SBIR-STTR Award

?Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a broad spectrum of clinical manifestations affecting several organs and associated with dysregulation of the immune system. This disease affects millions of individuals, with women and underserved minorities disproportionately burdened. It is associated with significant morbidity and mortality, yet treatment approaches remain broadly immunosuppressive, anti-inflammatory, or palliative. Despite the considerable progress on understanding SLE immune-pathogenesis, only one drug has been approved for the treatment of lupus patients in the last 50 years, emphasizing the urgent need for novel therapies. Considering the central role of auto-antibodies in the amplification of auto-immunity, a goal in lupus therapy is the elimination of auto-reactive antibody secreting cells (ASC). Karyopharm Therapeutics has pioneered the development of Selective Inhibitors of Nuclear Export (SINE) compounds, and wishes to investigate their potential utility in auto-immune diseases. In collaboration with the Anolik laboratory at the University of Rochester Medical Center, we will evaluate a novel approach to the treatment of autoimmune disease that targets the generation and survival of autoreactive plasma cells (PCs) via inhibition of nuclear export. SINE compounds have a potent effect on the generation of splenic T follicular helper cells (TFH) and germinal center (GC) B-cells, and selectively inhibit production of auto-reactive ASCs specific for double stranded DNA. SINEs had a compelling effect on GC formation/stability, prevented expansion of memory TFH and B cells, and markedly reduced mRNA expression of molecules critical for survival and recruitment of auto-reactive ASC including certain cytokines, interleukin and interferon induced chemokines. Thus, SINE drugs strongly and selectively ablated auto-reactive PCs by targeting pathways that are critical for their generation and survival/recruitment into inflamed kidneys. In the proposed project, we will define the efficacy of SINE compounds in SLE in order to accelerate the translation of these novel compounds into lupus clinical trials. In Aim 1, we will identify the optimal treatment strategy of SINE compounds in murine SLE model by (i) refining the dose and time required for GCs and PCs to exhibit a response in vivo, (ii) optimizing the induction treatment strategy, and (iii) determining the duration of SINE compound effect and define the need for maintenance therapy. In Aim 2, we will examine the protective immunity effects of the SINE compounds by (i) evaluating the immune responses in murine SLE during treatment and (ii) determining the recovery of protective immune responses after cessation of therapy. Successful completion of these studies will lead to a Phase II proposal to move SINE compounds into extensive preclinical safety testing in preparation for clinical trials. The goal is to develop an efficacious dosing strategy using a novel treatment approach that targets key synergistic pathways in SLE disease pathogenesis, with the long term goal of delivering an improved therapy for SLE and other autoimmune diseases.

Public Health Relevance Statement:


Public Health Relevance:
Systemic Systemic lupus erythematosus (SLE) is a complex autoimmune disease affecting multiple organs and with limited treatment options. We seek to investigate the potential utility of Selective Inhibitors of Nuclear Export (SINE) compounds in auto-immune diseases like SLE.

Project Terms:
Affect; African American; Anti-inflammatory; Anti-Inflammatory Agents; Antibodies; Attention; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Cells; chemokine; Clinical; Clinical Trials; Collaborations; Complex; Critical Pathways; cytokine; Cytokine Signaling; Data; Development; Dialysis procedure; Disease; Dose; ds-DNA; Exhibits; Funding; Generations; Goals; Head; Helper-Inducer T-Lymphocyte; Hematologic Neoplasms; Hispanics; Immune; Immune response; Immune system; Immune System Diseases; Immunity; Immunoglobulin-Secreting Cells; Immunosuppressive Agents; improved; in vivo; Individual; inhibitor/antagonist; Interferons; Interleukins; Investigational Drugs; Kidney; Knowledge; Laboratories; Lead; Lupus; Maintenance; Maintenance Therapy; Malignant Neoplasms; Medical center; Memory; men; Modeling; Morbidity - disease rate; Mortality Vital Statistics; mouse model; mRNA Expression; Multiple Myeloma; Mus; novel; novel strategies; novel therapeutics; Nuclear Export; Nuclear Pore; oncology; Organ; palliative; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasma Cells; Population; preclinical safety; preclinical study; Preparation; prevent; Production; public health relevance; Reaction; Reactive Plasma Cell; Recovery; response; Role; Safety; safety testing; Short Interspersed Nucleotide Elements; Small Business Innovation Research Grant; stem; Structure of germinal center of lymph node; Supportive care; systemic autoimmune disease; Systemic Lupus Erythematosus; Therapeutic; Time; Toxicology; Translations; Treatment Protocols; treatment strategy; Underrepresented Minority; United States National Institutes of Health; Universities; Woman; Work

