Gene Therapy for Leukocyte Adhesion Deficiency-I

• Research type

  Research Study

• Full title

  Gene Therapy for Leukocyte Adhesion Deficiency-I (LAD-I): A Phase I/II Clinical Trial to Evaluate the Safety and Efficacy of the Infusion of Autologous Hematopoietic Stem Cells Transduced with a Lentiviral Vector Encoding the ITGB2 Gene

• IRAS ID

  271744

• Contact name

  Jonathan D. Schwartz

• Contact email

  js@rocketpharma.com

• Sponsor organisation

  Rocket Pharmaceuticals Inc.

• Eudract number

  2020-000517-33

• Clinicaltrials.gov Identifier

  NCT03812263

• Clinicaltrials.gov Identifier

  n/a, n/a

• Duration of Study in the UK

  2 years, 3 months, 0 days

• Research summary

  Research Summary:
  Leukocyte adhesion deficiency (LAD) is a rare, genetic disorder affecting the immune system and affecting how white blood cells (leukocytes) respond and travel to the site of a wound or infection. This is a very complex process requiring several, precise steps. White blood cells attach themselves to the thin layer of cells lining the inside surface of blood vessels (endothelium). Specific chemicals (proteins) are necessary to allow white blood cells to stick to the endothelium. Individuals with LAD do not have enough of these proteins; their white blood cells cannot stick to the endothelium. Therefore, white blood cells cannot reach the site of infection. Severe forms of the disorder can cause life-threatening complications and death in childhood is common.

  LAD-I is caused by mutations of a gene called ITGB2. A white blood cell, (neutrophil), is most often affected in those individuals with LAD-I. Neutrophils defend the body against bacteria.
  LAD-I usually occurs in early infancy/childhood. Infections are common; bacterial and fungal infections most often affect skin, mucous membranes, digestive and respiratory tracts. After infancy, affected children may develop progressive inflammation of the teeth and gums leading to tooth loss.

  Antibiotics may be used for infections in the moderate form of LAD-I but currently, the only potentially curative treatment is a bone marrow (stem-cell) transplant from a compatible healthy donor, which may not be available for all patients. This procedure is associated with risk of infection or graft-versus-host disease where the donor cells may attack the patient's tissues.
  A stem-cell transplant, using cells from the patient's own body and adding healthy copies of the ITGB2 gene into the bone marrow may be a better treatment option. Although experimental, given the rare and serious nature of the disease, may potentially provide a cure.

  Lay summary of study results:
  Study RP-L201-0318 met its primary and secondary endpoints, demonstrating clinical benefit with all subjects alive and without allogeneic HSCT (haematopoietic stem cell transplantation) at data cut-off, no events of graft failure or Graft-versus-host disease (GvHD) and a marked post-treatment reduction in significant infections, infection-related hospitalizations, and prolonged infection-related hospitalizations. In addition, all subjects had evidence of genotypic and phenotypic correction with sustained PBMC Vector Copy Number (VCN) levels above 0.1 and neutrophil CD18 expression above 10%, with concomitant restored CD11a/CD11b expression. All evaluable parameters of efficacy indicate resolution of the severe LAD-I phenotype at genetic, molecular, cellular and clinical levels. In addition, Study RP L201-0318 demonstrated a favorable RP-L201 tolerability profile in subjects with severe LAD-I, a rare primary immunodeficiency causing near-universal paediatric mortality. The transformative therapeutic effect of RP-L201 (investigational product) favourably and comprehensively impacts survival and the quality of life of subjects, who can participate in age-appropriate normal educational and recreational activities despite extensive pre-study restrictions; there is concomitant substantive improvement in their caregivers’ and parents’ ability to pursue unrestricted family- and work-related endeavours.

• REC name

  London - West London & GTAC Research Ethics Committee

• REC reference

  20/LO/0687

• Date of REC Opinion

  14 Jul 2020

• REC opinion

  Further Information Favourable Opinion