Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency

Abstract

BACKGROUNDSevere combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. METHODSWe treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up. RESULTSOverall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade. CONCLUSIONSTreatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.

EBMT/ESID inborn errors working party guidelines for hematopoietic stem cell transplantation for inborn errors of immunity

“…In recent years, stem cell gene addition therapy (GT) has been explored for a limited number of IEI, including ADA-SCID, X-linked SCID, XL-CGD, and WAS. A retroviral ADA GT product (Strimvelis®) is licensed by the European Medicines Agency, and recently excellent results have been reported with lentiviral-based ADA GT [ 14 ]. There are ongoing clinical studies in a variety of other IEI [ 15 ].…”

Modular Lentiviral Vectors for Highly Efficient Transgene Expression in Resting Immune Cells

“…Thus, there is often the burden of choice during the development of gene/cell therapies as to which vector is best to mediate a therapeutic effect. Lentivirus-mediated gene therapy has shown promising results in recent years [ 44 , 45 , 46 ] and has been established to be one of the preferred tools for ex vivo gene delivery, showing wide adoption to treat human diseases. Therefore, we strongly argue in support of leveraging lentiviral vectors to mediate gene/cell therapy.…”

Designing Lentiviral Vectors for Gene Therapy of Genetic Diseases

“…The same design has been used in LVs for gene therapy for ADA-deficient and radiosensitive (RS) SCID. In the first case, sustained ADA expression resulted in metabolic correction, functional immune reconstitution and 100% survival in a large, multicenter clinical trial [ 10 ]. In the case of RS-SCID, however, the expression level of DCLRE1C/Artemis, a DNA repair protein, turned out to be too high both in vitro and in vivo, causing cell apoptosis and reducing the HSC repopulating capacity in an animal model of the disease.…”

“…These studies were the basis for the development of a safer and more efficacious vectors, derived from the human immunodeficiency lentivirus (HIV) and carrying carefully designed transgene expression cassettes based on cellular promoters and regulatory elements [ 6 ]. A number of seminal clinical studies addressing primary immunodeficiencies [ 7 , 8 , 9 , 10 ], hemoglobinopathies [ 11 , 12 ], stem cell deficiencies [ 13 ] and neurometabolic diseases [ 14 , 15 , 16 , 17 ] proved the therapeutic efficacy and safety of lentiviral vectors, which eventually allowed the commercial registration of Zynteglo ® for gene therapy of β-thalassemia ( , accessed on 1 August 2021) and Libmeldi ® for metachromatic leukodystrophy (MLD) ( , accessed on 1 August 2021).…”