The FIND Pipeline

Fluorescent Tissue Culture Plate

Our FIND Pipeline translates gene-directed approaches into therapeutics. We Focus on INherited Disease.

 

Gene-directed therapies--gene editing, gene therapy, mRNA replacement, oligonucleotide therapy--are transforming the treatment of inherited disease. The FIND Pipeline develops and tests in vivo safety and efficacy of prospective gene-directed therapeutics.

 

The FIND Pipeline integrates the Transgenic Core, In Vivo Core, Cell Core, and Imaging Research Core

 

Supported by CFF, RICH, JobsOhio, NCI, CWRU-CTSC, and the CWRU SOM

Leadership

Mitch Drumm, PhD
  • Professor, Department of Genetics and Genome Sciences
  • Vice Chair of Translational Research
  • Director, The Research Institute for Children’s Health
  • Connie and Jim Brown Professor in Cystic Fibrosis Research

 

Ron Conlon, PhD
  • Professor of Genetics and Genome Sciences
  • Director of the Case Transgenic and Targeting Facility

 

Chris Flask, PhD
  • Professor of Radiology, Pediatrics, and Biomedical Engineering
  • Director of the Imaging Research Core

 

Craig A. Hodges, PhD
  • Associate Professor of Genetics and Genome Sciences, and Pediatrics
  • Director of the Cystic Fibrosis Mouse Models Resource Center

 

Thomas Kelley, PhD
  • Professor of Genetics and Genome Sciences and Pharmacology
  • Director of the Epithelial Cell Core

Mission

            A new generation of therapies are transforming treatment of human genetic disease. These gene-centered approaches--gene editing, gene therapy, mRNA replacement, oligonucleotide therapy and related approaches--represent a significant new and rapidly growing sector in biomedical research that will transform healthcare. Development of these therapies requires dedicated pipelines to translate basic research into treatments for patients. Our FIND Pipeline is leading the way with tools to advance gene-centered therapeutics into clinical trials. Our integrated operation bridges candidate therapeutics from the bench to the patient and back. Our tools and services are widely used by academic and commercial researchers and physicians in Northeast Ohio and around the world.

            The small number of patients for many genetic diseases poses a challenge for advancement through clinical trials. Strong preclinical data in support of in vivo safety and efficacy are needed, and

Microinjection
Fluorescent Animal Study

About

            The constituent parts of the FIND Pipeline have served local, national and international researchers for decades. The FIND Pipeline is comprised of 4 components, the transgenic, mouse models, cell and imaging cores. Through this pipeline of core facilities, we are world-leaders in: 1) the generation of gene-edited mouse models for translating gene-centered therapeutics, 2) analysis of safety and efficacy in gene-edited mouse models, 3) analysis of safety and efficacy in animal and patient tissues and cells, and 4) development and implementation of quantitative imaging technologies to provide non-invasive assessments of therapeutic delivery and efficacy in both animal models and eventually in patients.

Shared Grant Support

            Shared grant support and a common mission integrate our operations. A grant from the National Cancer Institute (NCI) supports translation of therapeutic approaches for cancer (in the transgenic and imaging cores) and shared and programmatic grants from the Cystic Fibrosis Foundation (CFF) supports the entire pipeline for effective development and translation of gene-directed therapeutics for cystic fibrosis. Support from JobsOhio with matching funds from the Research Institute for Child Health helped us expand and integrate our operations, and apply our approaches to a wide array of genetic diseases. The pilot grant programs from the Clinical and Translational Science Collaborative (CTSC) provide support for local researchers accessing our services.

