Multifunctional Therapeutic Cyclodextrin-Appended Dendrimer Complex for Treatment of Systemic and Localized Amyloidosis.

Amyloidosis pathologically proceeds via production of amyloidogenic proteins by organs, formation of protein aggregates through structural changes, and their deposition on tissues. A growing body of evidence demonstrates that amyloidosis generally develops through three critical pathological steps: (1) production of amyloid precursor proteins, (2) amyloid formation, and (3) amyloid deposition. However, no clinically effective therapy that is capable of targeting each pathological step of amyloidosis independently is currently available. Here, we combined therapeutic effects and developed a short hairpin RNA expression vector (shRNA) complex with a cyclodextrin-appended cationic dendrimer (CDE) as a novel multitarget therapeutic drug that is capable of simultaneously suppressing these three steps. We evaluated its therapeutic effects on systemic transthyretin (ATTR) amyloidosis and Alzheimer's disease (AD) as localized amyloidosis, by targeting TTR and amyloid ß, respectively. CDE/shRNA exhibited RNAi effects to suppress amyloid protein production and also achieved both inhibition of amyloid formation and disruption of existing amyloid fibrils. The multitarget therapeutic effects of CDE/shRNA were confirmed by evaluating TTR deposition reduction in early- and late-onset human ATTR amyloidosis model rats and amyloid ß deposition reduction in AppNL-G-F/NL-G-F AD model mice. Thus, the CDE/shRNA complex exhibits multifunctional therapeutic efficacy and may reveal novel strategies for establishing curative treatments for both systemic and localized amyloidosis.

Therapeutic Potential of Polyamidoamine Dendrimer for Amyloidogenic Transthyretin Amyloidosis.

Amyloidogenic transthyretin (ATTR) amyloidosis is caused by a formation of ATTR amyloid fibrils. Because ATTR misfolding triggers the formation of aggregates and amyloid fibrils, which are considered to deposit on the tissues, novel clinically effective therapeutic strategies targeted to those processes are urgently needed. In this study, to discover a new drug candidate for ATTR amyloidosis therapy, we focused on polyamidoamine dendrimer (dendrimer), a 3D-structural nanomaterial, which has a branched cationic polymer repeating polyamidoamine units. Dendrimer (G2) not only inhibited ATTR V30M amyloid fibril formation, but also reduced already formed ATTR V30M amyloid fibrils by reducing ß-sheet structure of ATTR V30M protein. Moreover, intravenous administration of dendrimer (G2) reduced TTR deposition in human ATTR V30M transgenic rats. These results indicate that dendrimer (G2) may possess both inhibitory and breaking effects on ATTR V30M amyloid, suggesting that dendrimer has the potential as a dual effective agents against TTR amyloidosis.