Elucidating the pathogenesis of adenosine deaminase 2 deficiency: current status and unmet needs
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Abstract
Introduction
Humans have two adenosine deaminase isozymes, ADA1 and ADA2, which differ in affinity for their substrates, adenosine (Ado) and 2ʹdeoxyadenosine (dAdo), and their localization. Inherited deficiencies of ADA1 and ADA2 compromise different aspects of immune and hematological function. The metabolic consequences of ADA1 deficiency show that its enzymatic (ADA) activity is central to its biological function. By contrast, the function of ADA2 is uncertain and no direct metabolic consequences of the deficiency of ADA2 (DADA2) have yet been identified. Several potential pathogenetic mechanisms related to, or independent of, ADA2 enzymatic activity have been proposed.
Areas covered
We will review the discovery of ADA2 and DADA2, and two principal hypotheses: that ADA2 regulates the concentration of extracellular Ado and/or that it is a growth factor. We will consider two newer proposals that involve the effects of ADA2 products rather than its substrates, one of which postulates a pathogenic role for elevated levels of ADA2.
Expert opinion
Some currently proposed mechanisms of DADA2 pathogenesis are controversial or contradictory, and supportive evidence is inadequate. Progress in several areas may clarify the function of ADA2 and facilitate the development of new therapies for DADA2 based on elucidation of its pathogenesis.
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Tarrant, TK, Susan J Kelly and Michael S Hershfield (n.d.). Elucidating the pathogenesis of adenosine deaminase 2 deficiency: current status and unmet needs. Expert opinion on orphan drugs, 9(11-12). pp. 257–264. 10.1080/21678707.2021.2050367 Retrieved from https://hdl.handle.net/10161/25636.
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Scholars@Duke
Teresa Kathleen Tarrant
I first became interested in clinical immunology as a medical student studying autoimmune inflammatory eye disease at the National Institutes of Health. Since then, I have been inspired to understand what causes autoimmunity and immune deficiency disorders in order to improve the quality of life for my patients. I see patients with multiple complex immune disorders with particular expertise in autoimmune and Rheumatoid arthritis, primary Sjogren's syndrome, and the immunodeficiency disorders Common Variable Immunodeficiency (CVID), Adenosine Deaminase Deficiency (ADA) disorders, and WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis). My research investigates immune targets that may impact either the development of immune disease or identify new therapies for patients. The goal is to help us understand why and how immunologic diseases develop so that we may better treat them.
Michael Steven Hershfield
Molecular Basis and Therapy of Inherited Disorders of Purine Metabolism
ABSTRACT
We have a longstanding interest in inherited disorders of purine metabolism. Our primary focus has been the combined immunodeficiency disease caused by inherited deficiency of adenosine deaminase (ADA1) and purine nucleoside phosphorylase (PNP), an more recently the deficiency of the enzyme ADA2. In addition to these rare recessive disorders, we have maintained an interest in gout, the most common purine metabolic disease. We have also investigated the biochemistry, metabolism, and biological effects of nucleoside analogs, including their use for treating neoplastic and viral diseases.
During our first decade at Duke we studied the biochemical mechanisms responsible for immune deficiency caused by ADA and PNP deficiency. We subsequently investigated the operation of these mechanisms in vivo in collaboarative studies of ADA knockout mice and in ADA-deficient patients. We defined the molecular basis for the interaction between human ADA and CD26/Dipeptidyl Peptidase IV (DPPIV), a cell membrane associated multifunctional glycoprotein, also known as the adenosine deaminase complexing protein. This work has cast doubt on the postulated role of the ADA-DPPIV complex, or "ecto-ADA", in normal immune function.
About 40 years ago, in collaboration with Dr. Rebecca Buckley, we initiated, and subsequently played a central role in the clinical development of polyethylene glycol (PEG)-modified adenosine deaminase (PEG-ADA) as replacement therapy for severe combined immunodeficiency disease (SCID) due to ADA1 deficiency. PEG-ADA was the first PEG-modified therapeutic agent to receive USFDA approval (in 1990), and the first effective form of enzyme replacement therapy for an inherited metabolic disease. We have also collaborated in evaluating the metabolic efficacy of stem cell transplantation and stem cell gene therapy for treating ADA- SCID. We have systematically investigated the mutational basis for ADA deficiency, and the relationship between genotype and phenotype, both clinical and metabolic. For this purpose we developed a system for scoring ADA missense variants based on quantitating their effects on expression of ADA activity in an ADA-deleted strain of E. coli.
Over the past 4+ decades we have served as a worldwide resource for establishing the diagnosis of ADA1 and PNP deficiency, and to monitor the metabolic effects of PEG-ADA therapy as well as ADA gene therapy and stem cell transplantation in patients with ADA deficiency in the US and over 20 other countries. Over the past 15 years we have also served as a resource for functional testing to diagnose ADA2 deficiency (DADA2). Our laboratory is one of the few that has maintained CLIA certification for the above testing (for which we have never charged).
In addition to our work on rare inherited disorders we have conducted groundbreaking translational research related to gout, the most common disorder of purine metabolism in humans. We developed a PEGylated recombinant urate oxidase (Pegloticase, Krystexxa) as an Orphan Drug for treating patients with refractory gout and poorly controlled hyperuricemia. After demonstrating the effectiveness of Pegloticase in preventing uric acid nephropathy in a urate oxidase knockout mouse model, we participated with John Sundy and other members of the Duke Rheumatology division in the first in-human phase 1 clinical trials of Pegloticase in patients with refractory gout. We subsequently obtained support from the USFDA Office of Orphan Products Development to conduct a Phase II clinical study of Pegloticase in order to optimize dosing and assess the potential effects of profoundly reducing serum uric acid levels on oxidative stress status. We discovered the ability of treatment with pegloticase to induce antibodies to the PEG polymer, an observation relvant to the immune response to other PEGylated proteins and lipid nanaoparticles that contain PEG. In 2010 Pegloticase was one of 21 new drugs to receive FDA approval.
Keywords: human genetic disease; enzyme replacement therapy; polyethylene glycol modified enzymes; mutation; immune deficiency disease; ADA deficiency; purine nucleoside phosphorylase deficiency; gout
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