Gene therapy for Wiskott-Aldrich syndrome: History, new vectors, future directions

Ferrua, Francesca; Marangoni, Francesco; Aiuti, Alessandro; Roncarolo, Maria Grazia

doi:10.1016/j.jaci.2020.06.018

Cited by 37 publications

(22 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Blood tests and nasopharyngeal swabs were monitored weekly, showing mild increase in inflammatory indexes (Figure 2A), without lymphopenia. During infection period platelets ranged between 21 and 55 *10 9 /L (patient on ongoing TPO-agonist treatment) and showed normal volume, as expected based on previous studies (7,12). There was no evidence of pro-coagulant status, hyperferritinemia or dyslipidemia.…”

Section: Case Presentationsupporting

confidence: 75%

“…WAS is a PID associated with micro-thrombocytopenia, recurrent or severe infections, eczema and increased risk to develop autoimmune and autoinflammatory manifestations, which represented the main clinical features of our patient at disease onset (7). While antiviral treatment (HCQ + LPV/r) was started precociously in our patient, it was not sufficient to induce SARS-CoV-2 viral clearance, with specific swabs remaining positive for 40 days, at the higher range of asymptomatic patients (14).…”

Section: Discussionmentioning

confidence: 76%

See 1 more Smart Citation

Mild SARS-CoV-2 Infection After Gene Therapy in a Child With Wiskott-Aldrich Syndrome: A Case Report

et al. 2020

Self Cite

View full text Add to dashboard Cite

In this work we present the case of SARS-CoV-2 infection in a 1.5-year-old boy affected by severe Wiskott-Aldrich Syndrome with previous history of autoinflammatory disease, occurring 5 months after treatment with gene therapy. Before SARS-CoV-2 infection, the patient had obtained engraftment of gene corrected cells, resulting in WASP expression restoration and early immune reconstitution. The patient produced specific immunoglobulins to SARS-CoV-2 at high titer with neutralizing capacity and experienced a mild course of infection, with limited inflammatory complications, despite pre-gene therapy clinical phenotype.

show abstract

Section: Case Presentationsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 76%

Mild SARS-CoV-2 Infection After Gene Therapy in a Child With Wiskott-Aldrich Syndrome: A Case Report

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…This is not surprising since WASP knock-out CD34+ cells will not engraft in NSG mice if the KNOCK-out is not > 90% since they have a selective disadvantage compared to WASP-positive CD34 + cells (Mani et al, 2009 ). Moreover, from clinical trials it became clear that the WAS gene therapy conferred selective proliferative advantage for WASP expressing T and B cells and probably also HSCs (Ferrua et al, 2020 , JACI).…”

Section: Discussionmentioning

confidence: 99%

Baboon Envelope Pseudotyped “Nanoblades” Carrying Cas9/gRNA Complexes Allow Efficient Genome Editing in Human T, B, and CD34+ Cells and Knock-in of AAV6-Encoded Donor DNA in CD34+ Cells

et al. 2021

View full text Add to dashboard Cite

Programmable nucleases have enabled rapid and accessible genome engineering in eukaryotic cells and living organisms. However, their delivery into human blood cells can be challenging. Here, we have utilized “nanoblades,” a new technology that delivers a genomic cleaving agent into cells. These are modified murine leukemia virus (MLV) or HIV-derived virus-like particle (VLP), in which the viral structural protein Gag has been fused to Cas9. These VLPs are thus loaded with Cas9 protein complexed with the guide RNAs. Highly efficient gene editing was obtained in cell lines, IPS and primary mouse and human cells. Here, we showed that nanoblades were remarkably efficient for entry into human T, B, and hematopoietic stem and progenitor cells (HSPCs) thanks to their surface co-pseudotyping with baboon retroviral and VSV-G envelope glycoproteins. A brief incubation of human T and B cells with nanoblades incorporating two gRNAs resulted in 40 and 15% edited deletion in the Wiskott-Aldrich syndrome (WAS) gene locus, respectively. CD34+ cells (HSPCs) treated with the same nanoblades allowed 30–40% exon 1 drop-out in the WAS gene locus. Importantly, no toxicity was detected upon nanoblade-mediated gene editing of these blood cells. Finally, we also treated HSPCs with nanoblades in combination with a donor-encoding rAAV6 vector resulting in up to 40% of stable expression cassette knock-in into the WAS gene locus. Summarizing, this new technology is simple to implement, shows high flexibility for different targets including primary immune cells of human and murine origin, is relatively inexpensive and therefore gives important prospects for basic and clinical translation in the area of gene therapy.

show abstract

“…Subsequently, three clinical trials in the United States and Europe have used CD34+ peripheral blood stem cells transduced with a self-inactivating lentiviral vector containing a WAS cDNA with expression controlled by the endogenous WAS promoter [reviewed in (51)(52)(53)(54)(55)(56)(57)]. The four centers each used slightly different conditioning regiments, with busulfan dosed for non-myeloablative or myeloablative targets, fludarabine used at 60 or 120 mg/m 2 and two of the four trials including anti-CD20 monoclonal.…”

Section: Wiskott-aldrich Syndromementioning

confidence: 99%

“…These trials have treated at least 34 patients, with 91.5% aggregate survival ( 51 ). Despite WASP levels below normal, patients had improvement of immune function with increased T cell proliferation, vaccine antibody responses allowing discontinuation of immunoglobulin supplementation in most patients, and decreased infections.…”

Section: Wiskott-aldrich Syndromementioning

confidence: 99%

Gene Therapies for Primary Immune Deficiencies

Kohn

2021

Front. Immunol.

View full text Add to dashboard Cite

Gene therapy is an innovative treatment for Primary Immune Deficiencies (PIDs) that uses autologous hematopoietic stem cell transplantation to deliver stem cells with added or edited versions of the missing or malfunctioning gene that causes the PID. Initial studies of gene therapy for PIDs in the 1990–2000's used integrating murine gamma-retroviral vectors. While these studies showed clinical efficacy in many cases, especially with the administration of marrow cytoreductive conditioning before cell re-infusion, these vectors caused genotoxicity and development of leukoproliferative disorders in several patients. More recent studies used lentiviral vectors in which the enhancer elements of the long terminal repeats self-inactivate during reverse transcription (“SIN” vectors). These SIN vectors have excellent safety profiles and have not been reported to cause any clinically significant genotoxicity. Gene therapy has successfully treated several PIDs including Adenosine Deaminase Severe Combined Immunodeficiency (SCID), X-linked SCID, Artemis SCID, Wiskott-Aldrich Syndrome, X-linked Chronic Granulomatous Disease and Leukocyte Adhesion Deficiency-I. In all, gene therapy for PIDs has progressed over the recent decades to be equal or better than allogeneic HSCT in terms of efficacy and safety. Further improvements in methods should lead to more consistent and reliable efficacy from gene therapy for a growing list of PIDs.

show abstract

Gene therapy for Wiskott-Aldrich syndrome: History, new vectors, future directions

Cited by 37 publications

References 10 publications

Mild SARS-CoV-2 Infection After Gene Therapy in a Child With Wiskott-Aldrich Syndrome: A Case Report

Mild SARS-CoV-2 Infection After Gene Therapy in a Child With Wiskott-Aldrich Syndrome: A Case Report

Baboon Envelope Pseudotyped “Nanoblades” Carrying Cas9/gRNA Complexes Allow Efficient Genome Editing in Human T, B, and CD34+ Cells and Knock-in of AAV6-Encoded Donor DNA in CD34+ Cells

Gene Therapies for Primary Immune Deficiencies

Contact Info

Product

Resources

About