Chaperone-Based Therapies for Disease Modification in Parkinson’s Disease

Table 1

Examples of relevant therapeutics that either target endogenous molecular chaperones, exert their own chaperone function, or have promise for applying chaperone therapies in humans and their progress in preclinical research and clinical trials (CTs).

Chaperone therapies	Compounds	Current clinical trials (CTs)	Clinical utility
HSF-1 modulators
Trigger HSF-1 activation induces downstream Hsp70 expression [9]	Celastrol	Short-term CTs for rheumatoid arthritis [10]	Limited: strong human toxicity [9]
	Carbenoxolone	Phase II CTs in UK for psoriasis [10]	Potential: trials in PD patients needed
Hsp90 inhibitors
Inhibits the interaction between Hsp90 and HSF-1, leading to increased Hsp70 expression and activity [11, 12]	Geldanamycin		Limited: in vivo toxicity, poor solubility, and BBB penetration [13, 14]
	17-AAG	CTs for cancer treatment, discontinued	Limited: poor BBB penetration [13]
	17-DMAG	CTs for cancer treatment, discontinued	Limited: human toxicity [15]
	SNX-2112		Potential: trials in PD patients needed
Chemical chaperones
Nonspecific compounds that benefit protein stabilization and folding and antagonize protein aggregation [10]	Osmolytes (i.e., 2% trehalose, mannitol)	Mannitol is FDA-approved osmotic diuretic [16]	Limited: high concentration dose likely needed for use in PD patients
	Hydrophobic compounds (i.e., 4-PBA)	4-Phenylbutyrate is FDA-approved, currently used for urea cycle disorders [17]	Limited: HD mouse model indicates needing high doses near max tolerability for human benefits [18]
Pharmacological Chaperones
Specifically bind target protein for chaperone-mediated proteostasis [10]	Pharmacological chaperones (i.e., ambroxol, isofagomine)		Limited: high doses likely required for benefits in PD patients
Gene therapy
Nonpharmacological modulation of chaperones	Adeno-associated virus vector of gene delivery	Several CTs for viral-mediated gene delivery in PD patients	Potential: safety of gene therapy has been established in PD patients [19]. It will require identification of appropriate chaperone targets