Global Gene Therapy Clinical Trial for

 Severe Leukocyte Adhesion Deficiency-I (LAD-I)

What is Leukocyte Adhesion Deficiency-I (LAD-I)? 

LAD-I is a rare inherited primary immunodeficiency characterized by defective leukocyte adhesion and migration. It is caused by mutations in the ITGB2 gene that encodes for the β2-integrin component, CD18. Mutations in the ITGB2 gene prevent normal dimerization of the β2 subunit with corresponding α-subunits on leukocyte cell surfaces (primarily neutrophils).  This impairs the ability of neutrophils to adhere to inflamed endothelial surfaces and extravasate to infection sites, diminishing neutrophil antimicrobial activity.

In severe LAD-I, where neutrophil CD18 expression is <2% of normal levels, mortality is 60-75% by age 2 in the absence of an allogeneic stem cell transplant. Death typically results from recurrent, disseminated and life-threatening bacterial infections, most frequently originating in the skin, mucosal surfaces, digestive and respiratory tracts.

What is the purpose of this LAD-I gene therapy clinical trial? 

This study is an open-label adaptive Phase 1/2 clinical trial to assess the safety and efficacy of autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a lentiviral vector (LV) containing the ITGB2 gene encoding for the human CD18 receptor (β2 integrin subunit).

Who is eligible to participate in the LAD-I gene therapy clinical trial? 

Pediatric patients ≥ 3 months of age with severe LAD-I as demonstrated by CD18 expression on <2% neutrophils (polymorphonuclear neutrophils (PMNs)) are eligible.

Additionally, patients in whom CD18+ PMN expression is >2% will be considered eligible if there is <2% CD11a or CD11b PMN expression and there is a documented ITGB2 mutation and clinical history consistent with LAD-I (or known family history).

Patients for whom a hematopoietic stem cell transplantation (HSCT) with an HLA-identical sibling donor is either unavailable or unfeasible.

Where will the LAD-I gene therapy clinical trial be taking place? 

Two clinical centers will be enrolling severe LAD-I patients following very similar protocols:

  1. University of California, Los Angeles (UCLA) in Los Angeles, California, USA  learn more about US Site
  2. Hospital del Niño Jesús in Madrid, Spain learn more about European Site

What does participation in the LAD-I gene therapy clinical trial involve? 

Following screening of patients to confirm eligibility for the trial, participating in the study will involve:

  • Mobilization and Collection of HSPCs: Mobilization is performed via administration of granulocyte-colony stimulating factor (G-CSF) and plerixafor (AMD-3100).  Collection is performed via peripheral blood apheresis, requiring a temporary central venous catheter.  In select circumstances, HSPCs may also be collected by means of a bone marrow (BM) harvest.
  • Infusion of Genetically Modified Stem Cells (the Investigational Gene Therapy): Following ex vivo transduction of HSPCs with the LV encoding for the ITGB2 gene and busulfan conditioning, the gene-modified HSPCs are infused into the patient.
  • Follow-up after Administration of the Investigational Gene Therapy: Patients will need to return for follow-up visits, including blood and bone marrow tests, over the following 2 years.  In addition, patients will have long-term follow-up with their home physician approximately 1-2 times per year for an additional 13 years.

How much will it cost to participate in the trial? 

Financial support, including travel arrangements and housing accommodations for patients and a family member, both for the treatment and follow-up visits, will be provided.  This will also include assistance with passports, medical visas and translation services for patients and families if these are needed.

Who can I contact with any additional questions?

Send any questions to LADclinicaltrial@rocketpharma.com.