RARE DISEASE
Leukocyte adhesion deficiency type I
Leukocyte adhesion deficiency type I
Leukocyte adhesion deficiency type I
Synonyms: LAD-I
Synonyms: LAD-I
Synonyms: LAD-I
Drug discovery
2
drugs
With orphan designations
Overview
Leukocyte Adhesion Deficiency Type I (LAD-I) is a rare autosomal recessive immunodeficiency caused by ITGB2 gene mutations, leading to deficient CD18 β2-integrin expression on leukocytes. This impairs neutrophil adhesion and migration, resulting in recurrent bacterial/fungal infections, delayed umbilical cord separation (>3 weeks), severe gingivoperiodontitis, and absent pus formation. Diagnosis relies on flow cytometry (CD18 <2-30%) and genetic testing. Management includes aggressive antimicrobials, prophylactic antibiotics, and hematopoietic stem cell transplantation (HSCT), the only curative option [1][6][11][16].
Burden
Mortality: >60% mortality by age 2 in severe CD18 deficiency (<2%) without HSCT [7][14].
Morbidity: Recurrent skin/oral infections, tooth loss, chronic wounds, inflammatory bowel disease [4][7][12].
Quality of life: Frequent hospitalizations, lifelong antimicrobial dependence, and dental disfigurement [14][17].
Therapies
Antimicrobials: Prolonged IV antibiotics for active infections; prophylactic trimethoprim-sulfamethoxazole [8][16].
HSCT: Curative but carries ~25% mortality risk; 75% survival post-transplant [1][7][16].
Emerging therapies: Gene therapy (lentiviral vectors in trials) [13], IL-23/IL-12 blockade (ustekinumab) [3].
Categories: rare genetic diseases, rare immunological diseases, rare ophthalmic disorders
Research Papers
114 drug discovery papers about Leukocyte adhesion deficiency type I, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
114 drug discovery papers about Leukocyte adhesion deficiency type I, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2025-11-26 | Ustekinumab as an Adjunct Therapy for Leukocyte Adhesion Deficiency Type 1: Clincal Experience in Two Families
Introduction Leukocyte adhesion deficiency type 1 (LAD1) is caused by pathogenic variants in the ITGB2 gene, which encodes the CD18 subunit of b2 integrins. Defective neutrophil adhesion and migration results in predisposition to infection, periodontitis, and excessive inflammation. Inflamed tissues exhibit an IL-23 and IL-17 signature, and blockade of this pathway with ustekinumab has twice been reported as an effective adjunct therapy in LAD1 patients with severe skin and periodontal lesions Method We describe clinical and biochemical response of 3 patients from two families with LAD1 treated with ustekinumab. Family 1 included three affected children, two females and one male, aged 4, 2, and 3 months old, respectively. The eldest child presented with recurrent infections, periodontitis, and neutrophilia. CD11b and CD18 expression on neutrophils was absent, and genetics confirmed a homozygous missense mutation in the ITBG2 gene for all three children. Both girls had significant periodontitis with marked gingival recession prior to commencing ustekinumab. Family 2 included a single female diagnosed with LAD1 at 6 years old, following a suspected subcapsular splenic infection complicated by systemic hyperinflammation. This was against a background of long-standing poor wound healing and severe periodontitis. CD18 expression was absent, and genetics revealed compound heterozygous pathogenic variants in ITGB2. She was treated with corticosteroid therapy for her hyperinflammation and subsequently transitioned to ustekinumab and is currently planned for HSCT. Results All three patients received ustekinumab subcutaneously with a dosing regimen of 0.75 mg/kg at weeks 0 and 4, then every 12 weeks thereafter. There was a significant improvement in the severity of periodontal disease and a reduction in inflammatory markers. Conclusion We demonstrate effective use of ustekinumab to treat inflammatory and dental complications in LAD1 patients. Questions remain regarding the long-term safety, including vaccination recommendations and infectious complications, particularly the risk of invasive fungal infections, given IL-23 has an important role upstream of Th17 lymphocyte activation.
2024-04-01 | Ustekinumab for pyoderma gangrenosum-like skin ulcerations in late-onset leukocyte adhesion deficiency.
Leukocyte adhesion deficiency type 1 (LAD-1) is a congenital immunodeficiency leading to impaired trafficking of neutrophils to inflammation sites. Solitary or multiple pyoderma gangrenosum (PG)-like skin ulcers (PGLUs) have been reported previously in 13 children (aged 0.5-19 years) with LAD-1. Our aim was to report the case of a 10-year-old boy presenting with PGLUs as the first manifestation of LAD-1 treated with ustekinumab. We obtained in situ cytokine profiles. PGLUs were triggered by cutaneous ringworm infection (Trichophyton tonsurans). Skin biopsy samples showed increased intralesional expression of IL-17A, Il-23, and IL-1β as compared with their expression in healthy controls. After an unsuccessful attempt at treatment with oral methylprednisolone, ustekinumab induced regression of the ulcerations, associated with complete normalization of the cytokine profile. PGLUs, triggered by ringworm infection, can be a late harbinger of LAD-1. Ustekinumab is a safe and effective therapeutic option for patients with LAD-1 and PGLUs while bridging the time until stem cell transplantation.
2024-02-14 | Integrins in Health and Disease-Suitable Targets for Treatment?
Integrin receptors are heterodimeric surface receptors that play multiple roles regarding cell-cell communication, signaling, and migration. The four members of the β2 integrin subfamily are composed of an alternative α (CD11a-d) subunit, which determines the specific receptor properties, and a constant β (CD18) subunit. This review aims to present insight into the multiple immunological roles of integrin receptors, with a focus on β2 integrins that are specifically expressed by leukocytes. The pathophysiological role of β2 integrins is confirmed by the drastic phenotype of patients suffering from leukocyte adhesion deficiencies, most often resulting in severe recurrent infections and, at the same time, a predisposition for autoimmune diseases. So far, studies on the role of β2 integrins in vivo employed mice with a constitutive knockout of all β2 integrins or either family member, respectively, which complicated the differentiation between the direct and indirect effects of β2 integrin deficiency for distinct cell types. The recent generation and characterization of transgenic mice with a cell-type-specific knockdown of β2 integrins by our group has enabled the dissection of cell-specific roles of β2 integrins. Further, integrin receptors have been recognized as target receptors for the treatment of inflammatory diseases as well as tumor therapy. However, whereas both agonistic and antagonistic agents yielded beneficial effects in animal models, the success of clinical trials was limited in most cases and was associated with unwanted side effects. This unfavorable outcome is most probably related to the systemic effects of the used compounds on all leukocytes, thereby emphasizing the need to develop formulations that target distinct types of leukocytes to modulate β2 integrin activity for therapeutic applications.
2017-03-22 | Breaking a Vicious Cycle
In this issue of the Journal, Moutsopoulos et al.1 report on a patient with leukocyte adhesion deficiency type 1 (LAD1) who was successfully treated with ustekinumab, a monoclonal antibody to the p40 subunit common to interleukin-12 and interleukin-23. Patients with LAD1 have defective neutrophil adhesion, which results in few neutrophils making it into inflamed tissues. Typical locations of chronic inflammation in these patients include mucosal, skin, and periodontal sites. During 14 months of ustekinumab treatment, the patient’s severe chronic periodontitis and a deep sacral ulcer largely resolved.Blocking of p40 is unlikely to restore defective neutrophil function in patients with . . .
2017-03-22 | Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1
A patient with leukocyte adhesion deficiency type 1 (LAD1) had severe periodontitis and an intractable, deep, nonhealing sacral wound. We had previously found a dominant interleukin-23-interleukin-17 signature at inflamed sites in humans with LAD1 and in mouse models of the disorder. Blockade of this pathway in mouse models has resulted in resolution of the immunopathologic condition. We treated our patient with ustekinumab, an antibody that binds the p40 subunit of interleukin-23 and interleukin-12 and thereby blocks the activity of these cytokines, inhibiting interleukin-23-dependent production of interleukin-17. After 1 year of therapy, our patient had resolution of his inflammatory lesions without serious infections or adverse reactions. Inhibition of interleukin-23 and interleukin-17 may have a role in the management of LAD1. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
small molecules
2025-07-23 | Hematopoietic cell transplantation for leukocyte adhesion deficiency: prevention of graft-versus-host-disease.
