Challenge 12: UnTangle

Objective

To develop a physiologically relevant human stem cell-derived neuronal assay to predict the efficacy and unexpected pharmacological effects of new chemical entities and biologics targeting tau in Alzheimer’s disease.

Background

One of the most active areas of research into Alzheimer’s disease centres on the tau protein that forms the classic neurofibrillary tangles. Aberrant intracellular inclusions composed of hyperphosphorylated filamentous tau are not only a neuropathological hallmark of Alzheimer’s disease, but are also the key pathological species in progressive supranuclear palsy and other sporadic neurodegenerative disorders, which have been collectively termed tauopathies.

The discovery that pathogenic mutations in the tau gene microtubule associated protein tau (MAPT) can cause a familial neurodegenerative tauopathy has provided compelling evidence that tau dysfunction is sufficient to cause neurodegeneration. Many recent in vivo studies have shown that tau aggregates have ‘prion-like’ properties which not only allow them to transmit or seed further tau aggregation, but also spread to neighbouring cells or functionally connected brain regions. This process is referred to as ‘tau propagation’ and might explain the stereotypic progression of tau pathology in the brains of Alzheimer’s disease patients.

Study of the development and spread of tau pathology in animal models requires large numbers, is time consuming and expensive. Often, the mechanisms and/or potential drug targets that are identified do not translate into humans.

3Rs benefits

Thousands of transgenic mice are used per year in large pharmaceutical companies with additional breeding animals to obtain the required genotype. There are specific challenges associated with tau transgenics:

  1. Phenotypic variability. Mice often undergo chronic treatment with a candidate drug to test for disease modifying actions. Large numbers of animals are required per treatment arm to ensure clear results. For example, Lilly have noted wide phenotypic variability in mice expressing mutant human tau (JNPL3) leading to n=25 animals per treatment arm being required for drug studies.
  2. Variability in levels of tau expression. Some transgenic lines express varying levels of tau and/or only a certain portion of mice are suitable for drug testing (e.g. only 25% of tg4510 mice are bigenic).

Therefore, large breeding programmes are needed to generate sufficient numbers of mice for each study. A human cell-based assay would reduce the number of transgenic animals used to investigate tau pathology and also improve the research and development of new treatments in this area.

Phase 1 winners

Project teams led by:

  • Dr Eric Hill, University of Aston, £95,453.
  • Professor Maria Grazia Spillantini, University of Cambridge, £66,898. 
  • Dr Selina Wray, University College London, £99,956.
  • Dr Christopher Ward, University of Manchester, £81,956.

Phase 2 winner

Project team led by:

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Assessment information

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Budget information

Phase 1: up to £100K
Phase 2: up to £1 million

Sponsor(s)

Alzheimer's Research UK
Lilly
Janssen

Duration

Phase 1: six months. Phase 2: up to three years