Crohn’s Disease (Colitis) Archives - Sanford Burnham Prebys

Robert Oshima graduated from the University of California Santa Barbara in Cellular Biology. He earned his PhD from the University of California at San Diego in 1973 with Paul Price. He joined Dr. Jerry Schneider’s laboratory in the UCSD Medical School to work on the biochemistry of cystinosis, a genetic lysosomal storage disease. During that time, he contributed to the development of a treatment that extends the life of patients greatly. He acquired expertise in developmental biology and stem cells in the laboratories of Drs. Boris Ephrussi and Mary Weiss at the Centre National Recherche Scientifique, Gif-sur-Yvette, France in 1975. He continued those studies upon returning to UCSD and then moved to MIT in 1979 where he purified two markers of mouse stem cell differentiation that are widely used in the cancer pathology and developmental studies. He joined the Sanford Burnham Prebys (formerly known as the La Jolla Cancer Research Foundation) in 1982 where he acted as Associate Scientific Director, a Program Director in the NCI designated Cancer Center, Postdoctoral Training Program Director, started the Tumor Analysis Shared Service and directed research on stem cells and cancer that resulted in over 100 publications. He also served as a reviewer for multiple cancer research granting agencies and taught at UC San Diego as an Adjunct Professor of Pathology from 1997. He is currently Professor Emeritus (2015) and continues to advise and consult in cancer research. His particular cancer research interest is in methods of directing premalignant cancer cells to adopt a normal benign cell fate instead of becoming invasive malignant cancer.

Related Disease
Breast Cancer, Colorectal Cancer, Crohn’s Disease (Colitis), Preeclampsia

Cancer and development are closely related processes. The Oshima laboratory investigates the differences between normal stem cells and cancer stem cells. Furthermore, we are searching for genes and chemical compounds that control the differentiation of cancer cells and persuading them to adopt a normal developmental fate. Differentiation therapy has the promise of causing fewer deleterious side effects than killing cancer cells.

Robert Oshima’s Research Report

Stem Cells in Breast Cancer and Placental Development

Ets2 is one of a family of transcription factors that all utilize a conserved Ets protein domain for DNA binding. Like its Drosophila homologs, pointed and yan, Ets2 is regulated by growth factors and oncogenes that use Ras signaling pathways. The phosphorylation of a single threonine residue in an evolutionarily conserved protein-docking domain of Ets2 results in transcriptional activation and the induction of Ets2-dependent genes.

Early mouse placental development is dependent on the function of the Ets2 transcription factor. Ets2 regulates trophoblast stem (TS) cell self-renewal and thus placental development. One of the genes regulated by Ets2 in TS cells is the Cdx2 homeobox transcription factor. In collaboration with Dr. Mana Parast at UCSD, we extended our interest in placental development by developing a model system of human placental development. Human embryonic stem cells (ESC) and induced pluripotent stem cells (IPSC) can differentiate in culture to a trophoblast like derivative. We are screening chemical libraries by high content antibody staining methods for chemicals that improve the yield of trophoblast progenitors and direct their differentiation to either extra villous, invasive trophoblast cells or synchiotrophoblast layers.

Recently, we developed methods for the selective propagation of mouse mammary cancer stem cells in culture (Castro et al. Stem Cells 2013). These cells were shown to be capable of differentiation to a benign luminal epithelial-like fate both in culture and in animals. Inhibition of ROCK1 kinase inhibited both their spontaneous differentiation to luminal epithelial cells and their adoption of a mesenchymal tumorigenic phenotype.

Previously, in collaboration with Dr. Alexey Terskikh, we investigated the role of the Maternal Embyronic Leucine Zipper Kinase (MELK) in normal mammary epithelial stem cells and mouse mammary cancer. Using a transgenic reporter gene for Melk expression, we found that Melk expression is preferentially expressed in proliferative mammary epithelial progenitor cells and tumor cells. Both tumorsphere formation in culture and tumor formation in vivo is suppressed by knocking down Melk expression with Lentiviral-mediated shRNA in MMTV-Wnt1 tumor cells. These results have recently been confirmed in human triple negative breast cancer cells.

Furthermore, the development of differentiation therapy came from a collaborative project with Pfizer. Administration of bosutinib, a Src family inhibitor, to mice with mammary tumors caused by the MMTV-PyMT oncogene greatly restricted tumor progression by inducing differentiation of the tumor to epidermal and lactational cell fates without widespread cell death. This is an example of the possibility of restricting cancer by inducing differentiation.

