The novel HSP90 inhibitor, PU-H71, suppresses glial cell activation but weakly affects clinical signs of EAE

Peptidyl-prolyl cis/trans isomerases (PPIases), a unique family of molecular chaperones, regulate protein folding at proline residues. These residues are abundant within intrinsically disordered proteins, like the microtubule-associated protein tau. Tau has been shown to become hyperphosphorylated and accumulate as one of the two main pathological hallmarks in Alzheimer's disease (AD), the other being amyloid beta (Aβ). PPIases, including Pin1, FK506-binding protein (FKBP) 52, FKBP51, and FKBP12, have been shown to interact with and regulate tau biology. This interaction is particularly important given the numerous proline-directed phosphorylation sites found on tau and the role phosphorylation has been found to play in pathogenesis. This regulation then affects downstream aggregation and oligomerization of tau. However, many PPIases have yet to be explored for their effects on tau biology, despite the high likelihood of interaction based on proline content. Moreover, Pin1, FKBP12, FKBP52, cyclophilin (Cyp) A, CypB, and CypD have been shown to also regulate Aβ production or the toxicity associated with Aβ pathology. Therefore, PPIases directly and indirectly regulate pathogenic protein multimerization in AD and represent a family rich in targets for modulating the accumulation and toxicity.

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“…), and multiple sclerosis (Lisi et al . ). This suggests that there is a balance of these PPIases that becomes altered in disease.…”

Section: Discussionmentioning

confidence: 97%

The emerging role of peptidyl‐prolyl isomerase chaperones in tau oligomerization, amyloid processing, and Alzheimer's disease

Blair

Baker

Sabbagh

et al. 2015

Journal of Neurochemistry

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“…HSP90 exerts broad regulatory activity over many pro-inflammatory kinase cascades and plays important functional roles in processes that bridge innate and adaptive immune responses, including antigen presentation and lymphocyte maturation/activation [ 8 , 29 ]. Accordingly, pharmacological blockade of this chaperone using small molecule inhibitors has been shown to attenuate chronic inflammation and provide varying degrees of disease control in multiple inflammatory autoimmune disease models, including experimental autoimmune encephalomyelitis, rheumatoid arthritis, and uveitis [ 11 , 12 , 30 – 32 ]. For SLE, considerable experimental and clinical evidence has implicated a pathogenic role for HSP90, although a direct causative link remains to be established.…”

Section: Discussionmentioning

confidence: 99%

The HSP90 Inhibitor Ganetespib Alleviates Disease Progression and Augments Intermittent Cyclophosphamide Therapy in the MRL/lpr Mouse Model of Systemic Lupus Erythematosus

Liu

Ogawa

et al. 2015

PLoS ONE

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Systemic lupus erythematosus (SLE) is a complex, systemic autoimmune disease with a diverse range of immunological and clinical manifestations. The introduction of broad spectrum immunosuppressive therapies and better management of acute disease exacerbations have improved outcomes for lupus patients over recent years. However, these regimens are burdened by substantial toxicities and confer significantly higher risks of infection, thus there remains a significant and unmet medical need for alternative treatment options, particularly those with improved safety profiles. Heat shock protein 90 (HSP90) is a ubiquitously expressed molecular chaperone that acts as an important modulator of multiple innate and adaptive inflammatory processes. Of note, accumulating clinical and experimental evidence has implicated a role for HSP90 in the pathogenesis of SLE. Here we evaluated the potential of HSP90 as a therapeutic target for this disease using the selective small molecule inhibitor ganetespib in the well-characterized MRL/lpr autoimmune mouse model. In both the prophylactic and therapeutic dosing settings, ganetespib treatment promoted dramatic symptomatic improvements in multiple disease parameters, including suppression of autoantibody production and the preservation of renal tissue integrity and function. In addition, ganetespib exerted profound inhibitory effects on disease-related lymphadenopathy and splenomegaly, and reduced pathogenic T and B cell lineage populations in the spleen. Ganetespib monotherapy was found to be equally efficacious and tolerable when compared to an effective weekly dosing regimen of the standard-of-care immunosuppressive agent cyclophosphamide. Importantly, co-treatment of ganetespib with a sub-optimal, intermittent dosing schedule of cyclophosphamide resulted in superior therapeutic indices and maximal disease control. These findings highlight the potential of HSP90 inhibition as an alternative, and potentially complementary, strategy for therapeutic intervention in SLE. Such approaches may have important implications for disease management, particularly for limiting or preventing treatment-related toxicities, a major confounding factor in current SLE therapy.

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“…We cultured astrocytes, microglia, and mixed retinal neurons from retinae of newborn rat pups. Primary enriched cultures of rat retinal microglia and astrocytes were prepared from mixed cultures of retinal glial cells as we described previously [ 40 ]. Briefly, aseptically collected retinal tissues were mechanically dissociated by pipetting up and down and centrifuged to collect cells, re-suspended in Dulbecco’s Modified Eagle Medium (DMEM): F12 (1:1)/20% fetal bovine serum (FBS)/1% penicillin/streptomycin, and plated.…”

Section: Methodsmentioning

confidence: 99%

Uptake and Distribution of Administered Bone Marrow Mesenchymal Stem Cell Extracellular Vesicles in Retina

Mathew

Torres

Gamboa

et al. 2021

Cells

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Cell replacement therapy using mesenchymal (MSC) and other stem cells has been evaluated for diabetic retinopathy and glaucoma. This approach has significant limitations, including few cells integrated, aberrant growth, and surgical complications. Mesenchymal Stem Cell Exosomes/Extracellular Vesicles (MSC EVs), which include exosomes and microvesicles, are an emerging alternative, promoting immunomodulation, repair, and regeneration by mediating MSC’s paracrine effects. For the clinical translation of EV therapy, it is important to determine the cellular destination and time course of EV uptake in the retina following administration. Here, we tested the cellular fate of EVs using in vivo rat retinas, ex vivo retinal explant, and primary retinal cells. Intravitreally administered fluorescent EVs were rapidly cleared from the vitreous. Retinal ganglion cells (RGCs) had maximal EV fluorescence at 14 days post administration, and microglia at 7 days. Both in vivo and in the explant model, most EVs were no deeper than the inner nuclear layer. Retinal astrocytes, microglia, and mixed neurons in vitro endocytosed EVs in a dose-dependent manner. Thus, our results indicate that intravitreal EVs are suited for the treatment of retinal diseases affecting the inner retina. Modification of the EV surface should be considered for maintaining EVs in the vitreous for prolonged delivery.

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The novel HSP90 inhibitor, PU-H71, suppresses glial cell activation but weakly affects clinical signs of EAE

Cited by 8 publications

References 35 publications

The emerging role of peptidyl‐prolyl isomerase chaperones in tau oligomerization, amyloid processing, and Alzheimer's disease

The emerging role of peptidyl‐prolyl isomerase chaperones in tau oligomerization, amyloid processing, and Alzheimer's disease

The HSP90 Inhibitor Ganetespib Alleviates Disease Progression and Augments Intermittent Cyclophosphamide Therapy in the MRL/lpr Mouse Model of Systemic Lupus Erythematosus

Uptake and Distribution of Administered Bone Marrow Mesenchymal Stem Cell Extracellular Vesicles in Retina

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