Leukocyte adhesion deficiency (LAD) is a rare genetic disorder that impairs leukocyte migration, leading to severe immune dysfunction and recurrent infections. Although allogeneic hematopoietic cell transplantation (HCT) remains the primary curative treatment for severe LAD, it is complicated by a high incidence of graft-versus-host-disease (GVHD). This narrative review outlines the key factors influencing GVHD development in patients with LAD-I, the most common LAD subtype, undergoing HCT. It explores established and emerging strategies for preventing GVHD, focusing on their effectiveness and outcomes. The literature search was conducted using PubMed to identify studies reporting HCT for LAD published 1989-2025. Conventional GVHD prophylaxis regimens, primarily involving calcineurin inhibitors, have proven insufficient in preventing GVHD in high-risk populations. Among patients undergoing haploidentical HCT, post-transplantation cyclophosphamide has shown efficacy in preventing GVHD, although these results were based on limited cases. Graft manipulation techniques such as CD34+ selection have also been explored. However, these approaches are often associated with high graft failure rate and poor survival. Alemtuzumab, which is used in conditioning regimens, has shown promise in lowering GVHD incidence. Further studies are essential to optimize GVHD prophylaxis and improve survival outcomes in patients with LAD undergoing HCT.
2024-11-12 | Abstract 4136532: The Agonism of Macrophage Migration Inhibitory Factor Modulates Neutrophils Subsets and Rescues an Impaired Tolerance to Ischemic Insults in Aging
Introduction: An impaired cardiac macrophage migration inhibitory factor (MIF) signaling in aging during ischemia and reperfusion (I/R) can be rescued by a MIF agonist, MIF20. Alterations in cardiac metabolic homeostasis cause inflammation under I/R. Thus, MIF agonism with MIF20 could modulate cardiac inflammatory response during I/R. Hypothesis: MIF20 modulates the polarization of neutrophil subset and rescues the impaired immune response under I/R in aging. Methods: Young (3-months)/aged (24 months) C57BL/6 wild type (WT) mice and MIF flox/flox (3 months)/cMIF -/- (cardiomyocyte MIF deletion, 3 months) were subjected to LAD ligation of for 45 min of ischemia, followed by 24 hr of reperfusion. MIF20 (0.15 µg/kg, i.v.) was injected at 5 minutes before reperfusion. The immune cells were determined with flow cytometry. mRNA and protein were measured by real-time qPCR, immunoblotting/cytokine array. Results: Administration of MIF20 reduced myocardial infarct by I/R in young/aged WT and MIF flox/flox but not in cMIF -/- mice. The flow cytometry showed that I/R stress dramatically triggered neutrophils infiltration, which occurred in both left ventricle and right ventricle. Intriguingly, MIF20 treatment reduced the I/R-induced neutrophil recruitment in hearts. Aged versus young WT myocardium recruited more N1 neutrophils (CD206 - ), while MIF20 treatment rescued the impaired N1 neutrophils response in aging. Moreover, MIF20 can increase infiltration of N2 neutrophils (CD206 + ) in both young and aged WT hearts. The recombinant MIF can directly trigger N2 neutrophil polarization and N1 neutrophil reduction in cMIF -/- hearts, indicating the critical role of MIF/CD74 axis in neutrophil polarization by I/R challenge. The cytokine array showed that MIF20 treatment can trigger cardiac TGF-β levels and upregulate IL-10 levels in serum under I/R, since TGF-β and IL-10 are critical factors involved in the N2 neutrophils’ polarization. Interestingly, MIF20 increased SiglecF marker on neutrophils in the aged versus young hearts, suggesting that MIF20 rescue the long-lived neutrophil population (SiglecF high ) which could enhance phagocytosis to repair damaged myocardium during I/R conditions. Conclusions: An impairment of metabolic homeostasis and inflammatory response occurred in cardiac aging. MIF agonism with small molecule MIF20 can rescue the capacity of MIF/CD74 signaling to maintain metabolic homeostasis and inflammatory response in aging under I/R pathological conditions.
2024-07-20 | Mutations in the SLC35C1 gene, contributing to significant differences in fucosylation patterns, may underlie the diverse phenotypic manifestations observed in leukocyte adhesion deficiency type II patients.
Congenital disorders of glycosylation (CDG) are a large family of genetic diseases resulting from defects in the synthesis of glycans and the attachment of glycans to macromolecules. The CDG known as leukocyte adhesion deficiency II (LAD II) is an autosomal, recessive disorder caused by mutations in the SLC35C1 gene, encoding a transmembrane protein of the Golgi apparatus, involved in GDP-fucose transport from the cytosol to the Golgi lumen. In this study, a cell-based model was used as a tool to characterize the molecular background of a therapy based on a fucose-supplemented diet. Such therapies have been successfully introduced in some (but not all) known cases of LAD II. In this study, the effect of external fucose was analyzed in SLC35C1 KO cell lines, expressing 11 mutated SLC35C1 proteins, previously discovered in patients with an LAD II diagnosis. For many of them, the cis-Golgi subcellular localization was affected; however, some proteins were localized properly. Additionally, although mutated SLC35C1 caused different α-1-6 core fucosylation of N-glycans, which explains previously described, more or less severe disorder symptoms, the differences practically disappeared after external fucose supplementation, with fucosylation restored to the level observed in healthy cells. This indicates that additional fucose in the diet should improve the condition of all patients. Thus, for patients diagnosed with LAD II we advocate careful analysis of particular mutations using the SLC35C1-KO cell line-based model, to predict changes in localization and fucosylation rate. We also recommend searching for additional mutations in the human genome of LAD II patients, when fucose supplementation does not influence patients' state.
2023-04-06 | Mechano-Redox Control of Mac-1 De-Adhesion by PDI Promotes Directional Movement Under Flow
Background: Neutrophil migration is critical to the initiation and resolution of inflammation. Macrophage-1 antigen (Mac-1; CD11b/CD18, αMβ2) is a leukocyte integrin essential for firm adhesion to endothelial ICAM-1 (intercellular adhesion molecule 1) and migration of neutrophils in the shear forces of the circulation. PDI (protein disulfide isomerase) has been reported to influence neutrophil adhesion and migration. We aimed to elucidate the molecular mechanism of PDI control of Mac-1 affinity for ICAM-1 during neutrophil migration under fluid shear. Methods: Neutrophils isolated from whole blood were perfused over microfluidic chips coated with ICAM-1. Colocalization of Mac-1 and PDI on neutrophils was visualized by fluorescently labeled antibodies and confocal microscopy. The redox state of Mac-1 disulfide bonds was mapped by differential cysteine alkylation and mass spectrometry. Wild-type or disulfide mutant Mac-1 was expressed recombinantly in Baby Hamster Kidney cells to measure ligand affinity. Mac-1 conformations were measured by conformation-specific antibodies and molecular dynamics simulations. Neutrophils crawling on immobilized ICAM-1 were measured in presence of oxidized or reduced PDI, and the effect of PDI inhibition using isoquercetin on neutrophil crawling on inflamed endothelial cells was examined. Migration indices in the X- and Y-direction were determined and the crawling speed was calculated. Results: PDI colocalized with high-affinity Mac-1 at the trailing edge of stimulated neutrophils when crawling on ICAM-1 under fluid shear. PDI cleaved 2 allosteric disulfide bonds, C169-C176 and C224-C264, in the βI domain of the β2 subunit, and cleavage of the C224-C264 disulfide bond selectively controls Mac-1 disengagement from ICAM-1 under fluid shear. Molecular dynamics simulations and conformation-specific antibodies reveal that cleavage of the C224-C264 bond induces conformational change and mechanical stress in the βI domain. This allosterically alters the exposure of an αI domain epitope associated with a shift of Mac-1 to a lower-affinity state. These molecular events promote neutrophil motility in the direction of flow at high shear stress. Inhibition of PDI by isoquercetin reduces neutrophil migration in the direction of flow on endothelial cells during inflammation. Conclusions: Shear-dependent PDI cleavage of the neutrophil Mac-1 C224-C264 disulfide bond triggers Mac-1 de-adherence from ICAM-1 at the trailing edge of the cell and enables directional movement of neutrophils during inflammation.
2023-01-24 | Phosphorylation Regulation Mechanism of β2 Integrin for the Binding of Filamin Revealed by Markov State Model.