**Figure 1.** Regulation of cancer stem cell differentiation by low oxygen atmosphere. Single cancer stem cells were plated in two different concentrations of O2 and stained for markers of luminal (K8) or basal (K14) epithelial cells. In 20 percent O2 differentiated cells expressing only K8 or K14 are observed. (Castro et al. 2013)

**Figure 2.** Presumptive trophoblast derivatives on the top of an hES cell colony, identified by keratin 7 staining (red). Nuclei stained by DAPI (blue). (Maurer et al. 2008)

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Showing 3 of 3

Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells.

Wu B, Wang S, De SK, Barile E, Quinn BA, Zharkikh I, Purves A, Stebbins JL, Oshima RG, Fisher PB, Pellecchia M

Chem Biol 2015 Jul 23 ;22(7):876-887

ROCK1 inhibition promotes the self-renewal of a novel mouse mammary cancer stem cell.

Castro DJ, Maurer J, Hebbard L, Oshima RG

Stem Cells 2013 Jan ;31(1):12-22

Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors.

Islas JF, Liu Y, Weng KC, Robertson MJ, Zhang S, Prejusa A, Harger J, Tikhomirova D, Chopra M, Iyer D, Mercola M, Oshima RG, Willerson JT, Potaman VN, Schwartz RJ

Proc Natl Acad Sci U S A 2012 Aug 7 ;109(32):13016-21

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A career history of fundamental discovery and translational research in immunology has guided Dr. Ware to identify new drug targets and develop novel therapeutics. Dr. Ware’s career in immunology and virology began in 1982 when he became a Professor at the University of California, Riverside’s Division of Biomedical Sciences. In 1996, he joined the La Jolla Institute for Immunology in San Diego as Head of the Division of Molecular Immunology. Professor Ware joined Sanford Burnham Prebys Medical Discovery Institute in 2010, serving as the Director of the Infectious and Inflammatory Disease Center and Adjunct Professor of Biology at the University of California at San Diego. He is currently the Director of the Laboratory of Molecular Immunology, which focuses on discovering and designing immunotherapeutics.

As an educator, he taught medical students immunology and virology. He trained over 60 postdoctoral fellows and graduate students who chose careers in research in academic and pharmaceutical science, patent law, or teaching.

Dr. Ware advises scientific panels and review boards for the National Institutes of Health and serves on the scientific advisor boards for the Allen Institute for Immunology and the Arthritis National Research Foundation. Scientific advisor with several biotechnology and pharmaceutical companies on immunotherapy for cancer and autoimmune diseases using innovative approaches to target discovery and drug development.

Dr. Ware’s research program is dedicated to unraveling the intricate intercellular communication pathways that govern immune responses. His work, which centers on cytokines in the Tumor Necrosis Factor (TNF) Superfamily, particularly those that regulate cell survival and death in response to viral pathogens, spans the domains of cancer,autoimmune and infectious diseases.

At Sanford Burnham Prebys, Dr. Ware is pivotal in promoting the translation of the faculty’s scientific discoveries. His efforts have led to the Institute’s reputation as a productive and preferred partner in collaborations with Pharma, including multi-year research and drug development projects with Eli Lilly and Avalo Therapeutics. His success translating fundamental knowledge into rational drug design has led to three novel therapeutics targeting inflammatory pathways, currently in clinical trials.

Education

1981-1982: T cell Immunology, Dana-Farber Cancer Institute of Harvard Medical School in Boston, MA. Tim Springer and Jack Strominger, advisors.
1979-1981: Biochemistry of Complement, University of Texas Health Science Center, San Antonio, TX. W Kolb, advisor
1974-1979: PhD in Molecular Biology and Biochemistry from the University of California, Irvine; Gale Granger, PhD mentor.

