1. The authors developed a triple combination formula (TCF) with three components: the histone deacetylase inhibitor vorinostat (Vo), 2-Hydroxypropyl-β-cyclodextrin (HPBCD), and polyethylene glycol (PEG).
2. In a mouse model of Niemann-Pick type C (NPC) disease, TCF improved survival and delayed the onset of behavioral changes associated with neurodegeneration, while minimizing organ toxicity and inflammation.
Evidence Rating Level: 1 (Excellent)
Study Rundown: NPC disease is a genetic, neurodegenerative disorder usually caused by defects in the Npc1 gene. This disease is marked by the inability for cells to properly metabolize lipids and, as a result, damages vital organs such as the liver, spleen, and brain. In this study, the authors utilized a new formulation of Vo to increase expression levels of Npc1 in order to improve disease pathology and symptoms in a mouse model of NPC.
Because Vo is highly water-insoluble, the authors reformulated the drug through combination with PEG and HPBCD, a compound that is used to improve drug solubility and known to chelate cholesterol. This TCF, as compared to treatment with its individual components alone, significantly increased the survival time of NPC mice. Examination of neurobehavioral changes such as grooming, limb tone, and body weight demonstrated that TCF treatment significantly delayed the onset of NPC-associated neurodegenerative decline. Additionally, TCF treatment improved delivery of Vo to the brain and sustained Vo plasma levels. Because histone deacetylase inhibitors can affect a broad range of genes, toxicity of TCF treatment was assessed. Evaluation of the liver and kidney demonstrated minimal changes in plasma markers of toxicity. TCF administration also reduced expression of inflammatory markers in the liver and spleen.
Since treatments for NPC in the United States currently do not exist, this work provides powerful evidence in support of a new treatment paradigm for NPC. Because the components of the presented TCF are either regarded as safe by the FDA or already in use for treatment of other diseases, future expansion of TCF testing to clinical trials is promising.
In-Depth [animal study]: Male and female BALB/c mice carrying a D1005G mutation in the Npc1 gene were treated with the TCF consisting of Vo (50mg/kg), HPBCD (2000mg/kg), PEG 400 (45%), and DMSO (5%) via intraperitoneal injection once a week. Overall, TCF treatment significantly increased median survival compared to control treatments (p<0.001). Using a neurobehavioral symptomatic score system, the authors assessed the onset of degenerative changes in tremor, body position, gait, grooming, limb tone, and weight. The untreated cohort displayed symptom onset between day 77 and 84, whereas TCF-treated mice became affected between day 104 and 112 (equivalent to late adulthood).
To demonstrate the ability for Vo cross the blood-brain barrier with TCF therapy, the brains of Vo and TCF-treated mice were collected and evaluated for drug load. Mice with TCF treatment retained more Vo in the brain for up to 2 hours after treatment (p<0.05), though levels ultimately decreased to zero by 4 hours in both groups. Plasma levels of Vo were also evaluated 1 hour after Vo or TCF administration and demonstrated that TCF-treated mice had almost 3 times higher levels of Vo (p<0.05).
To test for systemic toxicity effects from non-specific histone deacetylase inhibition, the liver and spleens of TCF and control treatment cohorts were harvested and evaluated. Quantitative gene expression measurements determined that TCF treatment was effective in decreasing level of inflammatory markers to levels comparable to healthy, untreated mice. Finally, blood samples from TCF-treated, healthy mice demonstrated that long-term treatment (between 200 and 300 days) did not lead to drastic changes in levels of liver and kidney functional markers like alanine aminotransferase, albumin, and blood urea nitrogen.
©2016 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.