Leukocyte adhesion deficiency-1 (LAD-1) disorder is a severe immunodeficiency syndrome caused by deficiency or mutation of β2 integrin. The phosphorylation on threonine 758 of β2 integrin acts as a molecular switch inhibiting the binding of filamin. However, the switch mechanism of site-specific phosphorylation at the atom level is still poorly understood. To resolve the regulation mechanism, all-atom molecular dynamics simulation and Markov state model were used to study the dynamic regulation pathway of phosphorylation. Wild type system possessed lower binding free energy and fewer number of states than the phosphorylated system. Both systems underwent local disorder-to-order conformation conversion when achieving steady states. To reach steady states, wild type adopted less number of transition paths/shortest path according to the transition path theory than the phosphorylated system. The underlying phosphorylated regulation pathway was from P1 to P0 and then P4 state, and the main driving force should be hydrogen bond and hydrophobic interaction disturbing the secondary structure of phosphorylated states. These studies will shed light on the pathogenesis of LAD-1 disease and lay a foundation for drug development.
cell therapies
2026-05-26 | Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Leukocyte Adhesion Deficiency Types I and III: Expanded Single-Center Experience
Background Leukocyte adhesion deficiency (LAD) is a rare inborn error of immunity characterized by defective leukocyte trafficking leading to severe bacterial infections and early mortality without hematopoietic stem cell transplantation (HSCT). In 2011, our center reported outcomes of 11 patients with LAD type I. We now present an expanded cohort including LAD-I and -III, with extended follow-up and contemporary transplant approaches. Methods We performed a retrospective analysis of patients with genetically or immunophenotypically confirmed LAD who underwent allogeneic HSCT at a tertiary immunodeficiency center between 2010 and 2026. Data collected included LAD subtype, donor source, conditioning regimen, graft characteristics, graft versus host disease (GVHD) incidence, survival, and immune reconstitution including CD18 expression and lineage-specific chimerism. Results 13 patients underwent HSCT (10 LAD-I, 3 LAD-III). Median age at transplant was 6 months (interquartile range 4–14). Donors included matched sibling (n = 4), other family donors (n = 5), unrelated donors (n = 2), and cord blood (n = 2). All patients received busulfan (Bu)-based conditioning (Bu/cyclophosphamide ± antithymocyte globulin [ATG] or Bu/fludarabine ± ATG). With a median follow-up of 10.2 years among survivors, overall survival was 84.6% (11/13). Survival was 80% in LAD-I and 100% in LAD-III. Two deaths occurred in LAD-I, including one graft failure requiring second HSCT and one late infectious mortality. Acute GVHD occurred in 15% and was limited; no severe chronic GVHD was observed. Durable immune correction was achieved in the majority of survivors. Among evaluable LAD-I patients, post-HSCT neutrophil CD18 expression was high (median 96.5%), though two long-term survivors demonstrated stable mixed chimerism with partial CD18 correction (41–49%) and remained clinically well. Conclusions In this expanded single-center experience, allogeneic HSCT provides durable survival and sustained immune correction in LAD types I and III. Compared to our earlier report, outcomes remain favorable with low rates of severe GVHD and acceptable graft failure risk. Mixed chimerism with partial CD18 expression may be sufficient for long-term clinical stability, underscoring the importance of functional immune reconstitution rather than full donor chimerism alone.
2025-11-01 | INFANT WITH RECURRENT INFECTION AND SEVERE LEUKOCYTOSIS DIAGNOSED WITH LEUKOCYTE ADHESION DEFICIENCY TYPE 1
Leukocyte Adhesion Deficiency Type 1 (LAD-1) is a rare autosomal recessive primary immunodeficiency caused by ITGB2 mutations, resulting in impaired neutrophil migration. Early symptoms often mimic common infections, delaying diagnosis and treatment. An ex-36-week male first presented at 6 weeks with WBC >50K, ANC >39, and right acute otitis media (AOM) with tympanic membrane rupture, treated with amoxicillin. At 2 months of age, he re-presented with fever, nasal congestion, and left ear pain. Labs showed WBC >42K, ANC >36K, sterile CSF pleocytosis, and positive Bordetella parapertussis and Rhinovirus/Enterovirus. Immunologic workup revealed elevated lymphocyte subsets and slightly elevated IgG (902) with normal IgM and IgA. Given early-onset of infections with persistent leukocytosis, inborn error of immunity was suspected. Genetic testing revealed homozygous ITGB2 splice site variants (c.741+1G>A), and flow cytometry confirmed absent CD11b (0%) and markedly reduced CD18 (0.3%) expression, consistent with severe LAD-1. He was started on Bactrim and Itraconazole for prophylaxis. At 3 months of age, he underwent matched sibling donor hematopoietic stem cell transplant (HSCT) with Busulfan, Fludarabine, and Anti-thymocyte globulin. Post-HSCT complications included subdural hemorrhage, seizures, and veno-occlusive disease, all resolved. By 9 months post-HSCT, he showed full donor engraftment, robust immune reconstitution, and had discontinued immunoglobulin and antimicrobial prophylaxis. He is now receiving routine vaccinations. This case illustrates an uncommon immunodeficiency initially presenting as a common infection. Early suspicion enabled timely diagnosis and curative transplant. It underscores the importance of considering immunodeficiencies in infants with unexplained leukocytosis.
2025-06-18 | An atypical adolescent case of leukocyte adhesion deficiency I caused by a novel ITGB2 splicing variant with successful immune reconstitution following hematopoietic stem cell transplantation.
Leukocyte adhesion deficiency I (LAD-I) is an autosomal recessive immunodeficiency caused by mutations in the ITGB2 gene, characterized by recurrent severe infections, impaired pus formation, and delayed wound healing. In this study, we describe a late-onset presentation of LAD-I in a 22-year-old male who initially exhibited marked leukocytosis and neonatal omphalitis, followed by recurrent upper respiratory tract infections from 9 months of age. At age 13, the patient developed abdominal and left iliac fossa abscesses, which progressed to a vesicocutaneous fistula after a prolonged febrile episode. Extended catheterization and antibiotic treatment led to the formation of characteristic tin foil-like scarring. Recurrent purulent skin and soft tissue infections led to widespread scarring and pigmentary changes. Next-generation sequencing (NGS) identified a novel homozygous splice-site mutation in ITGB2 (NM_000211.5, c.1225-1G > A, IVS10-1G > A). In silico analysis predicted disruption of the acceptor site, while a minigene assay demonstrated two aberrant splicing events, namely a 12-bp deletion and complete skipping of exon 11 (188 bp). Flow cytometry analysis at age 13 showed CD18 expression reduced to less than 1% across granulocytes, monocytes, and lymphocytes, with concomitant decreases in β2-integrin α subunits (CD11a, CD11b, and CD11c). At 15 years of age, the patient underwent hematopoietic stem cell transplantation (HSCT) from a fully HLA-matched (10/10) heterozygous sister donor following a modified myeloablative conditioning regimen. Although initial chimerism fluctuated, full donor chimerism was ultimately achieved, restoring CD18 expression and normalizing ɑ-integrin levels. This study highlights the therapeutic efficacy of HSCT in correcting the molecular defects associated with LAD-I.
2025-04-08 | A novel ITGB2 variant in a patient with severe recurrent pyoderma gangrenosum-like lesions and underlying leukocyte adhesion deficiency type I: case report and literature review.
Leukocyte adhesion deficiency (LAD) is a group of inborn errors of immunity caused by mutations of integrin subunit b2 gene (ITGB2). Pyoderma gangrenosum (PG) is an uncommon neutrophilic dermatosis characterized by recurrent, sterile, and enlarging necrotic ulcers which may manifest as a single or multiple new lesions simultaneously. Here we report a 43-year-old woman from a consanguine marriage who was diagnosed with LAD-I in childhood, recurrent severe PG-like lesion, and atypical manifestations including celiac disease and low CD19 B-cell subsets. A targeted genetic panel revealed a novel homozygous missense variant c.988T>C (Tyr330His) in ITGB2 gene. While the treatment with prednisolone, cyclosporine, and antibiotics led to partial improvement, the patient unfortunately discontinued the therapy and later died from septicemia. Early hematopoietic cell transplantation (HCT) shortly after birth can be highly effective in managing patients with LAD and preventing life-threatening infections. However, evidence suggests that HCT does not prevent autoinflammatory and autoimmune disorders such as PG. Therefore, it is important to monitor LAD patients for the potential development of PG, even after HCT.
2025-01-23 | Dual in vivo T cell depleted haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide and anti-thymocyte globulin as a third salvage transplant for leukocyte adhesion deficiency with graft failure: a case report.