Honors and Recognition

Distinguished Fellow, American Association of Immunologists
Honorary Lifetime Membership Award International Cytokine and Interferon Society
Hans J. Muller-Eberhardt Memorial Lecture
Biotech All Star, San Diego Padres Award
“Pillars of Immunology” discovery of the Lymphotoxin-b Receptor, published in Science
Outstanding Alumnus, Ayala School of Biological Sciences, University of California, Irvine
National MERIT Award R37 (10 years), National Institute of Allergy and Infectious Disease, NIH
National Research Service Award, NIH Postdoctoral Fellowship

Related Disease
Arthritis, Breast Cancer, Cancer, Crohn’s Disease (Colitis), Infectious Diseases, Inflammatory Bowel Disease, Inflammatory/Autoimmune Disease, Inherited Disorders, Leukemia/Lymphoma, Myeloma, Pathogen Invasion, Psoriasis, Systemic Lupus Erythematosus, Type 1 Diabetes

Research in the Laboratory of Molecular Immunology is directed at defining the intercellular communication pathways controlling immune responses. Our work is focused on the Tumor Necrosis Factor (TNF)-related cytokines in regulating decisions of cell survival and death, especially in responses to viral pathogens. Translational research is redirecting the communication networks of TNF superfamily to alter the course of autoimmune and infectious disease and cancer.

Carl Ware’s Research Report

Discovery of the TNF-LIGHT-LTαβ Network

The molecular elements of this cellular communication network were revealed with our discovery of Lymphotoxin-β and its formation of the trimeric heterocomplex with LTαβ¹ and its signaling receptor, Lymphotoxin-β Receptor². The LTβR revealed a new inter-cellular communication pathway that provides a key mechanism underlying the development and homeostasis of lymphoid organs. A second ligand we discovered, LIGHT (TNFSF14), is a novel ligand for the herpesvirus entry mediator (HVEM; TNFRSF14), and surprisingly, the LTβR³ heralding the concept that TNF, LTαβ, and LIGHT form an integrated signaling network thru distinct receptors controlling inflammation and host defense.⁴

LTβR Signaling in Host Defense and Immune Evasion

Our investigations into the mechanisms of virus evasion of the immune system revealed an essential role of the LTβR pathway in regulating the type 1 interferon response to cytomegalovirus⁵ and now recognized as a major defense against other pathogens. LTβR signals differentiate macrophages and stromal cells into IFN-producing cells. LTβR transcriptomics and proteomics datasets we generated revealed a novel constellation of anti-viral host defense mechanisms⁶. Importantly the role of the LTβR pathway to alter tissue microenvironments by differentiation of specialized stromal cells has implications for promoting effective immune responses to cancer.

Discovery of the HVEM-BTLA Immune Checkpoint

The LTBR-HVEM-BTLA Network in the TNF Superfamilies. Arrows indicate ligand-receptor binding (black), inhibitors (red arrow) and bidirectional signaling (dual arrowheads); HSV, herpes simplex virus; CMV, human cytomegalovirus. BTLA and CD160 are Ig Superfamily proteins. BTLA is an inhibitory checkpoint receptor; DcR3, decoy receptor 3 inhibits LIGHT binding to HVEM and LTBR.

The discovery that HVEM is a coreceptor for the immune checkpoint, B and T lymphocyte attenuator (BTLA), an Ig superfamily member, established a new paradigm in TNF Receptor signaling pathways ⁷. Additional investigations revealed the importance of the HVEM-BTLA system in limiting immune responses, including T cell help for B cell clonal expansion, antibody maturation, and secretion⁸. HVEM-BTLA also regulates control of the intestinal microbiome, limiting invasion of pathogenic bacteria and enhancing Treg cell homeostasis ⁹. The diverse roles of this pathway are seen in the loss of BTLA signaling from mutations in HVEM frequently present in B cell lymphomas¹⁰. Additional layers of immune regulators, CD160 and DcR3, control the LIGHT-HVEM-BTLA pathways, revealing this network as a key mechanism controlling immune homeostasis.

Appreciating the fundamental features of the TNF-LIGHT-LTab Network in effector and homeostasis mechanisms presents a target-rich resource for therapeutic intervention in autoimmunity, infection, and cancer^{11, 12}.