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a broad spectrum of clinical manifestations that affect several organs. SLE affects millions of individuals, with women and minorities disproportionately burdened, and is associated with significant morbidity and mortality. Despite considerable progress made towards understanding the disease and the identification of the central roles plasma cells (PCs) and autoreactive antibody secreting cells (ASCs) play in SLE pathogenesis, most therapeutic approaches remain broadly immunosuppressive, anti-inflammatory, or palliative, which highlights the urgent need for novel therapies. Due to the essential role of auto-antibodies in the amplification of auto-immunity, a goal in lupus therapy is the elimination of auto-reactive ASCs. Karyopharm Therapeutics pioneered the development of Selective Inhibitors of Nuclear Export (SINE), and is investigating their utility in auto-immune diseases in collaboration with the Anolik laboratory at the University of Rochester Medical Center. Together we have shown that inhibiting nuclear export with KPT-350, a SINE, strongly and selectively ablates auto-reactive PCs by targeting pathways that are critical for their generation, survival, and recruitment into inflamed kidneys. Specifically, we have shown that KPT-350 selectively inhibits the production of auto-reactive ASCs and has a compelling effect on B-cell germinal center formation/stability, prevents expansion of memory T follicular helper cells, and markedly reduces mRNA expression of molecules critical for survival and recruitment of auto-reactive ASCs. In the proposed project, we will further define the efficacy of SINE treatment and identify viable combination and maintenance therapies to accelerate the translation of these novel compounds into SLE clinical trials. In Aim 1, we will define the optimal dosage conditions to restrain murine lupus progression after withdrawal of SINE therapy by (i) determining the duration of the SINE effect and defining the need for maintenance therapy, and (ii) defining the duration of the SINE effect on NF?B inhibition. In Aim 2, we will examine the effects of combination modality therapy on murine autoreactive PCs by (i) evaluating the efficacy and duration of SINE and proteasome inhibitors on autoimmune disease relapse, (ii) determining the effects of single vs combination therapy on PCs in SLE, and (iii) defining the impact of factors involved in the maintenance of autoreactive PCs. Finally, Aim 3 will expand our studies to human SLE by (i) defining the role of NF?B survival signals in SLE patient PCs, (ii) examining the effect SINE treatment has on SLE PC survival, (iii) defining the signals required for SLE bone marrow (BM) PC survival, (iv) identifying the source of PC survival factors in the BM, and (v) demonstrating that SINE therapy inhibits B-cell differentiation. Our goal is to delineate an efficacious combination dosing strategy, using a novel approach that targets key synergistic pathways in SLE disease pathogenesis, with the long term goal of delivering an improved therapy for SLE. Successful completion of these studies will allow us to pursue commercialization objectives and move SINE compounds into extensive preclinical safety testing.

Public Health Relevance Statement:
Systemic Systemic lupus erythematosus (SLE) is a complex autoimmune disease affecting multiple organs and with limited treatment options. We seek to investigate the potential utility of Selective Inhibitors of Nuclear Export (SINE) compounds in auto-immune diseases like SLE.

Project Terms:
Achievement; Adverse event; Affect; African American; Anti-Inflammatory Agents; Antibodies; Attention; Autoantibodies; Autoimmune Diseases; Autoimmunity; autoreactive B cell; autoreactivity; B cell differentiation; B-Lymphocytes; Bone Marrow; cancer cell; Cell Survival; Cellular biology; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; commercialization; Complex; Critical Pathways; cytokine; Data; Development; differentiated B cell; Disease; Disease remission; dosage; Dose; Frequencies; Funding; Generations; Goals; Grant; Helper-Inducer T-Lymphocyte; Hematologic Neoplasms; Hispanics; Human; IL6 gene; Immunity; Immunoglobulin-Secreting Cells; Immunosuppressive Agents; improved; Individual; inhibitor/antagonist; Interferon-alpha; Investigational Drugs; Kidney; Kinetics; Laboratories; Lupus; Maintenance; Maintenance Therapy; Medical center; Memory; men; Minority; Modality; Morbidity - disease rate; mortality; mouse model; mRNA Expression; Multiple Myeloma; Mus; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Neoadjuvant Therapy; novel; novel strategies; novel therapeutics; Nuclear Export; Nuclear Pore; oncology; Organ; palliative; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmacotherapy; Phase; Plasma Cells; Play; Population; preclinical safety; preclinical study; prevent; Production; Proteasome Inhibition; Proteasome Inhibitor; Reaction; Recovery; recruit; Recurrent disease; response; Role; Safety; safety testing; Signal Transduction; Small Business Innovation Research Grant; Source; Structure of germinal center of lymph node; systemic autoimmune disease; Systemic Lupus Erythematosus; Systemic Therapy; Therapeutic; Time; Toxicology; Translations; Universities; Withdrawal; Woman; Work