With recent advances in clinical practice, including the use of reduced-toxicity conditioning regimens and innovative approaches such as ex vivo TCRαβ/CD19 depletion of haploidentical donor stem cells or post-transplant cyclophosphamide (PTCY), hematopoietic stem cell transplantation (HSCT) has emerged as a curative treatment option for a growing population of patients with inborn errors of immunity (IEI). However, despite these promising developments, graft failure (GF) remains a significant concern associated with HSCT in these patients. Although a second HSCT is the only established salvage therapy for patients who experience GF, there are no uniform, standardized strategies for performing these second transplants. Furthermore, even less data is available regarding the outcomes and best practices for a third HSCT as a salvage measure when a second HSCT fails to achieve engraftment. A 6-year-old boy with leukocyte adhesion deficiency type I (LAD-I) experienced GF after the first and second HSCT from a matched unrelated donor. As a salvage measure, the patient received a dual in vivo T-cell depleted haploidentical HSCT. The conditioning regimen for this third HSCT included anti-thymocyte globulin (ATG) and PTCY. Complete donor chimerism was assessed using the short tandem repeat (STR) PCR technique. By day +28 after the transplant, the expression of the leukocyte adhesion molecules CD18, CD11b, and CD11c on the patient's peripheral blood neutrophils had recovered to over 99%. It remained stable throughout the 18-month follow-up period. T-cell replete haploidentical HSCT with ATG and PTCY may be a viable salvage option for LAD patients who have rejected prior HSCT.
gene therapies
2026-07-15 | Marnetegragene Autotemcel: First Approval.
Marnetegragene autotemcel (KRESLADI™), an autologous stem cell-based gene therapy that adds functional copies of the ITGB2 gene to haematopoietic stem cells, was developed by Rocket Pharmaceuticals for the treatment of leukocyte adhesion deficiency-I (LAD-I). In March 2026, marnetegragene autotemcel received its first approval in the USA for the treatment of paediatric patients with severe LAD-I due to biallelic variants in ITGB2 without an available human leukocyte antigen (HLA)-matched sibling donor for allogeneic haematopoietic stem cell transplant. This article summarises the milestones in the development of marnetegragene autotemcel leading to this first approval for treatment of paediatric patients with severe LAD-I.
2026-07-14 | 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
Background 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. Aims 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. Methods 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). Results 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. Summary/Conclusion 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.
2026-06-25 | Marnetegragene Autotemcel: First Approval
DeclarationsFunding The preparation of this review was not supported by any external funding.Authorship and Conflict of interest During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. S. Fung is a salaried employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to this article and are responsible for its content.Additional information about this Adis Drug Review can be found here.AbstractMarnetegragene autotemcel (KRESLADITM), an autologous stem cell-based gene therapy that adds functional copies of the ITGB2 gene to haematopoietic stem cells, was developed by Rocket Pharmaceuticals for the treatment of leukocyte adhesion deficiency-I (LAD-I). In March 2026, marnetegragene autotemcel received its first approval in the USA for the treatment of paediatric patients with severe LAD-I due to biallelic variants in ITGB2 without an available human leukocyte antigen (HLA)-matched sibling donor for allogeneic haematopoietic stem cell transplant. This article summarises the milestones in the development of marnetegragene autotemcel leading to this first approval for treatment of paediatric patients with severe LAD-I.© Springer Nature Switzerland AG 2026
2025-07-17 | A 2-MONTH-OLD INFANT PRESENTING WITH A NON-HEALING ULCER- A CASE OF LEUKOCYTE ADHESION DEFICIENCY TYPE 1 (LAD–1)
Introduction:Leukocyte adhesion deficiency with an occurrence of 1 in 100,000 is a rare primary immunodeficiency disorder. LAD-1 is an autosomal recessive hereditary condition with defective or deficient β-chain (CD18) of β2 integrins caused by mutati
2025-04-25 | Understanding the Burdens of Illness and Treatment in Severe Leukocyte Adhesion Deficiency Type I (LAD-I): Results from a Multi-Case Study with Caregivers
Background Leukocyte adhesion deficiency type I (LAD-I) is a rare inborn error of immunity affecting approximately 1 in 1 million individuals worldwide. Severe LAD-I is characterized by frequent life-threatening infections and significant pediatric mortality. Although this can have devastating effects on children and their families, there is little research about the lived experience of the disease. To fill this gap, we executed a multi-case study to describe the burden of severe LAD-I from the caregiver perspective. Methods Caregivers from 5 families with children with severe LAD-I participated in individual, in-depth interviews. Interviews followed a study-specific guide using concept and photo elicitation to obtain descriptions of caring for a child with severe LAD-I. Interview transcripts were analyzed using inductive and deductive approaches to describe the burdens of illness and treatment. Results Nine parents were interviewed. Among the 7 children, treatments included: allogeneic hematopoietic stem cell transplantation (alloHSCT; n = 2), investigational gene therapy (GT; n = 4), and antimicrobial prophylaxis (n = 1). Findings were organized under themes of burden of illness and burden of treatment (Table 1). The burden of illness included challenging journeys to diagnosis and frequent, hard-to-treat infections, leading children and caregivers to isolate physically and socially to reduce infection risk. All caregivers rearranged their jobs or career trajectories substantially to accommodate caregiving. Most parents were frustrated by the absence of LAD-I–specific resources and information. The burden of treatment differed by therapy. AlloHSCT families described difficult recoveries and, for 1 child, only partial success in treating LAD-I. GT families experienced a significant reduction of burden of illness, yet some expressed concerns for their child’s future given the novelty of the treatment. All participants agreed that antimicrobials were not a long-term treatment solution. Table 1.Main themes within burden of illness and treatment in severe LAD-I.BurdenThemesExamplesIllnessFrequent and varied infectionsRashes, skin/mucosal lesions, and infections in the lungs, ears, gums; poorly healing umbilical cordsPhysical restrictionsAvoiding water parks, beaches, other outdoor activities; limiting sports; preventing contact with petsSocial restrictionsLimiting visitors to the home; avoiding daycare; home schoolingJourney to diagnosis marked by lack of informationFailure of frequent severe infections and slow healing wounds to drive investigation and diagnosis; lack of resources, guidance, and information pre- and post-diagnosisTreatmentAlloHSCTSearching for a bone marrow match; complexity of alloHSCT process; managing alloHSCT complications; side-effects from post-transplant treatments; waning efficacyGene therapyGenerally positive outcomes, despite a long and complex process; required relocation for the duration of treatment; uncertainty about durability and longer-term effects given the novelty of GTProphylactic antimicrobialsIn 1 case, in the absence of a family donor match for alloHSCT, the clinician recommended this approach; parents indicated it is not a long-term nor complete solution Conclusion Together, the burdens of illness and treatment had profound impacts on these families. The parents’ descriptions also demonstrated that while none of the current treatments for severe LAD-I is perfect, GT shows great potential for improving patients’ health and minimizing disease burden. Moreover, this research provides critical insights for clinicians, whose care of children with severe LAD-I can be informed by understanding the struggles associated with the burdens of illness and treatment.
other
2022-05-31 | CD47 Binding on Vascular Endothelial Cells Inhibits IL-17-Mediated Leukocyte Adhesion.
To address the conflicting role of thrombospondin (TSP)-1 reported in acute and chronic pathologies, this study investigated the role of TSP-1 in regulating leukocyte recruitment and regulation of VCAM-1 expression using mouse models of uveitis. The spontaneously increased VCAM-1 expression and leukocyte adhesion in retinas of TSP-1-deficient mice suggested a TSP-1-mediated regulation of VCAM-1 expression. In a chronic uveitis model, induced by immunizing wild-type mice with specific interphotoreceptor retinoid-binding protein (IRBP) peptide, topically applied TSP-1-derived CD47-binding peptide significantly reduced the clinical disease course and retinal leukocyte adhesion as compared to the control peptide-treated group. In contrast, in LPS-mediated acute uveitis, TSP-1 deficiency significantly reduced the retinal leukocyte adhesion. The results of our in vitro study, using vascular endothelial cell (EC) cultures, demonstrate that unlike TNF-α, VCAM-1 expression induced by IL-17 is associated with a reduced expression of endogenous TSP-1. Such reduced endogenous TSP-1 expression in IL-17-stimulated ECs helps limit the CD36-mediated increased VCAM-1 expression, while favoring CD47-mediated inhibition of VCAM-1 expression and leukocyte adhesion. Thus, our study identifies TSP-1:CD47 interaction as a molecular pathway that modulates IL-17-mediated VCAM-1 expression, contributing to its anti-inflammatory effect in chronic inflammatory conditions.
2004-08-06 | Intracellular and cell surface localization of a complex between alphaMbeta2 integrin and promatrix metalloproteinase-9 progelatinase in neutrophils.
