Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome.

[omenn syndrome]

Recombination-activating gene 1 (RAG 1 ) deficiency results in severe combined immunodeficiency (SCID ) caused by a complete lack of T and B lymphocytes . If untreated , patients succumb to recurrent infections .We sought to develop lentiviral gene therapy for RAG 1 -induced SCID and to test its safety .Constructs containing the viral spleen-focus-forming virus (SF ), ubiquitous promoters , or cell type -restricted promoters driving sequence-optimized RAG 1 were compared for efficacy and safety in sublethally preconditioned Rag 1 (-/-) mice undergoing transplantation with transduced bone marrow progenitors .Peripheral blood CD 3 (+) T -cell reconstitution was achieved with SF , ubiquitous promoters , and cell type -restricted promoters but 3 - to 18 -fold lower than that seen in wild-type mice , and with a compromised CD 4 (+)/CD 8 (+) ratio . Mitogen-mediated T -cell responses and T cell-dependent and T cell-independent B-cell responses were not restored , and T -cell receptor patterns were skewed . Reconstitution of mature peripheral blood B cells was approximately 20 -fold less for the SF vector than in wild-type mice and often not detectable with the other promoters , and plasma immunoglobulin levels were abnormal . Two months after transplantation , gene therapy-treated mice had rashes with cellular tissue infiltrates , activated peripheral blood CD 44 (+)CD 69 (+) T cells , high plasma IgE levels , antibodies against double -stranded DNA , and increased B cell-activating factor levels . Only rather high SF vector copy numbers could boost T - and B-cell reconstitution , but mRNA expression levels during T - and B-cell progenitor stages consistently remained less than wild-type levels .These results underline that further development is required for improved expression to successfully treat patients with RAG 1 -induced SCID while maintaining low vector copy numbers and minimizing potential risks , including autoimmune reactions resembling Omenn syndrome .

Diseases
Validation

Diseases presenting "peripheral blood" symptom

adrenomyeloneuropathy

allergic bronchopulmonary aspergillosis

aniridia

cohen syndrome

congenital toxoplasmosis

cutaneous mastocytosis

erdheim-chester disease

esophageal adenocarcinoma

esophageal squamous cell carcinoma

familial mediterranean fever

gm1 gangliosidosis

junctional epidermolysis bullosa

lamellar ichthyosis

monosomy 21

oligodontia

omenn syndrome

scrub typhus

severe combined immunodeficiency

typhoid

von hippel-lindau disease

waldenström macroglobulinemia

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

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