Development of a ligand for in vivo imaging of mutant huntingtin in Huntington’s disease

Abstract

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin ( HTT ) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (polyQ) tract. Whereas several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, methods to visualize mHTT protein species in the living brain are lacking. Here, we demonstrate the development and characterization of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with 11 C ([ 11 C]CHDI-180R) allowed noninvasive monitoring of mHTT pathology in the brain and could track region- and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression in a rodent model. We further showed that in these animals, therapeutic agents that lowered mHTT in the striatum had a functional restorative effect that could be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.

Benefits of global mutant huntingtin lowering diminish over time in a Huntington’s disease mouse model

“…The global mHtt lowering exhibited in our novel model will be useful in the pre-clinical phase for discovering biomarkers that can be used to assess the distribution of mHtt lowering, for example, PET imaging with [ 11 C]-CHDI-180R to track mHTT aggregates (51) revealed a significant reduction in mHTT aggregates in this model, when examined at 13 months of age, after either early or late mHtt lowering (52). Since mHtt levels are titratable, our LacQ140 I (*) HD mouse model could also be useful to study the benefits of a "Huntingtin holiday", a therapeutic concept which posits that intermittent mHTT lowering for short periods of time could be beneficial.…”

Selective observation of semi-rigid non-core residues in dynamically complex mutant huntingtin protein fibrils

“…Yet, there is also a direct polyQ-core-solvent interface ( Fig. 1 B,C, “fibril-core surface”) that is of real interest, as it harbors binding sites for amyloid-specific dyes (like Congo red or thioflavin T) and PET ligands designed for in vivo imaging of mutant Htt ( Liu et al, 2020 , Bertoglio et al, 2021 , Bertoglio et al, 2022 ). Moreover, the fibril-core surface may be implicated in secondary nucleation events that play a prominent role in aggregation of HttEx1 and other amyloidogenic polypeptides ( Boatz et al, 2020 , Wagner et al, 2018 ).…”

Selective observation of semi-rigid non-core residues in dynamically complex mutant huntingtin protein fibrils

“…In HttEx1 fibrils studied by CP ssNMR, most of the polyQ ssNMR signal reflects residues internal to the rigid core (see also Boatz et al 2020). Yet, there is also a direct polyQ-core-solvent interface (Figure 1B,C, "fibrilcore surface") that is of real interest, as it harbors binding sites for amyloid-specific dyes (like congo red or thioflavin T) and PET ligands designed for in vivo imaging of mutant Htt (Liu et al, 2020;Bertoglio et al, 2021Bertoglio et al, , 2022. Moreover, the fibril-core surface may be implicated in secondary nucleation events that play a prominent role in aggregation of HttEx1 and other amyloidogenic polypeptides (Boatz et al, 2020;Wagner et al, 2018).…”