We have recently demonstrated that promatrix metalloproteinases (proMMPs), particularly proMMP-9, are potent ligands of the leukocyte beta(2) integrins. We studied here the complex formation between proMMP-9 and alpha(M)beta(2), the major MMP and integrin of neutrophils. On resting neutrophils, the proMMP-9/alpha(M)beta(2) complex was primarily detected in intracellular granules, but after cellular activation it became localized to the cell surface, as demonstrated by immunoprecipitation and double immunofluorescence. Further indication of the complex formation was that neutrophils and alpha(M)beta(2)-transfected L cells, but not the wild-type L cells or leukocyte adhesion deficiency cells, bound to immobilized proMMP-9 or its recombinant catalytic domain in a beta(2) integrin-dependent manner. Peptides that bound to the alpha(M) integrin-I domain and inhibited its complex formation with proMMP-9 prevented neutrophil migration in a transendothelial assay in vitro and in a thioglycolate-elicited peritonitis in vivo. These results suggest that the translocating proMMP-9/alpha(M)beta(2) complex may be part of the cell surface machinery guiding neutrophil migration.
antibodies
2025-11-26 | Ustekinumab as an Adjunct Therapy for Leukocyte Adhesion Deficiency Type 1: Clincal Experience in Two Families
Introduction Leukocyte adhesion deficiency type 1 (LAD1) is caused by pathogenic variants in the ITGB2 gene, which encodes the CD18 subunit of b2 integrins. Defective neutrophil adhesion and migration results in predisposition to infection, periodontitis, and excessive inflammation. Inflamed tissues exhibit an IL-23 and IL-17 signature, and blockade of this pathway with ustekinumab has twice been reported as an effective adjunct therapy in LAD1 patients with severe skin and periodontal lesions Method We describe clinical and biochemical response of 3 patients from two families with LAD1 treated with ustekinumab. Family 1 included three affected children, two females and one male, aged 4, 2, and 3 months old, respectively. The eldest child presented with recurrent infections, periodontitis, and neutrophilia. CD11b and CD18 expression on neutrophils was absent, and genetics confirmed a homozygous missense mutation in the ITBG2 gene for all three children. Both girls had significant periodontitis with marked gingival recession prior to commencing ustekinumab. Family 2 included a single female diagnosed with LAD1 at 6 years old, following a suspected subcapsular splenic infection complicated by systemic hyperinflammation. This was against a background of long-standing poor wound healing and severe periodontitis. CD18 expression was absent, and genetics revealed compound heterozygous pathogenic variants in ITGB2. She was treated with corticosteroid therapy for her hyperinflammation and subsequently transitioned to ustekinumab and is currently planned for HSCT. Results All three patients received ustekinumab subcutaneously with a dosing regimen of 0.75 mg/kg at weeks 0 and 4, then every 12 weeks thereafter. There was a significant improvement in the severity of periodontal disease and a reduction in inflammatory markers. Conclusion We demonstrate effective use of ustekinumab to treat inflammatory and dental complications in LAD1 patients. Questions remain regarding the long-term safety, including vaccination recommendations and infectious complications, particularly the risk of invasive fungal infections, given IL-23 has an important role upstream of Th17 lymphocyte activation.
2024-04-01 | Ustekinumab for pyoderma gangrenosum-like skin ulcerations in late-onset leukocyte adhesion deficiency.
Leukocyte adhesion deficiency type 1 (LAD-1) is a congenital immunodeficiency leading to impaired trafficking of neutrophils to inflammation sites. Solitary or multiple pyoderma gangrenosum (PG)-like skin ulcers (PGLUs) have been reported previously in 13 children (aged 0.5-19 years) with LAD-1. Our aim was to report the case of a 10-year-old boy presenting with PGLUs as the first manifestation of LAD-1 treated with ustekinumab. We obtained in situ cytokine profiles. PGLUs were triggered by cutaneous ringworm infection (Trichophyton tonsurans). Skin biopsy samples showed increased intralesional expression of IL-17A, Il-23, and IL-1β as compared with their expression in healthy controls. After an unsuccessful attempt at treatment with oral methylprednisolone, ustekinumab induced regression of the ulcerations, associated with complete normalization of the cytokine profile. PGLUs, triggered by ringworm infection, can be a late harbinger of LAD-1. Ustekinumab is a safe and effective therapeutic option for patients with LAD-1 and PGLUs while bridging the time until stem cell transplantation.
2024-02-14 | Integrins in Health and Disease-Suitable Targets for Treatment?
Integrin receptors are heterodimeric surface receptors that play multiple roles regarding cell-cell communication, signaling, and migration. The four members of the β2 integrin subfamily are composed of an alternative α (CD11a-d) subunit, which determines the specific receptor properties, and a constant β (CD18) subunit. This review aims to present insight into the multiple immunological roles of integrin receptors, with a focus on β2 integrins that are specifically expressed by leukocytes. The pathophysiological role of β2 integrins is confirmed by the drastic phenotype of patients suffering from leukocyte adhesion deficiencies, most often resulting in severe recurrent infections and, at the same time, a predisposition for autoimmune diseases. So far, studies on the role of β2 integrins in vivo employed mice with a constitutive knockout of all β2 integrins or either family member, respectively, which complicated the differentiation between the direct and indirect effects of β2 integrin deficiency for distinct cell types. The recent generation and characterization of transgenic mice with a cell-type-specific knockdown of β2 integrins by our group has enabled the dissection of cell-specific roles of β2 integrins. Further, integrin receptors have been recognized as target receptors for the treatment of inflammatory diseases as well as tumor therapy. However, whereas both agonistic and antagonistic agents yielded beneficial effects in animal models, the success of clinical trials was limited in most cases and was associated with unwanted side effects. This unfavorable outcome is most probably related to the systemic effects of the used compounds on all leukocytes, thereby emphasizing the need to develop formulations that target distinct types of leukocytes to modulate β2 integrin activity for therapeutic applications.
2017-03-22 | Breaking a Vicious Cycle
In this issue of the Journal, Moutsopoulos et al.1 report on a patient with leukocyte adhesion deficiency type 1 (LAD1) who was successfully treated with ustekinumab, a monoclonal antibody to the p40 subunit common to interleukin-12 and interleukin-23. Patients with LAD1 have defective neutrophil adhesion, which results in few neutrophils making it into inflamed tissues. Typical locations of chronic inflammation in these patients include mucosal, skin, and periodontal sites. During 14 months of ustekinumab treatment, the patient’s severe chronic periodontitis and a deep sacral ulcer largely resolved.Blocking of p40 is unlikely to restore defective neutrophil function in patients with . . .
2017-03-22 | Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1
A patient with leukocyte adhesion deficiency type 1 (LAD1) had severe periodontitis and an intractable, deep, nonhealing sacral wound. We had previously found a dominant interleukin-23-interleukin-17 signature at inflamed sites in humans with LAD1 and in mouse models of the disorder. Blockade of this pathway in mouse models has resulted in resolution of the immunopathologic condition. We treated our patient with ustekinumab, an antibody that binds the p40 subunit of interleukin-23 and interleukin-12 and thereby blocks the activity of these cytokines, inhibiting interleukin-23-dependent production of interleukin-17. After 1 year of therapy, our patient had resolution of his inflammatory lesions without serious infections or adverse reactions. Inhibition of interleukin-23 and interleukin-17 may have a role in the management of LAD1. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
small molecules
2025-07-23 | Hematopoietic cell transplantation for leukocyte adhesion deficiency: prevention of graft-versus-host-disease.
Leukocyte adhesion deficiency (LAD) is a rare genetic disorder that impairs leukocyte migration, leading to severe immune dysfunction and recurrent infections. Although allogeneic hematopoietic cell transplantation (HCT) remains the primary curative treatment for severe LAD, it is complicated by a high incidence of graft-versus-host-disease (GVHD). This narrative review outlines the key factors influencing GVHD development in patients with LAD-I, the most common LAD subtype, undergoing HCT. It explores established and emerging strategies for preventing GVHD, focusing on their effectiveness and outcomes. The literature search was conducted using PubMed to identify studies reporting HCT for LAD published 1989-2025. Conventional GVHD prophylaxis regimens, primarily involving calcineurin inhibitors, have proven insufficient in preventing GVHD in high-risk populations. Among patients undergoing haploidentical HCT, post-transplantation cyclophosphamide has shown efficacy in preventing GVHD, although these results were based on limited cases. Graft manipulation techniques such as CD34+ selection have also been explored. However, these approaches are often associated with high graft failure rate and poor survival. Alemtuzumab, which is used in conditioning regimens, has shown promise in lowering GVHD incidence. Further studies are essential to optimize GVHD prophylaxis and improve survival outcomes in patients with LAD undergoing HCT.
