Long-term efficacy of enzyme replacement therapy for Adenosine deaminase (ADA)-deficient Severe Combined Immunodeficiency (SCID)

doi:10.1016/j.clim.2005.07.006

Clinical Immunology

Volume 117, Issue 2, November 2005, Pages 133-143

https://doi.org/10.1016/j.clim.2005.07.006 Get rights and content

Abstract

Adenosine deaminase (ADA)-deficient Severe Combined Immunodeficiency (ADA-deficient SCID) is characterized by impaired lymphocyte development and function resulting from the adenosine metabolism defect. Enzyme replacement therapy with polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) minimizes infectious complications of ADA-deficient patients who have not received bone marrow transplantation. In PEG-ADA therapy, enzymatically active ADA continuously circulates to act as a metabolic sink, detoxifying the adenosine and deoxyadenosine metabolites that accumulate to high levels in the absence of ADA. Studies have shown that upon the initiation of PEG-ADA therapy, the absolute numbers of circulating T and B lymphocytes and NK cells increase and protective immune function develops. However, the long-term efficacy is unknown. This retrospective study was designed to assess the long-term effectiveness of PEG-ADA treatment, based on evaluation of the immune function of nine ADA-deficient SCID patients (age 5–15) treated over the past decade. The results showed that the lymphocyte counts of all of the PEG-ADA treated patients were below the normal range at all times, despite initial improvements. A gradual decline of mitogenic proliferative responses occurred after a few years of treatment and normal antigenic response occurred less than expected. To this date, these low numbers and functions of lymphocytes had been adequate to provide protective immunity. These patients should be followed closely to detect a premature decline in immune function with aging in future decades of PEG-ADA therapy.

Introduction

Adenosine deaminase (ADA)-deficient Severe Combined Immunodeficiency (ADA-deficient SCID) is a fatal disease if not treated by bone marrow transplantation or enzyme replacement therapy [1]. ADA degrades adenosine and deoxyadenosine into inosine and deoxyinosine, which are broken down into uric acid. ADA enzyme deficiency results in the build-up of toxic metabolites, including deoxyribonucleotides (dAXP), which inhibit lymphocyte maturation and survival. Patients suffer from pan-lymphopenia (T, B and NK lymphocytes), defective lymphocyte functions, and are susceptible to life-threatening infection. Allogeneic bone marrow transplantation can be curative, but the outcome for patients transplanted from other than HLA-matched sibling donors is generally poor. Gene therapy by gene correction of autologous hematopoietic stem cells has been under development for the past 15 years, with recent successes reported.

ADA enzyme replacement therapy was first evaluated in 1986 for SCID patients lacking HLA matched bone marrow donors [2]. Bovine adenosine deaminase, that can catabolize toxic adenosine and deoxyadenosine metabolites, is conjugated with polyethylene glycol (PEG) to prolong circulation of ADA enzyme in the blood. After initiating intramuscular injection of PEG-ADA biweekly, ADA-deficient SCID patients have shown improvement of their immune function, with a good quality of life, free of opportunistic infections [3], [4]. Studies have indicated that PEG-ADA allows an initial differentiation of T lymphocytes from immature thymic precursors and reconstitution of functional lymphocytes in the peripheral blood [3]. PEG-ADA enzyme replacement therapy is limited by requiring chronic ongoing therapy, and its cost may exceed $200,000–$300,000 per patient annually.

While initial improvement of immunity upon beginning PEG-ADA therapy has been documented, the long-term effects on the immune system have not been well characterized. To determine the long-term efficacy of PEG-ADA, we investigated the immunological functions of nine ADA-deficient SCID patients treated with PEG-ADA over a 12 year period, based on enumeration of their lymphocyte populations and in vitro lymphocyte proliferation assays.

Section snippets

Patients' profile

This study is a retrospective chart review of nine ADA-deficient SCID patients followed at Childrens Hospital Los Angeles (CHLA), the University of California at San Francisco (UCSF), and Children's Hospital San Diego (CHSD) during the period of April 1990 to November 2002. Medical records and immunological assay results spanning this time period were reviewed. This retrospective study was approved by the Institutional Review Boards of Childrens Hospital Los Angeles, University of California at

Clinical characteristics

The medical records were reviewed from nine ADA-deficient SCID patients covering the time period from April 1990 to November 2002. Demographic and clinical data of the patient cohort are summarized in Table 1. In the cohort, three patients were female and six were male. They were between 5 and 15 years old in 2002. ADA-deficient SCID was diagnosed at birth or up to 6.5 years of age. Most of the patients presented with recurrent opportunistic infections with delayed growth and development as

Discussion

We report clinical and laboratory studies on a cohort of nine ADA-deficient SCID patients treated for 5–12 years with enzyme replacement therapy using PEG-ADA. Most of these patients were in overall good health over this time, with the absence of major infections. This clinical course is far superior to the expected course with recurrent severe, life-threatening infections that would occur without intervention, demonstrating the ability of PEG-ADA therapy to be beneficial for at least a decade

Acknowledgments

DBK and BC were supported by a Distinguished Clinical Scientist Award from the Doris Duke Charitable Foundation. MSH was supported by NIH RO1 DK20902, and by a grant from Enzon Pharmaceuticals, the manufacturer of PEG-ADA. Statistical support for this study was provided by the General Clinical Research Center at Children's Hospital Los Angeles (NIH NCRR Grant MO1 RR-43). We wish to thank the laboratory technicians of the Clinical Transplant Immunology Laboratory of Children's Hospital Los

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ADAGEN, a bovine-based enzyme replacement therapy (ERT), has been used to treat adenosine deaminase severe combined immunodeficiency (ADA-SCID). In 2018, ADAGEN was replaced by REVCOVI (elapegademase), a modified bovine recombinant protein.
To determine the real-life long-term benefits of REVCOVI in ADA-SCID.
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REVCOVI is effective for the management of ADA-SCID.
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Long-term efficacy of enzyme replacement therapy for Adenosine deaminase (ADA)-deficient Severe Combined Immunodeficiency (SCID)

Abstract

Introduction

Section snippets

Patients' profile

Clinical characteristics

Discussion

Acknowledgments

J. Allergy Clin. Immunol.

J. Biol. Chem.

Blood

Lancet

Combined immune deficiencies due to purine enzyme defects

Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase

N. Engl. J. Med.

T lymphocyte ontogeny in adenosine deaminase-deficient severe combined immune deficiency after treatment with polyethylene glycol-modified adenosine deaminase

J. Clin. Invest.