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The Difference Between "A" and "U" Makes All the Difference...

Different splicing patterns in tau pre-mRNA lead to variants of the tau protein, and these can influence cellular health and function.

Precisely Modulating Gene Splicing opens new Therapeutic Avenues

The lack of current treatment options for tauopathies lends urgency to our drug discovery mission to positively impact the lives of patients.

Tauopathies in Dementia and Movement Disorders 

Tau (AD) pre-mRNA splicing

Program

From Care

- to Cure

?

Tauopathies in Dementia and Movement Disorders

The Expansion Therapeutics Difference

Expansion’s approach is directed at the source of 4R tau, rather than at its downstream oligomerizing properties. We have developed small molecules that can bind specifically to a structure in the intron10-exon10 junction of tau’s pre-mRNA and can modulate tau splicing such that the balance is pushed in the direction of exon 10 exclusion, in turn modifying the 3R/4R tau ratio in both the mRNA and the resulting protein. In animal studies using a mouse model expressing human tau, our tool compound was orally administered and crossed the blood brain barrier. The result was reduced tau brain pathology and improved behavior in a cognitive task. 

 
We plan to develop an innovative, small molecule tau splice modulator into a novel medicine to improve the cognitive function of dementia patients.

 

Disease Summary

Tauopathies are a group of brain disorders where the over-abundance of certain forms of the protein tau drives disease onset and/or progression. These mis-regulated forms of tau can include those that are highly phosphorylated and mis-folded. The most common disease with a tauopathy component is Alzheimer’s Disease. Other examples include progressive supranuclear palsy (PSP) and some forms of fronto-temporal dementia (FTD). Tau pathology can also be a feature of Parkinson’s Disease, cortico-basal degeneration, and traumatic brain injury.  Common disease symptoms include executive dysfunction, memory loss, and sometimes psychiatric or personality disturbances.

Tau is a complex protein that is made in 6 varieties, or splice variants, broadly grouped into the 3R and 4R categories. In 3R tau, exon 10 of the tau gene is excluded from the pre-mRNA during the splicing process, and this in turn excludes one of the microtubule binding regions (MBTRs) such that the resulting tau protein has 3 of these regions (i.e. the 3R form). If exon 10 is included during splicing, an additional MBTR is translated, leading to 4 such regions instead of 3 (i.e. 4R tau). The region encoded by exon 10 is a hotspot for tau phosphorylation, and this increases its propensity to misfold and form oligomers and aggregates. Tau oligomerization is a disease driver and the importance of tau splicing is demonstrated by the fact that a mutation in the splice junction between intron 10 and exon 10 of tau (leading to more 4R than 3R tau) causes the rare, genetically-defined disease FTDP-17. Thus, by changing the balance of 3R/4R tau, favoring the 3R direction, it will be possible to exert a therapeutic effect in various diseases. 

 

Currently approved treatments for tauopathies are symptomatic, rather than disease-modifying and none directly target tau. Controversary remains about whether it could be therapeutically beneficial to remove tau oligomers and aggregates after they have already formed. We believe that a better approach is to prevent their formation in the first place.

What to know about TAU

Tauopathies are a group of brain disorders where the protein tau is out of equilibrium. Tau is a complex protein that is made in 6 varieties broadly grouped into the 3R and 4R categories. In disease, there is an imbalance of the 3R and 4R forms.

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Jupiter, FL