2024-11-12 | Abstract 4136532: The Agonism of Macrophage Migration Inhibitory Factor Modulates Neutrophils Subsets and Rescues an Impaired Tolerance to Ischemic Insults in Aging
Introduction: An impaired cardiac macrophage migration inhibitory factor (MIF) signaling in aging during ischemia and reperfusion (I/R) can be rescued by a MIF agonist, MIF20. Alterations in cardiac metabolic homeostasis cause inflammation under I/R. Thus, MIF agonism with MIF20 could modulate cardiac inflammatory response during I/R. Hypothesis: MIF20 modulates the polarization of neutrophil subset and rescues the impaired immune response under I/R in aging. Methods: Young (3-months)/aged (24 months) C57BL/6 wild type (WT) mice and MIF flox/flox (3 months)/cMIF -/- (cardiomyocyte MIF deletion, 3 months) were subjected to LAD ligation of for 45 min of ischemia, followed by 24 hr of reperfusion. MIF20 (0.15 µg/kg, i.v.) was injected at 5 minutes before reperfusion. The immune cells were determined with flow cytometry. mRNA and protein were measured by real-time qPCR, immunoblotting/cytokine array. Results: Administration of MIF20 reduced myocardial infarct by I/R in young/aged WT and MIF flox/flox but not in cMIF -/- mice. The flow cytometry showed that I/R stress dramatically triggered neutrophils infiltration, which occurred in both left ventricle and right ventricle. Intriguingly, MIF20 treatment reduced the I/R-induced neutrophil recruitment in hearts. Aged versus young WT myocardium recruited more N1 neutrophils (CD206 - ), while MIF20 treatment rescued the impaired N1 neutrophils response in aging. Moreover, MIF20 can increase infiltration of N2 neutrophils (CD206 + ) in both young and aged WT hearts. The recombinant MIF can directly trigger N2 neutrophil polarization and N1 neutrophil reduction in cMIF -/- hearts, indicating the critical role of MIF/CD74 axis in neutrophil polarization by I/R challenge. The cytokine array showed that MIF20 treatment can trigger cardiac TGF-β levels and upregulate IL-10 levels in serum under I/R, since TGF-β and IL-10 are critical factors involved in the N2 neutrophils’ polarization. Interestingly, MIF20 increased SiglecF marker on neutrophils in the aged versus young hearts, suggesting that MIF20 rescue the long-lived neutrophil population (SiglecF high ) which could enhance phagocytosis to repair damaged myocardium during I/R conditions. Conclusions: An impairment of metabolic homeostasis and inflammatory response occurred in cardiac aging. MIF agonism with small molecule MIF20 can rescue the capacity of MIF/CD74 signaling to maintain metabolic homeostasis and inflammatory response in aging under I/R pathological conditions.
2024-07-20 | Mutations in the SLC35C1 gene, contributing to significant differences in fucosylation patterns, may underlie the diverse phenotypic manifestations observed in leukocyte adhesion deficiency type II patients.
Congenital disorders of glycosylation (CDG) are a large family of genetic diseases resulting from defects in the synthesis of glycans and the attachment of glycans to macromolecules. The CDG known as leukocyte adhesion deficiency II (LAD II) is an autosomal, recessive disorder caused by mutations in the SLC35C1 gene, encoding a transmembrane protein of the Golgi apparatus, involved in GDP-fucose transport from the cytosol to the Golgi lumen. In this study, a cell-based model was used as a tool to characterize the molecular background of a therapy based on a fucose-supplemented diet. Such therapies have been successfully introduced in some (but not all) known cases of LAD II. In this study, the effect of external fucose was analyzed in SLC35C1 KO cell lines, expressing 11 mutated SLC35C1 proteins, previously discovered in patients with an LAD II diagnosis. For many of them, the cis-Golgi subcellular localization was affected; however, some proteins were localized properly. Additionally, although mutated SLC35C1 caused different α-1-6 core fucosylation of N-glycans, which explains previously described, more or less severe disorder symptoms, the differences practically disappeared after external fucose supplementation, with fucosylation restored to the level observed in healthy cells. This indicates that additional fucose in the diet should improve the condition of all patients. Thus, for patients diagnosed with LAD II we advocate careful analysis of particular mutations using the SLC35C1-KO cell line-based model, to predict changes in localization and fucosylation rate. We also recommend searching for additional mutations in the human genome of LAD II patients, when fucose supplementation does not influence patients' state.
2023-04-06 | Mechano-Redox Control of Mac-1 De-Adhesion by PDI Promotes Directional Movement Under Flow
Background: Neutrophil migration is critical to the initiation and resolution of inflammation. Macrophage-1 antigen (Mac-1; CD11b/CD18, αMβ2) is a leukocyte integrin essential for firm adhesion to endothelial ICAM-1 (intercellular adhesion molecule 1) and migration of neutrophils in the shear forces of the circulation. PDI (protein disulfide isomerase) has been reported to influence neutrophil adhesion and migration. We aimed to elucidate the molecular mechanism of PDI control of Mac-1 affinity for ICAM-1 during neutrophil migration under fluid shear. Methods: Neutrophils isolated from whole blood were perfused over microfluidic chips coated with ICAM-1. Colocalization of Mac-1 and PDI on neutrophils was visualized by fluorescently labeled antibodies and confocal microscopy. The redox state of Mac-1 disulfide bonds was mapped by differential cysteine alkylation and mass spectrometry. Wild-type or disulfide mutant Mac-1 was expressed recombinantly in Baby Hamster Kidney cells to measure ligand affinity. Mac-1 conformations were measured by conformation-specific antibodies and molecular dynamics simulations. Neutrophils crawling on immobilized ICAM-1 were measured in presence of oxidized or reduced PDI, and the effect of PDI inhibition using isoquercetin on neutrophil crawling on inflamed endothelial cells was examined. Migration indices in the X- and Y-direction were determined and the crawling speed was calculated. Results: PDI colocalized with high-affinity Mac-1 at the trailing edge of stimulated neutrophils when crawling on ICAM-1 under fluid shear. PDI cleaved 2 allosteric disulfide bonds, C169-C176 and C224-C264, in the βI domain of the β2 subunit, and cleavage of the C224-C264 disulfide bond selectively controls Mac-1 disengagement from ICAM-1 under fluid shear. Molecular dynamics simulations and conformation-specific antibodies reveal that cleavage of the C224-C264 bond induces conformational change and mechanical stress in the βI domain. This allosterically alters the exposure of an αI domain epitope associated with a shift of Mac-1 to a lower-affinity state. These molecular events promote neutrophil motility in the direction of flow at high shear stress. Inhibition of PDI by isoquercetin reduces neutrophil migration in the direction of flow on endothelial cells during inflammation. Conclusions: Shear-dependent PDI cleavage of the neutrophil Mac-1 C224-C264 disulfide bond triggers Mac-1 de-adherence from ICAM-1 at the trailing edge of the cell and enables directional movement of neutrophils during inflammation.
2023-01-24 | Phosphorylation Regulation Mechanism of β2 Integrin for the Binding of Filamin Revealed by Markov State Model.
Leukocyte adhesion deficiency-1 (LAD-1) disorder is a severe immunodeficiency syndrome caused by deficiency or mutation of β2 integrin. The phosphorylation on threonine 758 of β2 integrin acts as a molecular switch inhibiting the binding of filamin. However, the switch mechanism of site-specific phosphorylation at the atom level is still poorly understood. To resolve the regulation mechanism, all-atom molecular dynamics simulation and Markov state model were used to study the dynamic regulation pathway of phosphorylation. Wild type system possessed lower binding free energy and fewer number of states than the phosphorylated system. Both systems underwent local disorder-to-order conformation conversion when achieving steady states. To reach steady states, wild type adopted less number of transition paths/shortest path according to the transition path theory than the phosphorylated system. The underlying phosphorylated regulation pathway was from P1 to P0 and then P4 state, and the main driving force should be hydrogen bond and hydrophobic interaction disturbing the secondary structure of phosphorylated states. These studies will shed light on the pathogenesis of LAD-1 disease and lay a foundation for drug development.