Fluorescent Cells

Publications

 

Collaborative Publications
  1. Hodges CA, Conlon RA. Delivering on the promise of gene editing for cystic fibrosis. Genes & Diseases 2019  6(2) 97-108 PMID: 31193992
  2. Rosenjack J, Hodges CA, Darrah RJ, Kelley TJ. HDAC6 depletion improves cystic fibrosis mouse airway responses to bacterial challenge. Sci Rep. 2019 9(1):10282. PMID: 31311988
  3. Lu B, Li L, Schneider M, Hodges CA, Cotton CU, Burgess JD, Kelley TJ. Electrochemical measurement of membrane cholesterol correlates with CFTR function and is HDAC6-dependent. J Cyst Fibros. 2019 18(2):175-181. PMID: 29941319
  4. McHugh DR, Steele MS, Valerio DM, Miron A, Mann RJ, LePage DF, Conlon RA, Cotton CU, Drumm ML, Hodges CA. A G542X cystic fibrosis mouse model for examining nonsense mutation directed therapies. PLoS One. 2018 13(6):e0199573. PMID: 29924856
  5. McHugh DR, Cotton CU, Moss FJ, Vitko M, Valerio DM, Kelley TJ, Hao S, Jafri A, Drumm ML, Boron WF, Stern RC, McBennett K, Hodges CA. Linaclotide improves gastrointestinal transit in cystic fibrosis mice by inhibiting sodium/hydrogen exchanger 3. Am J Physiol Gastrointest Liver Physiol. 2018 315(5):G868-G878. PMID: 30118317
  6. Rymut SM, Corey DA, Valerio DM, Erokwu BO, Flask CA, Kelley TJ, Hodges CA. Improved Growth Patterns in Cystic Fibrosis Mice after Loss of Histone Deacetylase 6. Sci Rep. 2017 7(1):3676. PMID: 28623308
  7. Ross KR, Darrah RJ, Hodges CA, Lang L, Kelley TJ. Increased Expression of RhoA in Epithelium and Smooth Muscle of Obese Mouse Models: Implications for Isoprenoid Control of Airway Smooth Muscle and Fibroblasts. J Allergy. 2013 2013:740973. PMID: 23840226
Biomedical Research Building
Publications of Translation of Gene-directed Therapies
  1. Elitt MS, Barbar L, Shick HE, Powers BE, Maeno-Hikichi Y, Madhavan M, Allan KC, Nawash BS, Gevorgyan AS, Hung S, Nevin ZS, Olsen HE, Hitomi M, Schlatzer DM, Zhao HT, Swayze A, LePage DF, Jiang W, Conlon RA, Rigo F, Tesar PJ. Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease. Nature. 2020 585(7825):397-403 PMID: 32610343
  2. Khalifa AO, Kavran M, Mahran A, Isali I, Woda J, Flask CA, Penn MS, Hijaz AK. Stromal derived factor-1 plasmid as a novel injection for treatment of stress urinary incontinence in a rat model. Int Urogynecol J. 2020 31(1):107-115. PMID: 30666428
Organoids
Publication of Therapeutic Translation
  1. Viotti Perisse I, Fan Z, Van Wettere A, Liu Y, Leir SH, Keim J, Regouski M, Wilson MD, Cholewa KM, Mansbach SN, Kelley TJ, Wang Z, Harris A, White KL, Polejaeva IA. Sheep models of F508del and G542X cystic fibrosis mutations show cellular responses to human therapeutics. FASEB Bioadv. 2021 3(10):841-854. PMID: 34632318
  2. MacAskill CJ, Erokwu BO, Markley M, Parsons A, Farr S, Zhang Y, Tran U, Chen Y, Anderson CE, Serai S, Hartung EA, Wessely O, Ma D, Dell KM, Flask CA. Multi-parametric MRI of kidney disease progression for autosomal recessive polycystic kidney disease: mouse model and initial patient results. Pediatr Res. 2021 89(1):157-162. PMID: 32283547
