Gene Therapy for Netherton Syndrome

This study is not yet open for participant recruitment.
Verified October 2013 by Great Ormond Street Hospital for Children NHS Foundation Trust
Sponsor:
Information provided by (Responsible Party):
Great Ormond Street Hospital for Children NHS Foundation Trust
ClinicalTrials.gov Identifier:
NCT01545323
First received: March 1, 2012
Last updated: October 17, 2013
Last verified: October 2013

March 1, 2012
October 17, 2013
July 2012
July 2016   (final data collection date for primary outcome measure)
  • Safety of gene modified grafts [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    Adverse events will be monitored and assessed throughout the duration of the trial. Patients will be followed-up on-trial for 1 year. Subsequently, patients will be followed-up off-trial for life, as part of normal clinical care.
  • Histological evidence of correction of graft skin architecture [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    A skin biopsy will be taken from the graft area to determine correction of the skin architecture and to identify expression of LEKTI at time points 1, 3, 6 & 12 months post-grafting.
Same as current
Complete list of historical versions of study NCT01545323 on ClinicalTrials.gov Archive Site
  • Detection of increased LEKT1 staining at site outside the graft [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    A skin biopsy will be taken from the graft area to enable LEKTI staining at time points 1, 3, 6 & 12 months post-grafting.
  • Immune response to graft/transgene [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    ELISPOT will be used to detect possible cell mediated responses against the gene modified graft at time points 1, 3, 6 & 12 months post-grafting.
Same as current
Not Provided
Not Provided
 
Gene Therapy for Netherton Syndrome
Phase I Study of Ex-vivo Lentiviral Gene Therapy for the Inherited Skin Disease Netherton Syndrome

Netherton Syndrome is a serious skin disorder caused by damage in a gene called SPINK5. This gene controls the formation of a protein called LEKTI, which important for skin barrier function. LEKTI inhibits certain enzymes (serine proteinases) in the outermost layer of the skin (epidermis). The function of the serine proteinases is to break down the intracellular cement that holds together the horny cells in the epidermis, in order for the skin to be able to shed cells (known as cell desquamation). LEKTI deficiency leads to an uninhibited desquamation of horny cells, and as a result the skin becomes red and scaly. The barrier function of the skin is also affected. The permeability of the skin increases, and its capacity to bind water decreases, which causes dryness. The thinness of the barrier also results in over absorption of chemicals, for example topical medical treatments. Historically one in ten infants dies before their first birthday. Currently there are no proven treatments to cure this condition.

The investigators have been developing a gene therapy approach to treat this disorder. The investigators have used a disabled virus (vector) to carry a functional copy of the SPINK5 gene into skin stem cells. Proof-of-principle experiments have shown the investigators can restore almost normal shape and size of the upper layer of the skin in skin grafts grown in the lab. Even if only a small number of cells are genetically modified to carry the corrected SPINK5 gene, there seems to be a correction over a wide area of the graft.

In this trial the investigators propose grafting of autologous epidermal sheets generated from genetically modified skin stem cells for the treatment of patients with Netherton Syndrome. The investigators anticipate production and release of LEKTI protein from even a small patch of skin will be beneficial.

Netherton Syndrome is a serious skin disorder caused by damage in a gene called SPINK5. This gene controls the formation of a protein called LEKTI, which important for skin barrier function. LEKTI inhibits certain enzymes (serine proteinases) in the outermost layer of the skin (epidermis). The function of the serine proteinases is to break down the intracellular cement that holds together the horny cells in the epidermis, in order for the skin to be able to shed cells (known as cell desquamation). LEKTI deficiency leads to an uninhibited desquamation of horny cells, and as a result the skin becomes red and scaly. The barrier function of the skin is also affected. The permeability of the skin increases, and its capacity to bind water decreases, which causes dryness. The thinness of the barrier also results in over absorption of chemicals, for example topical medical treatments. Historically one in ten infants dies before their first birthday. Currently there are no proven treatments to cure this condition.

The investigators have been developing a gene therapy approach to treat this disorder. The investigators have used a disabled virus (vector) to carry a functional copy of the SPINK5 gene into skin stem cells. Proof-of-principle experiments have shown the investigators can restore almost normal shape and size of the upper layer of the skin in skin grafts grown in the lab. Even if only a small number of cells are genetically modified to carry the corrected SPINK5 gene, there seems to be a correction over a wide area of the graft.

In this trial the investigators propose grafting of autologous epidermal sheets generated from genetically modified skin stem cells for the treatment of patients with Netherton Syndrome. The investigators anticipate production and release of LEKTI protein from even a small patch of skin will be beneficial.

Interventional
Phase 1
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Netherton Syndrome
Genetic: One 20cm2/10cm2 autologous skin sheet graft
Adults will receive a graft of approximately 20cm2. Children under 16 years of age will receive a graft around half this size, around 10cm2 .The graft is derived from SPINK5 transduced cells
Experimental: One 20cm2/10cm2 autologous skin sheet graft
Adults will receive a graft of approximately 20cm2. Children under 16 years of age will receive a graft around half this size, around 10cm2 .The graft is derived from SPINK5 transduced cells
Intervention: Genetic: One 20cm2/10cm2 autologous skin sheet graft

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Not yet recruiting
5
July 2016
July 2016   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Confirmed SPINK5 mutations in both alleles by direct DNA sequencing
  • Absence of LEKTI protein expression in the skin by in situ immunostaining
  • Patient informed consent, or parental/guardian consent in the case of minor participant

Exclusion Criteria:

  • History of skin malignancy or evidence of current active malignant skin disease
  • Pregnancy
  • Hepatitis A, B, C or HIV positive
  • Current antibiotic resistant bacterial colonisation
Both
Not Provided
No
Contact: Waseem Qasim, Dr 00442079052764 ext 2794 w.qasim@ucl.ac.uk
Contact: Anne-Marie McNicol, Dr 00442079052292 ext 2292 anne-marie.mcnicol@ucl.ac.uk
United Kingdom
 
NCT01545323
10MI30
Yes
Great Ormond Street Hospital for Children NHS Foundation Trust
Great Ormond Street Hospital for Children NHS Foundation Trust
Not Provided
Principal Investigator: Jemima Mellerio, Dr Great Ormond Street Hospital for Children NHS Foundation Trust
Principal Investigator: Jemima Mellerio, Dr Guy's and St thomas Hospital NHS Trust
Great Ormond Street Hospital for Children NHS Foundation Trust
October 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP