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

Chan, Belinda; Wara, Diane W.; Bastian, John F.; Hershfield, Michael S.; Bohnsack, John F.; Azen, Colleen; Parkman, Robertson; Weinberg, Kenneth I.; Kohn, Donald B.

doi:10.1016/j.clim.2005.07.006

Cited by 156 publications

(93 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It was hypothesized that providing the active enzyme outside PNP-deficient cells creates a concentration gradient that removes the toxic purine nucleosides from inside the cells, thereby allowing recovery of the immune system (8). Yet prior studies of PNP-deficient patients (10) and ADAdeficient patients treated for extended periods with extracellular enzyme replacement therapy such as PEG-ADA have shown the benefit was only partial (52,53). Similarly, we observed limited benefit with nonfused PNP treatment, possibly reflecting an inability to adequately transfer nucleosides across membranes, which is dependent on nucleoside transporters (56).…”

Section: Figurecontrasting

confidence: 44%

“…Moreover, in many conditions, including hemophilia, ADA deficiency, Gaucher disease, and others, enzyme replacement therapy is used over the course of many years (37,(52)(53)(54); thus we anticipated that TAT-PNP may also be required for extended periods. Therefore we extended the treatment of TAT-PNP PTD in PNP -/-mice, which also provided additional confidence about the successful effect of TAT-PNP PTD treatment on mortality.…”

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

TAT-mediated intracellular delivery of purine nucleoside phosphorylase corrects its deficiency in mice

Toro-Montoya¹,

Grunebaum²

2006

Journal of Clinical Investigation

View full text Add to dashboard Cite

Defects in purine nucleoside phosphorylase (PNP) enzyme activity result in abnormal nucleoside homeostasis, severe T cell immunodeficiency, neurological dysfunction, and early death. Protein transduction domain (PTD) can transfer molecules into cells and may help restore PNP activity in cases of PNP deficiency. However, long-term use of PTD to replace enzymes in animal models or patients has not previously been described. We fused human PNP to the HIV-TAT PTD and found that the fusion with TAT changed the retention and distribution of PNP in PNP-deficient mice. TAT induced rapid intracellular delivery of PNP into tissues, including the brain, prevented urinary excretion of PNP, and protected PNP from neutralizing antibodies, resulting in significant extension of the enzyme's biological activity in vivo. Frequent TAT-PNP injections in PNP-deficient mice corrected the metabolic disorder and immune defects with no apparent toxicity. TAT-PNP remained effective over 24 weeks of treatment, resulting in continued improvement in immune function and extended survival. Our data demonstrate that TAT changes the properties of PNP in vivo and that long-term intracellular delivery of PNP by TAT corrects PNP deficiency in mice. We provide evidence to promote further use of PTD to treat diseases that require repeated intracellular enzyme or protein delivery.

show abstract

Section: Figurecontrasting

confidence: 44%

Section: Figurementioning

confidence: 99%

TAT-mediated intracellular delivery of purine nucleoside phosphorylase corrects its deficiency in mice

Toro-Montoya¹,

Grunebaum²

2006

Journal of Clinical Investigation

View full text Add to dashboard Cite

show abstract

“…12 Survival may be as high as 78% over 20 years. However, PEG-ADA is expensive and has limited availability in some countries, 14 while decreasing lymphocyte counts and functionality over time (possibly because of the development of anti-ADA neutralizing antibodies 3 ) leave patients susceptible to infection, autoimmunity, and malignancy. 14,15 Autologous transplant of hematopoietic stem cells corrected by gene transfer has been investigated as an alternative therapeutic approach.…”

Section: Introductionmentioning

confidence: 99%

Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency

Cicalese

Ferrua

Castagnaro

et al. 2016

Blood

181

146

View full text Add to dashboard Cite

show abstract

“…Reports suggest that, despite being well detoxified, patients on long-term PEG-ADA have T-cell numbers that are well below normal levels. 23 The specific reasons for this are unclear, but data suggest that intracellular ADA expression either through transplantation of wild-type cells or GT of autologous cells corrects T-cell function more effectively than exogenous enzyme replacement. 24 B-cell function and in particular antigen diversity is affected by the build up of dATP as a consequence of ADA deficiency.…”

Section: Discussionmentioning

confidence: 99%

Outcome of hematopoietic stem cell transplantation for adenosine deaminase–deficient severe combined immunodeficiency

Hassan¹,

Booth²,

Brightwell³

et al. 2012

Blood

159

134

View full text Add to dashboard Cite

Deficiency of the purine salvage enzyme adenosine deaminase leads to SCID (ADA-SCID). Hematopoietic cell transplantation (HCT) can lead to a permanent cure of SCID; however, little data are available on outcome of HCT for ADA-SCID in particular. In this multicenter retrospective study, we analyzed outcome of HCT in 106 patients with ADA-SCID who received a total of 119 transplants. HCT from matched sibling and family donors (MSDs, MFDs) had significantly better overall survival (86% and 81%) in comparison with HCT from matched unrelated (66%; P < .05) and haploidentical donors (43%; P < .001). Superior overall survival was also seen in patients who received unconditioned transplants in comparison with myeloablative procedures (81% vs 54%; P < .003), although in unconditioned haploidentical donor HCT, nonengraftment was a major problem. Long-term immune recovery showed that regardless of transplant type, overall T-cell numbers were similar, although a faster rate of T-cell recovery was observed after MSD/MFD HCT. Humoral immunity and donor B-cell engraftment was achieved in nearly all evaluable surviving patients and was seen even after unconditioned HCT. These data detail for the first time the outcomes of HCT for ADA-SCID and show that, if patients survive HCT, long-term cellular and humoral immune recovery is achieved. (Blood. 2012;120(17):3615-3624)

show abstract

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

Cited by 156 publications

References 12 publications

TAT-mediated intracellular delivery of purine nucleoside phosphorylase corrects its deficiency in mice

TAT-mediated intracellular delivery of purine nucleoside phosphorylase corrects its deficiency in mice

Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency

Outcome of hematopoietic stem cell transplantation for adenosine deaminase–deficient severe combined immunodeficiency

Contact Info

Product

Resources

About