Translational research and Immunotherapy

2021-current: Lead Scientific Advisor, Avalo Therapeutics
A neutralizing, fully human mAb (quisovalimab) to the proinflammatory cytokine LIGHT (TNFSF14) completed Phase I with an excellent safety profile and a Phase II trial establishing efficacy in COVID-19 pneumonia (NCT0441205)¹³. We identified elevated serum levels of LIGHT in hospitalized patients with COVID19¹⁴ spurring a randomized, double-blind, multicenter, proof-of-concept trial with adults hospitalized with COVID-19-associated pneumonia and mild to moderate ARDS¹⁵. The results established efficacy with a significant proportion of patients remaining alive and free of respiratory failure through day 28 after receiving quisovalimab, most pronounced in patients >60 years of age (76.5% vs. 47.1%, respectively; P = 0.042). These results and animal models validated LIGHT as a target for non-COVID inflammatory conditions, clinical trials ongoing in asthma (NCT05288504)¹².
2021-current: Principal Investigator, Avalo Therapeutics – Sanford Burnham Prebys collaboration
Bioengineered a first-in-class checkpoint agonist targeting BTLA immune checkpoint¹⁶ in preclinical development
2019-current: Director and Principal Investigator, Fair Journey Biologics – Sanford Burnham Prebys collaboration
Immunotherapy for TNBC and PANC, in preclinical development
2015-2022: Director and Lead Principal Investigator, LILLY-Sanford Burnham Prebys Collaboration in Autoimmunity
Collaborative research partnership with Eli Lilly involved target discovery and therapeutic development directed at immune regulators for autoimmune diseases. The collaboration produced three novel biologics currently in Phase I/2 trials (NCT03933943). The collaboration included a target discovery platform for T cell effector memory and NK cell immunomodulators.
2015-2020: Lead Principal Investigator, Sanford Burnham Prebys – Capella Biosciences collaboration
Created a fully human mAb specific for membrane LIGHT (CBS001); phase I initiated (NCT05323110).
2016-2020: Lead Scientific Investigator, Boehringer Ingelheim – Sanford Burnham Prebys Collaboration
Target discovery collaboration in inflammatory and fibrotic diseases⁶
2012-2014: Pfizer Innovation Center, Principal Investigator Bioengineering TNFR Superfamily in Autoimmune disease

1. Browning, J.L. et al. Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell 72,847-856 (1993).
2. Crowe, P.D. et al. A lymphotoxin-beta-specific receptor. Science 264,707-710 (1994).
3. Mauri, D.N. et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity 8,21-30 (1998).
4. Ward-Kavanagh, L.K., Lin, W.W., Sedy, J.R. & Ware, C.F. The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses. Immunity 44,1005-1019 (2016).
5. Schneider, K. et al. Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus. Cell Host Microbe 3,67-76 (2008).
6. Virgen-Slane, R. et al. Cutting Edge: The RNA-Binding Protein Ewing Sarcoma Is a Novel Modulator of Lymphotoxin beta Receptor Signaling. J Immunol 204,1085-1090 (2020).
7. Sedy, J.R. et al. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol 6,90-98 (2005).
8. Mintz, M.A. et al. The HVEM-BTLA Axis Restrains T Cell Help to Germinal Center B Cells and Functions as a Cell-Extrinsic Suppressor in Lymphomagenesis. Immunity 51,310-323 e317 (2019).
9. Stienne, C. et al. Btla signaling in conventional and regulatory lymphocytes coordinately tempers humoral immunity in the intestinal mucosa. Cell reports 38,110553 (2022).
10. Sedy, J.R. & Ramezani-Rad, P. HVEM network signaling in cancer. Adv Cancer Res 142,145-186 (2019).
11. Croft, M., Benedict, C.A. & Ware, C.F. Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 12,147-168 (2013).
12. Ware, C.F., Croft, M. & Neil, G.A. Realigning the LIGHT signaling network to control dysregulated inflammation. J Exp Med 219 (2022).
13. Zhang, M., Perrin, L. & Pardo, P. A Randomized Phase 1 Study to Assess the Safety and Pharmacokinetics of the Subcutaneously Injected Anti-LIGHT Antibody, SAR252067. Clin Pharmacol Drug Dev 6,292-301 (2017).
14. Perlin, D.S. et al. Levels of the TNF-Related Cytokine LIGHT Increase in Hospitalized COVID-19 Patients with Cytokine Release Syndrome and ARDS. mSphere 5 (2020).
15. Perlin, D.S. et al. Randomized, double-blind, controlled trial of human anti-LIGHT monoclonal antibody in COVID-19 acute respiratory distress syndrome. J Clin Invest 132 (2022).
16. Sedy, J.R. et al. A herpesvirus entry mediator mutein with selective agonist action for the inhibitory receptor B and T lymphocyte attenuator. J Biol Chem 292,21060-21070 (2017).

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Showing 3 of 3

Targeting the TNF and TNFR superfamilies in autoimmune disease and cancer.

Croft M, Salek-Ardakani S, Ware CF

Nat Rev Drug Discov 2024 Dec ;23(12):939-961

Epitope topography of agonist antibodies to the checkpoint inhibitory receptor BTLA.

