Clinical, Immunological and Genetic Analyses of ALPS and Related Immunedysregulatory Disorders

National Institute Of Allergy And Infectious Diseases

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Abstract

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 with 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) Continued search for novel pathogenic genetic variants 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 and most recently TLR8 genetic disorder. 5) We completed enrolling 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). We have recruited 19 patients in our clinic at NIHCC into this 2:1 placebo controlled international multicenter clinical trial, so that this investigational agent can be licensed for this rare genetic disease. Data analysis is in progress for this study and we hope to publish our results soon. Reference: 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.