cell therapies
2026-05-26 | Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Leukocyte Adhesion Deficiency Types I and III: Expanded Single-Center Experience
Background Leukocyte adhesion deficiency (LAD) is a rare inborn error of immunity characterized by defective leukocyte trafficking leading to severe bacterial infections and early mortality without hematopoietic stem cell transplantation (HSCT). In 2011, our center reported outcomes of 11 patients with LAD type I. We now present an expanded cohort including LAD-I and -III, with extended follow-up and contemporary transplant approaches. Methods We performed a retrospective analysis of patients with genetically or immunophenotypically confirmed LAD who underwent allogeneic HSCT at a tertiary immunodeficiency center between 2010 and 2026. Data collected included LAD subtype, donor source, conditioning regimen, graft characteristics, graft versus host disease (GVHD) incidence, survival, and immune reconstitution including CD18 expression and lineage-specific chimerism. Results 13 patients underwent HSCT (10 LAD-I, 3 LAD-III). Median age at transplant was 6 months (interquartile range 4–14). Donors included matched sibling (n = 4), other family donors (n = 5), unrelated donors (n = 2), and cord blood (n = 2). All patients received busulfan (Bu)-based conditioning (Bu/cyclophosphamide ± antithymocyte globulin [ATG] or Bu/fludarabine ± ATG). With a median follow-up of 10.2 years among survivors, overall survival was 84.6% (11/13). Survival was 80% in LAD-I and 100% in LAD-III. Two deaths occurred in LAD-I, including one graft failure requiring second HSCT and one late infectious mortality. Acute GVHD occurred in 15% and was limited; no severe chronic GVHD was observed. Durable immune correction was achieved in the majority of survivors. Among evaluable LAD-I patients, post-HSCT neutrophil CD18 expression was high (median 96.5%), though two long-term survivors demonstrated stable mixed chimerism with partial CD18 correction (41–49%) and remained clinically well. Conclusions In this expanded single-center experience, allogeneic HSCT provides durable survival and sustained immune correction in LAD types I and III. Compared to our earlier report, outcomes remain favorable with low rates of severe GVHD and acceptable graft failure risk. Mixed chimerism with partial CD18 expression may be sufficient for long-term clinical stability, underscoring the importance of functional immune reconstitution rather than full donor chimerism alone.
2025-11-01 | INFANT WITH RECURRENT INFECTION AND SEVERE LEUKOCYTOSIS DIAGNOSED WITH LEUKOCYTE ADHESION DEFICIENCY TYPE 1
Leukocyte Adhesion Deficiency Type 1 (LAD-1) is a rare autosomal recessive primary immunodeficiency caused by ITGB2 mutations, resulting in impaired neutrophil migration. Early symptoms often mimic common infections, delaying diagnosis and treatment. An ex-36-week male first presented at 6 weeks with WBC >50K, ANC >39, and right acute otitis media (AOM) with tympanic membrane rupture, treated with amoxicillin. At 2 months of age, he re-presented with fever, nasal congestion, and left ear pain. Labs showed WBC >42K, ANC >36K, sterile CSF pleocytosis, and positive Bordetella parapertussis and Rhinovirus/Enterovirus. Immunologic workup revealed elevated lymphocyte subsets and slightly elevated IgG (902) with normal IgM and IgA. Given early-onset of infections with persistent leukocytosis, inborn error of immunity was suspected. Genetic testing revealed homozygous ITGB2 splice site variants (c.741+1G>A), and flow cytometry confirmed absent CD11b (0%) and markedly reduced CD18 (0.3%) expression, consistent with severe LAD-1. He was started on Bactrim and Itraconazole for prophylaxis. At 3 months of age, he underwent matched sibling donor hematopoietic stem cell transplant (HSCT) with Busulfan, Fludarabine, and Anti-thymocyte globulin. Post-HSCT complications included subdural hemorrhage, seizures, and veno-occlusive disease, all resolved. By 9 months post-HSCT, he showed full donor engraftment, robust immune reconstitution, and had discontinued immunoglobulin and antimicrobial prophylaxis. He is now receiving routine vaccinations. This case illustrates an uncommon immunodeficiency initially presenting as a common infection. Early suspicion enabled timely diagnosis and curative transplant. It underscores the importance of considering immunodeficiencies in infants with unexplained leukocytosis.
2025-06-18 | An atypical adolescent case of leukocyte adhesion deficiency I caused by a novel ITGB2 splicing variant with successful immune reconstitution following hematopoietic stem cell transplantation.
Leukocyte adhesion deficiency I (LAD-I) is an autosomal recessive immunodeficiency caused by mutations in the ITGB2 gene, characterized by recurrent severe infections, impaired pus formation, and delayed wound healing. In this study, we describe a late-onset presentation of LAD-I in a 22-year-old male who initially exhibited marked leukocytosis and neonatal omphalitis, followed by recurrent upper respiratory tract infections from 9 months of age. At age 13, the patient developed abdominal and left iliac fossa abscesses, which progressed to a vesicocutaneous fistula after a prolonged febrile episode. Extended catheterization and antibiotic treatment led to the formation of characteristic tin foil-like scarring. Recurrent purulent skin and soft tissue infections led to widespread scarring and pigmentary changes. Next-generation sequencing (NGS) identified a novel homozygous splice-site mutation in ITGB2 (NM_000211.5, c.1225-1G > A, IVS10-1G > A). In silico analysis predicted disruption of the acceptor site, while a minigene assay demonstrated two aberrant splicing events, namely a 12-bp deletion and complete skipping of exon 11 (188 bp). Flow cytometry analysis at age 13 showed CD18 expression reduced to less than 1% across granulocytes, monocytes, and lymphocytes, with concomitant decreases in β2-integrin α subunits (CD11a, CD11b, and CD11c). At 15 years of age, the patient underwent hematopoietic stem cell transplantation (HSCT) from a fully HLA-matched (10/10) heterozygous sister donor following a modified myeloablative conditioning regimen. Although initial chimerism fluctuated, full donor chimerism was ultimately achieved, restoring CD18 expression and normalizing ɑ-integrin levels. This study highlights the therapeutic efficacy of HSCT in correcting the molecular defects associated with LAD-I.
2025-04-08 | A novel ITGB2 variant in a patient with severe recurrent pyoderma gangrenosum-like lesions and underlying leukocyte adhesion deficiency type I: case report and literature review.
Leukocyte adhesion deficiency (LAD) is a group of inborn errors of immunity caused by mutations of integrin subunit b2 gene (ITGB2). Pyoderma gangrenosum (PG) is an uncommon neutrophilic dermatosis characterized by recurrent, sterile, and enlarging necrotic ulcers which may manifest as a single or multiple new lesions simultaneously. Here we report a 43-year-old woman from a consanguine marriage who was diagnosed with LAD-I in childhood, recurrent severe PG-like lesion, and atypical manifestations including celiac disease and low CD19 B-cell subsets. A targeted genetic panel revealed a novel homozygous missense variant c.988T>C (Tyr330His) in ITGB2 gene. While the treatment with prednisolone, cyclosporine, and antibiotics led to partial improvement, the patient unfortunately discontinued the therapy and later died from septicemia. Early hematopoietic cell transplantation (HCT) shortly after birth can be highly effective in managing patients with LAD and preventing life-threatening infections. However, evidence suggests that HCT does not prevent autoinflammatory and autoimmune disorders such as PG. Therefore, it is important to monitor LAD patients for the potential development of PG, even after HCT.
2025-01-23 | Dual in vivo T cell depleted haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide and anti-thymocyte globulin as a third salvage transplant for leukocyte adhesion deficiency with graft failure: a case report.
With recent advances in clinical practice, including the use of reduced-toxicity conditioning regimens and innovative approaches such as ex vivo TCRαβ/CD19 depletion of haploidentical donor stem cells or post-transplant cyclophosphamide (PTCY), hematopoietic stem cell transplantation (HSCT) has emerged as a curative treatment option for a growing population of patients with inborn errors of immunity (IEI). However, despite these promising developments, graft failure (GF) remains a significant concern associated with HSCT in these patients. Although a second HSCT is the only established salvage therapy for patients who experience GF, there are no uniform, standardized strategies for performing these second transplants. Furthermore, even less data is available regarding the outcomes and best practices for a third HSCT as a salvage measure when a second HSCT fails to achieve engraftment. A 6-year-old boy with leukocyte adhesion deficiency type I (LAD-I) experienced GF after the first and second HSCT from a matched unrelated donor. As a salvage measure, the patient received a dual in vivo T-cell depleted haploidentical HSCT. The conditioning regimen for this third HSCT included anti-thymocyte globulin (ATG) and PTCY. Complete donor chimerism was assessed using the short tandem repeat (STR) PCR technique. By day +28 after the transplant, the expression of the leukocyte adhesion molecules CD18, CD11b, and CD11c on the patient's peripheral blood neutrophils had recovered to over 99%. It remained stable throughout the 18-month follow-up period. T-cell replete haploidentical HSCT with ATG and PTCY may be a viable salvage option for LAD patients who have rejected prior HSCT.
gene therapies
2026-07-15 | Marnetegragene Autotemcel: First Approval.
