Browsing by Subject "small molecule"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Mucosal Inflammatory and Wound Healing Gene Programmes Reveal Targets for Stricturing Behaviour in Paediatric Crohn’s Disease
    (Oxford University Press, 2020-08-08) Haberman, Yael; Minar, Phillip; Karns, Rebekah; Dexheimer, Phillip J.; Ghandikota, Sudhir; Tegge, Samuel; Shapiro, Daniel; Shuler, Brianne; Venkateswaran, Suresh; Braun, Tzipi; Ta, Allison; Walters, Thomas D.; Baldassano, Robert N.; Noe, Joshua D.; Rosh, Joel; Markowitz, James; Dotson, Jennifer L.; Mack, David R.; Kellermayer, Richard; Griffiths, Anne M.; Heyman, Melvin B.; Baker, Susan S.; Moulton, Dedrick; Patel, Ashish S.; Gulati, Ajay S.; Steiner, Steven J.; LeLeiko, Neal; Otley, Anthony; Oliva-Hemker, Maria; Ziring, David; Gokhale, Ranjana; Kim, Sandra; Guthery, Stephen L.; Cohen, Stanley A.; Snapper, Scott; Aronow, Bruce J.; Stephens, Michael; Gibson, Greg; Dillman, Jonathan R.; Dubinsky, Marla; Hyams, Jeffrey S.; Kugathasan, Subra; Jegga, Anil G.; Denson, Lee A.; Pediatrics, School of Medicine
    Background and aims: Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures. Methods: Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. Results: 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)). Conclusion: An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.
  • Thumbnail Image
    Item
    Small Molecules in Development for the Treatment of Spinal Muscular Atrophy
    (ACS, 2016-08) Calder, Alyssa N.; Androphy, Elliot J.; Hodgetts, Kevin J.; Department of Dermatology, School of Medicine
    Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease resulting from pathologically low levels of survival motor neuron (SMN) protein. The majority of mRNA from the SMN2 allele undergoes alternative splicing and excludes critical codons, causing an SMN protein deficiency. While there is currently no FDA-approved treatment for SMA, early therapeutic efforts have focused on testing repurposed drugs such as phenylbutyrate (2), valproic acid (3), riluzole (6), hydroxyurea (7), and albuterol (9), none of which has demonstrated clinical effectiveness. More recently, clinical trials have focused on novel small-molecule compounds identified from high-throughput screening and medicinal chemistry optimization such as olesoxime (11), CK-2127107, RG7800, LMI070, and RG3039 (17). In this paper, we review both repurposed drugs and small-molecule compounds discovered following medicinal chemistry optimization for the potential treatment of SMA.