Cheung TC, Atwell S, Bafetti L, Cuenca PD, Froning K, Hendle J, Hickey M, Ho C, Huang J, Lieu R, Lim S, Lippner D, Obungu V, Ward-Kavanagh L, Weichert K, Ware CF, Vendel AC

Structure 2023 Aug 3 ;31(8):958-967.e3

Realigning the LIGHT signaling network to control dysregulated inflammation.

Ware CF, Croft M, Neil GA

J Exp Med 2022 Jul 4 ;219(7):

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After receiving his early training in clinical chemistry/biochemistry at the University of Buenos Aires, Argentina, Dr. Millán first joined the La Jolla Cancer Research Foundation (LJCRF) in 1977, the predecessor of Sanford Burnham Prebys, as a trainee in clinical enzymology. He completed his PhD studies in Medical Biochemistry at the University of Umeå, Sweden and after post-doctoral stints in Copenhagen and LJCRF he was appointed to the faculty at SBP in 1986. He served as Professor of Medical Genetics in the Department of Medical Biosciences at his alma mater, Umeå University, Sweden, from 1995-2000. He was appointed Sanford Investigator at the Sanford Children’s Health Research Center at Sanford Burnham Prebys in 2008.

Honors and Recognition

2018: ASBMR Lawrence G. Raisz Award for Pre-clinical Research.
2001: Gold Medal of the Royal Academy of Medicine and Surgery, Murcia, Spain
1992: Honorary title of AcadémicoCorresponsal at the Royal Academy of Medicine and Surgery, Murcia, Spain.

Other Affiliations

Member, Scientific Advisory Board, Soft Bones

Related Disease
Arthritis, Bone Mineralization Disorders, Cardiovascular Diseases, Colorectal Cancer, Crohn’s Disease (Colitis), Heart Disease, Inherited Disorders, Metabolic Syndrome, Peripheral Vascular Disease, Testicular Cancer

Phenomena or Processes
Cardiovascular Biology, Disease Therapies, Extracellular Matrix, Protein Structure-Function Relationships

Anatomical Systems and Sites
Cardiovascular System, Musculoskeletal System, Vasculature

Research Models
Mouse

The Millán laboratory works on understanding the mechanisms that control normal skeletal and dental mineralization and elucidating the pathophysiological abnormalities that lead to heritable soft bones conditions such as Hypophosphatasia (HPP) and to soft-tissue calcification, including vascular calcification, that is a hallmark in patients affected by a variety of rare genetic diseases as well as in chronic kidney disease. Dr. Millán’s research has already contributed to the implementation of a novel therapy for HPP, a genetic disease caused by deficiency in tissue-nonspecific alkaline phosphatase (TNAP) function, that leads to accumulation in the extracellular space of inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. HPP is characterized by defective mineralization of bones (rickets or osteomalacia), and teeth that display a lack of acellular cementum, hypomineralized dentin and enamel, and periodontal defects. Dr. Millán’s team has demonstrated the effectiveness of enzyme replacement therapy using mineral-targeted recombinant TNAP (asfotase alfa) to prevent the skeletal and dental defects in the TNAP knockout mouse model of infantile HPP. This therapy was approved in 2015 for the treatment of patients with pediatric-onset HPP.

Current efforts, in collaboration with Professor Miyake’s group in Japan (https://www.nms-gt.org/en/members), focus on developing gene therapy as an alternative approach to treat HPP. Dr. Millán’s group has also identified key pathophysiological changes that lead to calcification of the arteries in animal models of generalized arterial calcification of infancy, pseudoxanthoma elasticum and related genetic diseases as well as in animal models of chronic kidney disease. His group, in collaboration with scientists at the Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys, has developed proprietary compounds able to ameliorate the soft-tissue calcification in these conditions and clinical trials are now underway using these first-in-class small molecule inhibitors.

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Showing 3 of 3

Inhibition of tissue-nonspecific alkaline phosphatase protects against medial arterial calcification and improves survival probability in the CKD-MBD mouse model.

Tani T, Fujiwara M, Orimo H, Shimizu A, Narisawa S, Pinkerton AB, Millán JL, Tsuruoka S

J Pathol 2020 Jan ;250(1):30-41

Visualization of Mineral-Targeted Alkaline Phosphatase Binding to Sites of Calcification In Vivo.