Marnetegragene autotemcel (KRESLADI™), an autologous stem cell-based gene therapy that adds functional copies of the ITGB2 gene to haematopoietic stem cells, was developed by Rocket Pharmaceuticals for the treatment of leukocyte adhesion deficiency-I (LAD-I). In March 2026, marnetegragene autotemcel received its first approval in the USA for the treatment of paediatric patients with severe LAD-I due to biallelic variants in ITGB2 without an available human leukocyte antigen (HLA)-matched sibling donor for allogeneic haematopoietic stem cell transplant. This article summarises the milestones in the development of marnetegragene autotemcel leading to this first approval for treatment of paediatric patients with severe LAD-I.
2026-07-14 | 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
Background 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. Aims 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. Methods 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). Results 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. Summary/Conclusion 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.
2026-06-25 | Marnetegragene Autotemcel: First Approval
DeclarationsFunding The preparation of this review was not supported by any external funding.Authorship and Conflict of interest During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. S. Fung is a salaried employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to this article and are responsible for its content.Additional information about this Adis Drug Review can be found here.AbstractMarnetegragene autotemcel (KRESLADITM), an autologous stem cell-based gene therapy that adds functional copies of the ITGB2 gene to haematopoietic stem cells, was developed by Rocket Pharmaceuticals for the treatment of leukocyte adhesion deficiency-I (LAD-I). In March 2026, marnetegragene autotemcel received its first approval in the USA for the treatment of paediatric patients with severe LAD-I due to biallelic variants in ITGB2 without an available human leukocyte antigen (HLA)-matched sibling donor for allogeneic haematopoietic stem cell transplant. This article summarises the milestones in the development of marnetegragene autotemcel leading to this first approval for treatment of paediatric patients with severe LAD-I.© Springer Nature Switzerland AG 2026
2025-07-17 | A 2-MONTH-OLD INFANT PRESENTING WITH A NON-HEALING ULCER- A CASE OF LEUKOCYTE ADHESION DEFICIENCY TYPE 1 (LAD–1)
Introduction:Leukocyte adhesion deficiency with an occurrence of 1 in 100,000 is a rare primary immunodeficiency disorder. LAD-1 is an autosomal recessive hereditary condition with defective or deficient β-chain (CD18) of β2 integrins caused by mutati
2025-04-25 | Understanding the Burdens of Illness and Treatment in Severe Leukocyte Adhesion Deficiency Type I (LAD-I): Results from a Multi-Case Study with Caregivers
Background Leukocyte adhesion deficiency type I (LAD-I) is a rare inborn error of immunity affecting approximately 1 in 1 million individuals worldwide. Severe LAD-I is characterized by frequent life-threatening infections and significant pediatric mortality. Although this can have devastating effects on children and their families, there is little research about the lived experience of the disease. To fill this gap, we executed a multi-case study to describe the burden of severe LAD-I from the caregiver perspective. Methods Caregivers from 5 families with children with severe LAD-I participated in individual, in-depth interviews. Interviews followed a study-specific guide using concept and photo elicitation to obtain descriptions of caring for a child with severe LAD-I. Interview transcripts were analyzed using inductive and deductive approaches to describe the burdens of illness and treatment. Results Nine parents were interviewed. Among the 7 children, treatments included: allogeneic hematopoietic stem cell transplantation (alloHSCT; n = 2), investigational gene therapy (GT; n = 4), and antimicrobial prophylaxis (n = 1). Findings were organized under themes of burden of illness and burden of treatment (Table 1). The burden of illness included challenging journeys to diagnosis and frequent, hard-to-treat infections, leading children and caregivers to isolate physically and socially to reduce infection risk. All caregivers rearranged their jobs or career trajectories substantially to accommodate caregiving. Most parents were frustrated by the absence of LAD-I–specific resources and information. The burden of treatment differed by therapy. AlloHSCT families described difficult recoveries and, for 1 child, only partial success in treating LAD-I. GT families experienced a significant reduction of burden of illness, yet some expressed concerns for their child’s future given the novelty of the treatment. All participants agreed that antimicrobials were not a long-term treatment solution. Table 1.Main themes within burden of illness and treatment in severe LAD-I.BurdenThemesExamplesIllnessFrequent and varied infectionsRashes, skin/mucosal lesions, and infections in the lungs, ears, gums; poorly healing umbilical cordsPhysical restrictionsAvoiding water parks, beaches, other outdoor activities; limiting sports; preventing contact with petsSocial restrictionsLimiting visitors to the home; avoiding daycare; home schoolingJourney to diagnosis marked by lack of informationFailure of frequent severe infections and slow healing wounds to drive investigation and diagnosis; lack of resources, guidance, and information pre- and post-diagnosisTreatmentAlloHSCTSearching for a bone marrow match; complexity of alloHSCT process; managing alloHSCT complications; side-effects from post-transplant treatments; waning efficacyGene therapyGenerally positive outcomes, despite a long and complex process; required relocation for the duration of treatment; uncertainty about durability and longer-term effects given the novelty of GTProphylactic antimicrobialsIn 1 case, in the absence of a family donor match for alloHSCT, the clinician recommended this approach; parents indicated it is not a long-term nor complete solution Conclusion Together, the burdens of illness and treatment had profound impacts on these families. The parents’ descriptions also demonstrated that while none of the current treatments for severe LAD-I is perfect, GT shows great potential for improving patients’ health and minimizing disease burden. Moreover, this research provides critical insights for clinicians, whose care of children with severe LAD-I can be informed by understanding the struggles associated with the burdens of illness and treatment.
other
2022-05-31 | CD47 Binding on Vascular Endothelial Cells Inhibits IL-17-Mediated Leukocyte Adhesion.
To address the conflicting role of thrombospondin (TSP)-1 reported in acute and chronic pathologies, this study investigated the role of TSP-1 in regulating leukocyte recruitment and regulation of VCAM-1 expression using mouse models of uveitis. The spontaneously increased VCAM-1 expression and leukocyte adhesion in retinas of TSP-1-deficient mice suggested a TSP-1-mediated regulation of VCAM-1 expression. In a chronic uveitis model, induced by immunizing wild-type mice with specific interphotoreceptor retinoid-binding protein (IRBP) peptide, topically applied TSP-1-derived CD47-binding peptide significantly reduced the clinical disease course and retinal leukocyte adhesion as compared to the control peptide-treated group. In contrast, in LPS-mediated acute uveitis, TSP-1 deficiency significantly reduced the retinal leukocyte adhesion. The results of our in vitro study, using vascular endothelial cell (EC) cultures, demonstrate that unlike TNF-α, VCAM-1 expression induced by IL-17 is associated with a reduced expression of endogenous TSP-1. Such reduced endogenous TSP-1 expression in IL-17-stimulated ECs helps limit the CD36-mediated increased VCAM-1 expression, while favoring CD47-mediated inhibition of VCAM-1 expression and leukocyte adhesion. Thus, our study identifies TSP-1:CD47 interaction as a molecular pathway that modulates IL-17-mediated VCAM-1 expression, contributing to its anti-inflammatory effect in chronic inflammatory conditions.
2004-08-06 | Intracellular and cell surface localization of a complex between alphaMbeta2 integrin and promatrix metalloproteinase-9 progelatinase in neutrophils.
We have recently demonstrated that promatrix metalloproteinases (proMMPs), particularly proMMP-9, are potent ligands of the leukocyte beta(2) integrins. We studied here the complex formation between proMMP-9 and alpha(M)beta(2), the major MMP and integrin of neutrophils. On resting neutrophils, the proMMP-9/alpha(M)beta(2) complex was primarily detected in intracellular granules, but after cellular activation it became localized to the cell surface, as demonstrated by immunoprecipitation and double immunofluorescence. Further indication of the complex formation was that neutrophils and alpha(M)beta(2)-transfected L cells, but not the wild-type L cells or leukocyte adhesion deficiency cells, bound to immobilized proMMP-9 or its recombinant catalytic domain in a beta(2) integrin-dependent manner. Peptides that bound to the alpha(M) integrin-I domain and inhibited its complex formation with proMMP-9 prevented neutrophil migration in a transendothelial assay in vitro and in a thioglycolate-elicited peritonitis in vivo. These results suggest that the translocating proMMP-9/alpha(M)beta(2) complex may be part of the cell surface machinery guiding neutrophil migration.
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Drug Discovery Landscape
2 orphan drug designations for Leukocyte adhesion deficiency type I, including 1 approved therapy.
2 orphan drug designations for Leukocyte adhesion deficiency type I, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
marnetegragene autotemcel [Kresladi] | gene therapies | FDA | 2016-11-09 | 2026-03-26 | Rocket Pharmaceuticals, Inc. |
Haematopoietic stem cells modified with a lentiviral vector containing the CD18 gene | gene therapies | EMA | 2016-10-14 | — | Rocket Pharmaceuticals B.V. |
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