdown or overexpression of the corresponding gene in ALS model mice, or by testing tool compounds known to inhibit the target. If your project is selected by the Independent Review Committee, we will do the work for you and hand you back the data to dispose of as you wish, free of any IP constraints. Nevertheless, we hope most investigators will agree to include the data in the Target ALS database to guide other researchers. The In Vivo Target Validation Core currently tests whether loss- or gain-of-function of the candidate target affects loss of muscle innervation in mutant SOD1 mice, but the range will be extended as new mouse models and endpoints become available.
- b) In human ALS patient-derived cells. We will provide you with access to patient-derived cells, tools and techniques to test the involvement of your candidate target in human iPS-derived cells of multiple origins and degrees of differentiation, including the vital isogenic controls and reporter lines. Through a unique MTA that makes these samples available to both for-profit and not-for-profit organizations, we have assured that these tools are available to all bona fide ALS researchers. See Target ALS Stem Cell Core for more details on the tools available and how to apply.
- 3) How can I modulate the levels of my target in different contexts in vitro and in vivo. The Target ALS Viral Vector Core will generate high-titer AAV particles containing the cDNA or shRNA of your choice, and proposes a range of different capsid isotypes to allow you to answer the appropriate question about target validation in the cell type of your preference.
- The overall goal of these core facilities is to:
- Facilitate access to techniques that are not feasible or cost-effective for most individual laboratories to undertake themselves
- Perform experiments in parallel on the same platform using standardized techniques to generate objective data that can be compared between/among different laboratories
- Facilitate generation and analysis of large datasets that can be mined at the network level
- Stimulate academic groups to explore the translational potential of the mechanisms they study
- Enhance early access of potential pharma/biotech partners to the data they need for internal support of a new program