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A. Schambach

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Open access Jul 2026

Autologous Ex Vivo Lentiviral Gene Therapy for Severe Leukocyte Adhesion Deficiency-I Achieves Durable Immune Reconstitution and Reduction of Infection-Related Morbidity: Updated 3.5-5.5-Year Results from a Phase I/II Study

Severe leukocyte adhesion deficiency-I (LAD-I) is caused by biallelic deleterious variants in ITGB2, resulting in <2% CD18 expression and impaired leukocyte extravasation, particularly neutrophils. Affected infants and children experience recurrent, life-threatening bacterial and fungal infections, poor wound healing, and significant mortality in the absence of allogeneic hematopoietic stem cell transplantation (alloHSCT). Although alloHSCT can be curative, many patients lack suitable donors and remain at risk for graft-versus-host disease (GvHD), graft failure, and transplant-related morbidity and mortality. Treatment with a durable autologous hematopoietic stem cell (HSC) gene therapy was developed to address these limitations. To evaluate the long-term safety and efficacy of RP-L201 (marnetegragene autotemcel), an autologous CD34+ HSC gene therapy using a Chim-CD18-WPRE lentiviral vector incorporating ITGB2, we investigated restoration of CD18 expression, normalization of neutrophil function, and reduction in infection-related morbidity in children with severe LAD-I. Children ≥3 months old with severe LAD-I were enrolled in the phase I/II study (NCT03812263). CD34+ cells obtained via G-CSF/plerixafor mobilization and apheresis were transduced ex vivo with RP-L201 and infused following therapeutic drug-monitored myeloablative conditioning. Endpoints included survival without alloHSCT, restoration of peripheral blood (PB) polymorphonuclear (PMN) CD18 expression, peripheral blood mononuclear cell (PBMC) vector copy number (VCN), integration site analysis, resolution of baseline leukocytosis, and incidence of infection-related hospitalizations. All treated patients entered the long-term follow-up (LTFU) study (NCT06282432). Nine patients (age 9.8-117.4 months at infusion) received RP-L201 and were followed for a median (range) of 50.92 (42.6-67.9) months as of the June 18, 2025, LTFU data cut. AlloHSCT-free survival was 100% with no cases of graft failure. PBMC VCN/cell rose to 0.42-2.4 at month 3 and remained stable through month 12 (mean 1.73) with persistent long-term VCN levels across months 42-60. All patients achieved sustained PB PMN CD18 expression within or approaching the target levels, maintained through >3.5 years post-infusion. Longer-term results demonstrate markedly lower annualized incidences of prespecified serious infections, infection-related hospitalizations, and prolonged infection-related hospitalizations after RP-L201 treatment relative to pre-treatment incidences. No new skin or oral infections occurred in the LTFU period. RP-L201 was well-tolerated; no RP-L201-related adverse events occurred. Integration site analyses demonstrated polyclonal integration patterns without dominant or expanding clones. RP-L201 conferred durable engraftment, sustained CD18 restoration, and significant reductions in infection-related morbidity in nine children with severe LAD-I, with at least 3.5 years of follow-up. All nine patients are alive without alloHSCT. There were no RP-L201-related adverse events. These updated results support autologous HSC gene therapy as an effective alternative to alloHSCT with a favorable risk-benefit profile for severe LAD-I.

C. Booth, J. Sevilla, E. Almarza et al. · 0 citations
Aug 2026

Novel VSV-G Variants with Enhanced Blinding for Targeted Delivery of Lentiviral Vectors

Targeted in vivo transduction, entailing direct administration of viral vector preparations to patients, is the next big step in gene therapy. To redirect lentiviral vector (LV) particles selectively to desired cell type(s), different glycoproteins have been engineered to alter their tropism, including the glycoprotein G from Vesicular Stomatitis Virus (VSV-G) as the most commonly employed tropism-defining protein for LV particles. For detargeting from its natural receptor, the low-density lipoprotein receptor (LDLR), a VSV-G variant with two blinding substitutions, K47Q and R354A, is commonly used (VSV-G.pub). We provide first evidence for insufficient blinding of VSV-G.pub in human and murine cell lines and primary cells. In silico modeling pointed toward only slightly reduced LDLR binding affinity of VSV-G.pub. To lower the affinity further, we generated three novel VSV-G variants based on charge-reversing substitutions in two, four, or six key residues. These variants achieved a more stringent blinding compared with VSV-G.pub in the tested cell lines and primary cells. Codisplay of a CD4 binder enabled lentiviral particles pseudotyped with the novel variants to selectively transduce CD4-expressing cells. In summary, we present improved VSV-G variants with a better on/off-target ratio as attractive tools for in vivo gene therapy applications.

Felix L. Warnecke, M. Ertelt, Anjali Shrivastava et al. · 0 citations
Review Jul 2026

Addressing the package: Cell-specific gene delivery using lentiviral vectors.

Lentiviral vectors have revolutionized gene therapy by efficient and stable transduction of dividing and non-dividing cells, their large packaging capacity, and their compatibility with pseudotyping to alter viral tropism. The vesicular stomatitis virus glycoprotein (VSV-G) is widely used as a viral envelope protein of choice to pseudotype lentiviral vector particles as it confers exceptional particle stability and a broad tropism, due to the ubiquitous nature of the low-density lipoprotein receptor (LDLR). While this broad tropism facilitates transduction of diverse cell types, it precludes accurate in vivo targeting of specific cell populations. Structural insights into VSV-G have made receptor-blinding possible and revealed sites amenable to mutation while preserving fusion capacity. Coupled with targeting moieties, VSV-G pseudotyped lentiviral particles are redirected towards cells expressing target antigens. Such targeted vectors open new possibilities for in vivo gene therapy across oncology, infectious diseases, transplantation medicine, and other diseases. Use of targeted vectors will make in vivo gene therapy more accessible than cost-intensive ex vivo gene therapies. Since targeted vectors will be available as 'off-the-shelf' drugs, they will also drastically reduce time-to-treatment. This review highlights advances in bioengineering to exploit the versatility of VSV-G-pseudotyped lentiviral vectors and explores their vast potential for targeted gene delivery.

Anjali Shrivastava, Felix L. Warnecke, J. Schott et al. · 0 citations