Amadeu de Oliveira F, Narisawa S, Bottini M, Millán JL

J Bone Miner Res 2020 Sep ;35(9):1765-1771

Gene Therapy Using Adeno-Associated Virus Serotype 8 Encoding TNAP-D(10) Improves the Skeletal and Dentoalveolar Phenotypes in Alpl(-/-) Mice.

Kinoshita Y, Mohamed FF, Amadeu de Oliveira F, Narisawa S, Miyake K, Foster BL, Millán JL

J Bone Miner Res 2021 Sep ;36(9):1835-1849

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Dr. Freeze earned his PhD from the University of California, San Diego in 1976. Subsequently he held fellowships in Biology, Medicine and Neurosciences later joined the faculty at the same institution. In 1988 Dr. Freeze was recruited to Sanford Burnham Prebys.

Related Disease
Cancer, Congenital Disorders of Glycosylation, Crohn’s Disease (Colitis), Glycosylation-Related Disorders

Dr. Freeze’s research focuses on the pathology resulting from faulty glycosylation, the process of adding carbohydrate (sugar) chains to proteins and lipids. Carbohydrates are required for proper secretion and targeting of thousands of proteins – an often over looked fact of biology. He is driven by the search for novel therapeutics to treat patients with mutations leading to glycosylation defects called Congenital Disorders of Glycosylation (CDG).

Hudson Freeze’s Research Report

Glycosylation: An Essential Function

The entire cell surface is coated with sugars in complex chains that promote (or sometimes interfere) with cell-to-cell communication. These sugar chains are first attached to proteins deep inside the cell where they help them get into shape for their jobs. As the proteins percolate toward to cell surface and beyond, the sugar chains are sculpted for specific needs. This entire process, called glycosylation, recruits a force of more than 500 genes for this job. The Freeze lab works on several facets of glycosylation, all of them with an eye toward therapeutic applications for diseases that impair the functions of these critical genes.

Human Glycosylation Disorders

We focus is on a group of metabolic diseases called Congenital Disorders of Glycosylation (CDG). Today we know of defects in over 140 genes, well over double those known only 10 years ago. Patients with these diseases have highly variable mental and motor developmental delay, seizures, failure to grow, hypoglycemia (low blood sugar), clotting and digestion abnormalities and skeletal abnormalities to name just a few. These are rare disorders having a few thousand known patients worldwide, but it is likely that many remain undiagnosed, especially in developing countries.

Growing Awareness

Physicians are becoming more aware of glycosylation disorders in general, and basic scientists continue to discover sugar chains at the helm of many basic metabolic processes. Defective glycosylation is also known to cause 15 types of muscular dystrophy.

The explosive growth in the number of different diseases caused by defective glycosylation.

Working with CDG Kids

Rocket: We helped diagnose this young man over 10 years ago, and although he tragically passed away, his gentle face still reminds us of who we work for.

Rocket Williams reaches out to us. Learn more about the Rocket Fund.

Brianna: Sometimes our work leads to brighter outcomes as in the case of Brianna who we met over 20 years ago and treated with a simple therapy.

Flourishing, Brianna is now training to become a veterinarian.

Our Collaborations

The Freeze lab not only identifies new glycosylation disorders, but also tries to understand how these defects cause the disease manifestations. Defects occur in genes that activate and transport sugars, assemble them into glycans and remodel them. Some also traffic and distribute the glycosylation machinery within cells. Ongoing collaborations with academic physicians provide a steady flow of new patients for analysis. Since very few laboratories in the United States work on CDG, we are developing new molecular diagnostic methods to handle the increasing number of patients. Increased awareness of CDG in the medical community generated expanded government funding that allies us with 10 medical centers in the US seeking additional patients to study their natural history, develop biomarkers and test emerging therapies. Those avenues along with the help of generous philanthropic support, enables us to extend efforts to supplement the depleted glycosylation pathways in patients.

In this image and film clip above, Harrison Ford poses a few questions for us.

Watch: Our inspiration for CDG research

Watch: Para-equestrian with rare disorder meets Olympian in San Diego

Watch: “Miracle:” Uridine at 2 days and 5.5 months

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Showing 3 of 3

N-Glycanase 1 Transcriptionally Regulates Aquaporins Independent of Its Enzymatic Activity.

Tambe MA, Ng BG, Freeze HH

Cell Rep 2019 Dec 24 ;29(13):4620-4631.e4

SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals.