  3. Zhao Y, Feng X, Chen Y, Selfridge JE, Gorityala S, Du Z, Wang JM, Hao Y, Cioffi G, Conlon RA, Barnholtz-Sloan JS, Saltzman J, Krishnamurthi SS, Vinayak S, Veigl M, Xu Y, Bajor DL, Markowitz SD, Meropol NJ, Eads JR, Wang Z. 5-fluorouracil enhances the anti-tumor activity of the glutaminase inhibitor CB-839 against PIK3CA-mutant colorectal cancers. Cancer Res. 2020 PMID: 32907836
  4. Covarrubias G, Johansen ML, Vincent J, Erokwu BO, Craig SEL, Rahmy A, Cha A, Lorkowski M, MacAskill C, Scott B, Gargesha M, Roy D, Flask CA, Karathanasis E, Brady-Kalnay SM. PTPmu-targeted nanoparticles label invasive pediatric and adult glioblastoma. Nanomedicine. 2020 28:102216. PMID: 32413511
  5. McHugh DR, Cotton CU, Hodges CA. Synergy between Readthrough and Nonsense Mediated Decay Inhibition in a Murine Model of Cystic Fibrosis Nonsense Mutations. Int J Mol Sci. 2020 22(1):344. PMID: 33396210
  6. Lu B, Corey DA, Kelley TJ. Resveratrol restores intracellular transport in cystic fibrosis epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2020 318(6):L1145-L1157. PMID: 32267731
  7. Kutney K, Donnola SB, Flask CA, Gubitosi-Klug R, O'Riordan M, McBennett K, Sferra TJ, Kaminski B. Lumacaftor/ivacaftor therapy is associated with reduced hepatic steatosis in cystic fibrosis patients. World J Hepatol. 2019 11(12):761-772. PMID: 31966908
  8. Farr GW, Hall CH, Farr SM, Wade R, Detzel JM, Adams AG, Buch JM, Beahm DL, Flask CA, Xu K, LaManna JC, McGuirk PR, Boron WF, Pelletier MF. Functionalized Phenylbenzamides Inhibit Aquaporin-4 Reducing Cerebral Edema and Improving Outcome in Two Models of CNS Injury. Neuroscience. 2019 404:484-498. PMID: 30738082
  9. Rosenjack J, Hodges CA, Darrah RJ, Kelley TJ. HDAC6 depletion improves cystic fibrosis mouse airway responses to bacterial challenge. Sci Rep. 2019 9(1):10282. PMID: 31311988
  10. Darrah RJ, Jacono FJ, Joshi N, Mitchell AL, Sattar A, Campanaro CK, Litman P, Frey J, Nethery DE, Barbato ES, Hodges CA, Corvol H, Cutting GR, Knowles MR, Strug LJ, Drumm ML. AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations. J Cyst Fibros. 2019 18(1):127-134. PMID: 29937318
  11. Lord R, Fairbourn N, Mylavarapu C, Dbeis A, Bowman T, Chandrashekar A, Banayat T, Hodges CA, Al-Nakkash L. Consuming Genistein Improves Survival Rates in the Absence of Laxative in ΔF508-CF Female Mice. Nutrients. 2018 10(10):1418. PMID: 30282922
  12. McHugh DR, Cotton CU, Moss FJ, Vitko M, Valerio DM, Kelley TJ, Hao S, Jafri A, Drumm ML, Boron WF, Stern RC, McBennett K, Hodges CA. Linaclotide improves gastrointestinal transit in cystic fibrosis mice by inhibiting sodium/hydrogen exchanger 3. Am J Physiol Gastrointest Liver Physiol. 2018 315(5):G868-G878. PMID: 30118317
  13. Rymut SM, Kampman CM, Corey DA, Endres T, Cotton CU, Kelley TJ. Ibuprofen regulation of microtubule dynamics in cystic fibrosis epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2016 311(2):L317-27. PMID: 27317686
  14.  Zaman K, Sawczak V, Zaidi A, Butler M, Bennett D, Getsy P, Zeinomar M, Greenberg Z, Forbes M, Rehman S, Jyothikumar V, DeRonde K, Sattar A, Smith L, Corey D, Straub A, Sun F, Palmer L, Periasamy A, Randell S, Kelley TJ, Lewis SJ, Gaston B. Augmentation of CFTR maturation by S-nitrosoglutathione reductase. Am J Physiol Lung Cell Mol Physiol. 2016 310(3):L263-70. PMID: 26637637
Wolstein Research Building