Research accomplishments of this project include: 1) This project allows us to study the largest cohort of patients with ALPS, one of the first genetic disorders of immunedysregulation. ALPS natural history study based on follow up of these patients over 20 yeas has been completed and a manuscript summarizing the critical features of the clinical and molecular pathogenesis in 150 patients with ALPS-FAS with a median followup of 13 years has been published as a plenary paper in an eminent hematological journal (Blood. 2014 Mar 27;123(13):1989-99). This included the validation of novel biomarkers of disease activity such as increased serum Vitamin B12 levels as well as establishing new modes of treatment for the disorder. Study of ALPS has elucidated the role of fas mediated apoptosis in lymphocyte homeostasis and lymphoma genesis. 2)This project has also led to identifying new genetic causes of ALPS like disorders by identification of mutations affecting RAS pathway in 14 patients, otherwise known as Ras Associated Leukoproliferative Disorder (RALD) : RALD: Patients with this ALPS like syndrome caused by somatic mutations in NRAS and KRAS are currently classified separately as ALPS related apoptosis disorders. These patients with somatic NRAS and KRAS mutations present with autoimmune phenomena, massive splenomegaly, modest lymphadenopathy and normal or only marginally elevated TCR alpha/beta+ DNT cells. Their lymph node histopathology is also not typical of ALPS-FAS. Additionally, these patients show abnormalities of the myeloid compartment, with chronic persistent monocytosis, mimicking juvenile myelomonocytic leukemia (JMML) in otherwise asymptomatic young patients. (Blood 2015 Apr 30;125(18):2753-8). 3) With support from NCBI we have implemented a web based publication of the existing databases of pathogenic FAS mutations, by far the commonest cause of ALPS, which is publicly available and can be used for diagnostic help by referring to NCBI NIH ALPS website <>. We are also continuing our efforts to streamline the techniques of apoptosis assay by evaluating Fas mediated cell death and cell survival with serum starvation in lymphocyte and monocyte subsets so that these test procedures can be readily adapted in more clinical laboratories for patient evaluation in ALPS and RALD respectively. 4) Continued search for new genetic mutations in the subgroup of patients with ALPS and ALPS like disorders with undetermined genetic defects using emerging genomic and cell biology tools. Currently a large group of patients with unknown molecular etiologies are being subjected to whole exome DNA sequencing and analysis. Some novel immunedysregulatory syndromes are identified leading to validation of novel candidate genes and therapeutic targets such as pathogenic variants in the CTLA4, LRBA, STAT3 gain of function, MagT1 and PI3Kinase gene family. 5) We are actively recruiting patients for a randomized placebo controlled trial to assess the safety and efficacy of a targeted small molecule, Leniolisib (CDZ173) in patients with APDS/PASLI (Activated phosphoinositide 3-kinase delta syndrome/ p110-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency). Preliminary results are promising in six patients treated with this investigational agent and currently we plan to recruit up to 30 patients with PI3Kinase pathway genetic defects into this 2:1 placebo controlled international multicenter clinical trial. Part of this work was published in 2017: Rao VK, Webster S, Dalm VASH, ediv A, van Hagen PM, Holland S, Rosenzweig SD, Christ AD, Sloth B, Cabanski M, Joshi AD, de Buck S, Doucet J, Guerini D, Kalis C, Pylvaenaeinen I, Soldermann N, Kashyap A, Uzel G, Lenardo MJ, Patel DD, Lucas CL, Burkhart C. Effective 'Activated PI3K Syndrome'-targeted therapy with the PI3K inhibitor leniolisib. Blood. 2017 Sep 29. pii: blood-2017-08-801191. doi: 10.1182/blood-2017-08-801191. PubMed PMID: 28972011; PubMed Central PMCID: PMC5701526. Abstract:Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase (PI3K) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3K syndrome APDS). Knowing the genetic etiology of APDS afforded us the opportunity to explore PI3K inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3K in APDS. Treatment with leniolisib (CDZ173), a selective PI3K inhibitor, caused dose-dependent suppression of PI3K pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110 variants and in T-cell blasts derived from patients. A clinical trial with 6 APDS patients was conducted as a 12-week, open-label, multisite, within-subject, dose-escalation study of oral leniolisib to assess safety, pharmacokinetics, and effects on lymphoproliferation and immune dysregulation. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. We observed normalization of circulating transitional and naive B cells, reduction in PD-1+CD4+ and senescent CD57+CD4- T cells, and decreases in elevated serum immunoglobulin M and inflammatory markers including interferon , tumor necrosis factor, CXCL13, and CXCL10 with leniolisib therapy. After 12 weeks of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen volumes reduced by 39% (mean; range, 26%-57%) and 40% (mean; range, 13%-65%), respectively. Thus, leniolisib was well tolerated and improved laboratory and clinical parameters in APDS, supporting the specific inhibition of PI3K as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3K pathway. This trial was registered at as #NCT02435173.

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Comrie, William A; Faruqi, Aiman J; Price, Susan et al. (2018) RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias. J Allergy Clin Immunol 141:1507-1510.e8
Buchbinder, David; Seppanen, Mikko; Rao, V Koneti et al. (2018) Clinical Challenges: Identification of Patients With Novel Primary Immunodeficiency Syndromes. J Pediatr Hematol Oncol 40:e319-e322
Ucar, Didar; Kim, Jane S; Bishop, Rachel J et al. (2017) Ocular Inflammatory Disorders in Autoimmune Lymphoproliferative Syndrome (ALPS). Ocul Immunol Inflamm 25:703-709
Ozen, Ahmet; Comrie, William A; Ardy, Rico C et al. (2017) CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med 377:52-61
Rao, V Koneti; Webster, Sharon; Dalm, Virgil A S H et al. (2017) Effective ""activated PI3K? syndrome""-targeted therapy with the PI3K? inhibitor leniolisib. Blood 130:2307-2316
Dulau Florea, Alina E; Braylan, Raul C; Schafernak, Kristian T et al. (2017) Abnormal B-cell maturation in the bone marrow of patients with germline mutations in PIK3CD. J Allergy Clin Immunol 139:1032-1035.e6
Xie, Yi; Pittaluga, Stefania; Price, Susan et al. (2017) Bone marrow findings in autoimmune lymphoproliferative syndrome with germline FAS mutation. Haematologica 102:364-372
Weinreich, Michael Alexander; Vogel, Tiphanie P; Rao, V Koneti et al. (2017) Up, Down, and All Around: Diagnosis and Treatment of Novel STAT3 Variant. Front Pediatr 5:49
Rao, V Koneti (2016) Serendipity in splendid isolation: rapamycin. Blood 127:5-6
Cruz, Anthony C; Ramaswamy, Madhu; Ouyang, Claudia et al. (2016) Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction. Nat Commun 7:13895

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