Ng BG, Sosicka P, Agadi S, Almannai M, Bacino CA, Barone R, Botto LD, Burton JE, Carlston C, Chung BH, Cohen JS, Coman D, Dipple KM, Dorrani N, Dobyns WB, Elias AF, Epstein L, Gahl WA, Garozzo D, Hammer TB, Haven J, Héron D, Herzog M, Hoganson GE, Hunter JM, Jain M, Juusola J, Lakhani S, Lee H, Lee J, Lewis K, Longo N, Lourenço CM, Mak CCY, McKnight D, Mendelsohn BA, Mignot C, Mirzaa G, Mitchell W, Muhle H, Nelson SF, Olczak M, Palmer CGS, Partikian A, Patterson MC, Pierson TM, Quinonez SC, Regan BM, Ross ME, Guillen Sacoto MJ, Scaglia F, Scheffer IE, Segal D, Singhal NS, Striano P, Sturiale L, Symonds JD, Tang S, Vilain E, Willis M, Wolfe LA, Yang H, Yano S, Powis Z, Suchy SF, Rosenfeld JA, Edmondson AC, Grunewald S, Freeze HH

Hum Mutat 2019 Jul ;40(7):908-925

Pathogenic Variants in Fucokinase Cause a Congenital Disorder of Glycosylation.

Ng BG, Rosenfeld JA, Emrick L, Jain M, Burrage LC, Lee B, Undiagnosed Diseases Network, Craigen WJ, Bearden DR, Graham BH, Freeze HH

Am J Hum Genet 2018 Dec 6 ;103(6):1030-1037

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Related Disease: Crohn’s Disease (Colitis)

Robert Oshima’s Research Report

Stem Cells in Breast Cancer and Placental Development

Select Publications

Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells.

ROCK1 inhibition promotes the self-renewal of a novel mouse mammary cancer stem cell.

Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors.

Education

Honors and Recognition

Carl Ware’s Research Report

Discovery of the TNF-LIGHT-LTαβ Network

LTβR Signaling in Host Defense and Immune Evasion

Discovery of the HVEM-BTLA Immune Checkpoint

Translational research and Immunotherapy

Select Publications

Targeting the TNF and TNFR superfamilies in autoimmune disease and cancer.

Epitope topography of agonist antibodies to the checkpoint inhibitory receptor BTLA.

Realigning the LIGHT signaling network to control dysregulated inflammation.

Honors and Recognition

Other Affiliations

Inhibition of tissue-nonspecific alkaline phosphatase protects against medial arterial calcification and improves survival probability in the CKD-MBD mouse model.

Visualization of Mineral-Targeted Alkaline Phosphatase Binding to Sites of Calcification In Vivo.

Gene Therapy Using Adeno-Associated Virus Serotype 8 Encoding TNAP-D(10) Improves the Skeletal and Dentoalveolar Phenotypes in Alpl(-/-) Mice.

Hudson Freeze’s Research Report

Glycosylation: An Essential Function

Human Glycosylation Disorders

N-Glycanase 1 Transcriptionally Regulates Aquaporins Independent of Its Enzymatic Activity.

SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals.

Pathogenic Variants in Fucokinase Cause a Congenital Disorder of Glycosylation.

Biography

Research

Select Publications

Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells.

ROCK1 inhibition promotes the self-renewal of a novel mouse mammary cancer stem cell.

Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors.

Biography

Education

Honors and Recognition

Research

Select Publications

Targeting the TNF and TNFR superfamilies in autoimmune disease and cancer.

Epitope topography of agonist antibodies to the checkpoint inhibitory receptor BTLA.

Realigning the LIGHT signaling network to control dysregulated inflammation.

Biography

Honors and Recognition

Other Affiliations

Research

Select Publications

Inhibition of tissue-nonspecific alkaline phosphatase protects against medial arterial calcification and improves survival probability in the CKD-MBD mouse model.

Visualization of Mineral-Targeted Alkaline Phosphatase Binding to Sites of Calcification In Vivo.

Gene Therapy Using Adeno-Associated Virus Serotype 8 Encoding TNAP-D(10) Improves the Skeletal and Dentoalveolar Phenotypes in Alpl(-/-) Mice.

Biography

Research

Select Publications

N-Glycanase 1 Transcriptionally Regulates Aquaporins Independent of Its Enzymatic Activity.

SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals.

Pathogenic Variants in Fucokinase Cause a Congenital Disorder of Glycosylation.