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:
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
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.
2025-11-26 | 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.
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
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.
2025-11-26 | 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.
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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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