TY - JOUR AB - While the extensive hunt for therapeutics combating Alzheimer's disease (AD) has fallen short of delivering effective treatments, breakthroughs towards understanding the disease mechanisms and identifying areas for future research have nevertheless been enabled. The majority of clinical trials with beta- and gamma-secretase modulators have been suspended from additional studies or terminated due to toxicity issues and health concerns. The lack of progress in developing innovative AD therapies has also prompted a resurgence of interest in more traditional symptomatic treatments with cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, as well as in the research of immune response modulators. Recently, evidence has emerged showing that inhibitors of arginine metabolism and in particular blockers of arginase, an enzyme that catalyzes the breakdown of L-arginine, could present an effective therapeutic candidate for halting the progression of AD and boosting cognition and memory. In this commentary, we present a brief overview of reports on arginase inhibitors in AD mouse models and discuss emerging advantages and areas for careful consideration on the road to clinical translation. AU - Ovsepian, S.V. AU - O’Leary, V.B.* C1 - 54511 C2 - 45646 CY - 233 Spring St, New York, Ny 10013 Usa SP - 1032-1035 TI - Can arginase inhibitors be the answer to therapeutic challenges in Alzheimer's disease? JO - Neurotherapeutics VL - 15 IS - 4 PB - Springer PY - 2018 SN - 1933-7213 ER - TY - JOUR AB - Flatworms of the species Schmidtea mediterranea are immortal-adult animals contain a large pool of pluripotent stem cells that continuously differentiate into all adult cell types. Therefore, single-cell transcriptome profiling of adult animals should reveal mature and progenitor cells. By combining perturbation experiments, gene expression analysis, a computational method that predicts future cell states from transcriptional changes, and a lineage reconstruction method, we placed all major cell types onto a single lineage tree that connects all cells to a single stem cell compartment. We characterized gene expression changes during differentiation and discovered cell types important for regeneration. Our results demonstrate the importance of single-cell transcriptome analysis for mapping and reconstructing fundamental processes of developmental and regenerative biology at high resolution. AU - O’Leary, V.B.* AU - O’Connell, M.* AU - Antyborzec, I.* AU - Ntziachristos, V. AU - Oliver Dolly, J.* AU - Ovsepian, S.V. C1 - 52993 C2 - 44335 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 489-499 TI - Alleviation of trigeminal nociception using p75 neurotrophin receptor targeted lentiviral interference therapy. JO - Neurotherapeutics VL - 15 IS - 2 PB - Amer Assoc Advancement Science PY - 2018 SN - 1933-7213 ER - TY - JOUR AB - Basal forebrain cholinergic neurons (BFCNs) are one of the most affected neuronal types in Alzheimer's disease (AD), with their extensive loss documented at late stages of the pathology. While discriminatory provision of neuroprotective agents and trophic factors to these cells is thought to be of substantial therapeutic potential, the intricate topography and structure of the forebrain cholinergic system imposes a major challenge. To overcome this, we took advantage of the physiological enrichment of BFCNs with a low-affinity p75 neurotrophin receptor (p75(NTR)) for their targeting by lentiviral vectors within the intact brain of adult rat. Herein, a method is described that affords selective and effective transduction of BFCNs with a green fluorescence protein (GFP) reporter, which combines streptavidin-biotin technology with anti-p75(NTR) antibody-coated lentiviral vectors. Specific GFP expression in cholinergic neurons was attained in the medial septum and nuclei of the diagonal band Broca after a single intraventricular administration of such targeted vectors. Bioelectrical activity of GFP-labeled neurons was proven to be unchanged. Thus, proof of principle is obtained for the utility of the low-affinity p75(NTR) for targeted transduction of vectors to BFCNs in vivo. AU - Antyborzec, I.* AU - O'Leary, V.B. AU - Dolly, J.O.* AU - Ovsepian, S.V. C1 - 48706 C2 - 41274 CY - New York SP - 859-870 TI - Low-affinity neurotrophin receptor p75 promotes the transduction of targeted lentiviral vectors to cholinergic neurons of rat basal forebrain. JO - Neurotherapeutics VL - 13 IS - 4 PB - Springer PY - 2016 SN - 1933-7213 ER - TY - JOUR AB - Advancing research and clinical care, and conducting successful and cost-effective clinical trials requires characterizing a given patient population. To gather a sufficiently large cohort of patients in rare diseases such as amyotrophic lateral sclerosis (ALS), we developed the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) platform. The PRO-ACT database currently consists of >8600 ALS patient records from 17 completed clinical trials, and more trials are being incorporated. The database was launched in an open-access mode in December 2012; since then, >400 researchers from >40 countries have requested the data. This review gives an overview on the research enabled by this resource, through several examples of research already carried out with the goal of improving patient care and understanding the disease. These examples include predicting ALS progression, the simulation of future ALS clinical trials, the verification of previously proposed predictive features, the discovery of novel predictors of ALS progression and survival, the newly identified stratification of patients based on their disease progression profiles, and the development of tools for better clinical trial recruitment and monitoring. Results from these approaches clearly demonstrate the value of large datasets for developing a better understanding of ALS natural history, prognostic factors, patient stratification, and more. The increasing use by the community suggests that further analyses of the PRO-ACT database will continue to reveal more information about this disease that has for so long defied our understanding. AU - Zach, N.* AU - Ennist, D.L.* AU - Taylor, A.A.* AU - Alon, H.* AU - Sherman, A.V.* AU - Küffner, R. AU - Walker, J.* AU - Sinani, E.* AU - Katsovskiy, I.* AU - Cudkowicz, M.E.* AU - Leitner, M.L.* C1 - 43224 C2 - 36328 CY - New York SP - 417-423 TI - Being PRO-ACTive: What can a clinical trial database reveal about ALS? JO - Neurotherapeutics VL - 12 IS - 2 PB - Springer PY - 2015 SN - 1933-7213 ER -