The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease
• Striatal S1R is upregulated in both mice and patients with advanced but not early HD.
• Pridopidine stabilizes MSN spines in aging YAC128 corticostriatal co-cultures via S1R.
• Pridopidine normalizes synaptic and ER Ca2 + homeostasis in YAC128 MSNs.
• Pridopidine upregulates calbindin and homer1a, which are downregulated in HD models.
• The therapeutic effects of pridopidine in HD treatment are likely mediated by the S1R.
Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors
DOI: 10.1016/j.ccell.2016.11.006 PMID: 27960087
Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.
Pridopidine activates neuroprotective pathways impaired in Huntington Disease
HUM MOL GENET. 2016 JUL 27. PII: DDW238. PMID: 27466197 DOI: 10.1093/HMG/DDW238
Pridopidine has demonstrated improvement in Huntington Disease (HD) motor symptoms as measured by secondary endpoints in clinical trials. Originally described as a dopamine stabilizer, this mechanism is insufficient to explain the clinical and preclinical effects of pridopidine. This study therefore explored pridopidine’s potential mechanisms of action. The effect of pridopidine versus sham treatment on genome-wide expression profiling in the rat striatum was analysed and compared to the pathological expression profile in Q175 knock-in (Q175 KI) vs Q25 WT mouse models. A broad, unbiased pathway analysis was conducted, followed by testing the enrichment of relevant pathways. Pridopidine upregulated the BDNF pathway (P = 1.73E-10), and its effect on BDNF secretion was sigma 1 receptor (S1R) dependent. Many of the same genes were independently found to be downregulated in Q175 KI mice compared to WT (5.2e-7 < P < 0.04). In addition, pridopidine treatment upregulated the glucocorticoid receptor (GR) response, D1R-associated genes and the AKT/PI3K pathway (P = 1E-10, P = 0.001, P = 0.004, respectively). Pridopidine upregulates expression of BDNF, D1R, GR and AKT/PI3K pathways, known to promote neuronal plasticity and survival, as well as reported to demonstrate therapeutic benefit in HD animal models. Activation of S1R, necessary for its effect on the BDNF pathway, represents a core component of the mode of action of pridopidine. Since the newly identified pathways are downregulated in neurodegenerative diseases, including HD, these findings suggest that pridopidine may exert neuroprotective effects beyond its role in alleviating some symptoms of HD.
© The Author 2016. Published by Oxford University Press.
Functional effects of the antigen glatiramer acetate are complex and tightly associated with its composition
Glatiramer acetate (Copaxone®; GA) is a non-biological complex drug for multiple sclerosis. GA modulated thousands of genes in genome-wide expression studies conducted in THP-1 cells and mouse splenocytes. Comparing GA with differently-manufactured glatiramoid Polimunol (Synthon) in mice yielded hundreds of differentially expressed probesets, including biologically-relevant genes (e.g. Il18, adj p < 9e−6) and pathways. In human monocytes, 700+ probesets differed between Polimunol and GA, enriching for 130+ pathways including response to lipopolysaccharide (adj. p < 0.006). Key differences were confirmed by qRT-PCR (splenocytes) or proteomics (THP-1). These studies demonstrate the complexity of GA’s mechanisms of action, and may help inform therapeutic equivalence assessment.
Leveraging existing data sets to generate new insights into Alzheimer’s disease biology in specific patient subsets
Sci Rep. 2015; 5: 14324. PMCID: PMC4585817 Published online 2015 Sep 23. doi: 10.1038/srep14324
In recent years, many investigators have thoughtfully applied genetics and genomics approaches to investigate the biology of Alzheimer’s Disease (AD)1,2,3. These efforts have yielded a rich collection of gene expression and single-nucleotide polymorphism (SNP) data sets, along with extensive analyses of particular data sets. The availability of such studies provides the opportunity to generate fresh insights into the biology of AD, independently of prevailing hypotheses, by integrating existing data sets in novel and innovative ways.
Gene expression studies of a human monocyte cell line identify dissimilarities between differently manufactured glatiramoids
Sci Rep. 2015 May 22;5:10191. doi: 10.1038/srep10191. PMID: 25998228 Free PMC Article
Glatiramer Acetate (GA) has provided safe and effective treatment for multiple sclerosis (MS) patients for two decades. It acts as an antigen, yet the precise mechanism of action remains to be fully elucidated, and no validated pharmacokinetic or pharmacodynamic biomarkers exist. In order to better characterize GA’s biological impact, genome-wide expression studies were conducted with a human monocyte (THP-1) cell line.
Use of genetic technologies to compare medicines
Clin Genet. 2014 Nov;86(5):441-6. doi: 10.1111/cge.12462. Epub 2014 Sep 8. Review. PMID: 25046029
In order to ensure that patients receive the safest and most effective medicines possible, it is often necessary to compare medicines and assess the extent to which they are similar in their clinical impact. Full clinical trials with appropriate endpoints remain the only method to compare the clinical impact of two medicines with absolute certainty.
Comparing the biological impact of glatiramer acetate with the biological impact of a generic
PLoS One. 2014 Jan 8;9(1):e83757. doi: 10.1371/journal.pone.0083757. eCollection 2014. PMID: 24421904 Free PMC Article
For decades, policies regarding generic medicines have sought to provide patients with economical access to safe and effective drugs, while encouraging the development of new therapies. This balance is becoming more challenging for physicians and regulators as biologics and non-biological complex drugs (NBCDs) such as glatiramer acetate demonstrate remarkable efficacy, because generics for these medicines are more difficult to assess. We sought to develop computational methods that use transcriptional profiles to compare branded medicines to generics, robustly characterizing differences in biological impact. We combined multiple computational methods to determine whether differentially expressed genes result from random variation, or point to consistent differences in biological impact of the generic compared to the branded medicine.
Defining the Transcriptional and Cellular Landscape of Type 1 Diabetes in the NOD Mouse
PLoS One. 2013; 8(3): e59701. Published online 2013 Mar 26. doi: 10.1371/journal.pone.0059701 PMCID: PMC3608568
Our ability to successfully intervene in disease processes is dependent on definitive diagnosis. In the case of autoimmune disease, this is particularly challenging because progression of disease is lengthy and multifactorial. Here we show the first chronological compendium of transcriptional and cellular signatures of diabetes in the non-obese diabetic mouse. Our data relates the immunological environment of the islets of Langerhans with the transcriptional profile at discrete times. Based on these data, we have parsed diabetes into several discrete phases. First, there is a type I interferon signature that precedes T cell activation. Second, there is synchronous infiltration of all immunological cellular subsets and a period of control. Finally, there is the killing phase of the diabetogenic process that is correlated with an NF-kB signature. Our data provides a framework for future examination of autoimmune diabetes and its disease progression markers.
Maximizing the efficacy of angiogenesis inhibitors
J Clin Oncol. 2012 Jan 20;30(3):337-8; author reply 338-9. doi: 10.1200/JCO.2011.38.5435. Epub 2011 Dec 5. No abstract available. PMID: 22147743 Free Article
The article “Phase II Study of Aflibercept in Recurrent Malignant Glioma: A North American Brain Tumor Consortium Study” by de Groot et al1 was published in Journal of Clinical Oncology. We commend the authors for investigating correlations between gene expression and clinical outcome and believe that their findings may provide important clues for maximizing the efficacy of antiangiogenic therapies.