The ALS Association

association-alsfindingacure

Grand Challenge: Generation of a PET Tracer for TDP43 Aggregates

Deadline for submission of Letter of Intent: March 22, 2016

A partnership between The ALS Association and ALS Finding a Cure

Release Date: February 8, 2016

Transactive response DNA-binding protein 43 (TDP43) is the primary protein aggregate in frontotemporal lobar degeneration and amyotrophic lateral sclerosis, but TDP43 also forms pathologic aggregates in other proteinopathies such as Alzheimer’s disease (AD), suggesting that it may contribute to cognitive dysfunction in these disorders as well. TDP43 is normally a nuclear protein, but in these disorders, aggregates of TDP43 form in the cytoplasm and abnormalities in the nuclear import mechanisms have been implicated in the disease process. How TDP43 is linked to the clinical disease and whether these cytoplasmic aggregates are toxic remains unclear. Hypotheses have been published arguing for a gain of toxic function or a loss of function. Whether both or any of these mechanisms are indeed involved, a PET tracer specific for TDP43 aggregates could be extremely informative and could enable more widespread use of this biomarker for drug development programs. Furthermore, a tracer for TDP43 aggregates could enhance programs to develop small molecules that can repair the abnormal trafficking of TDP43 from the nucleus to the cytoplasm.

The Grand Challenge, a two phase program, is soliciting teams that will bring together the most appropriate reagents, as well as industry and academic expertise to develop a PET tracer specific to TDP43 aggregates. Recognizing that TDP-43 may share common features with other protein aggregates such as tau or amyloid, teams that have already identified PET ligands to similar proteins would be viewed more favorably presuming that modifications can be made to enhance the ligand specificity for TDP43. Teams with expertise in TDP43 biochemistry are also encouraged to apply. The successful team(s) with the most developed plan and the appropriate reagents will receive up to $1 million in milestone payments for phase I of the challenge.

Phase II of the program will ensure that if phase I is successful, funds will be provided to further the development of the PET tracer towards the clinic. Should submitting teams provide significant expertise in any of the areas below and are interested to collaborate in areas they are deficient The ALS Association and ALS Finding a Cure will facilitate the necessary partnerships. Industry-academic partnerships are encouraged, however not required.

Such resources include but are not limited to:

  • Access to compound libraries
  • Capability to develop high throughput screening assays
  • Access to TDP-43 from cell culture, preclinical or human tissue
  • Radiochemistry and PET tracer optimization expertise
  • Experience with tracer validation and E-IND submission

Research groups to apply (but not limited to):

  • TDP43 & preclinical biology groups
  • Radiochemistry and PET groups
  • Discovery and medicinal chemistry groups

Some of the tasks may include (but not limited to):

  • Determination of the most authentic and feasible source of aggregated TDP-43 for screening
  • Acquisition of TDP43 enriched homogenates from human post-mortem material
  • Isolation of purified aggregates from tissue
  • Generation of recombinant TDP43
  • Purified aggregates from tissue
  • Recombinant TDP43
  • Identification of a ligand that can act as an initial screening control
  • Development of an in-vitro binding assay suitable for screening of a reasonable number of compounds
  • Development of an assay to assess ligand cross-reactivity toward other protein aggregates (tau, amyloid, etc.)
  • Plan to access libraries of compounds from historical amyloid and tau tracer screening efforts
  • Plan to mature initial compound hits to optimize affinity and selectivity toward TDP43 aggregates Development of radiotracer binding assay to verify binding in brain tissue

Deadline for submission of Letter of Intent: March 22, 2016
Download the Letter of Intent here

PROGRAM RECEIPT DATES:

Letter of Intent March 22, 2016
Request to submit full application April 11, 2016
Submission of full application May 20, 2016
Notification of award July 2016
Funding commences on receipt of all relevant signatures.


E-mail lucie@alsa-national.org for queries. Please include TDP43 PET TRACER CHALLENGE in the subject line.

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