Gene Therapy for Netherton Syndrome

This study is not yet open for participant recruitment. (see Contacts and Locations)
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
  Purpose

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.


Condition Intervention Phase
Netherton Syndrome
Genetic: One 20cm2/10cm2 autologous skin sheet graft
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of Ex-vivo Lentiviral Gene Therapy for the Inherited Skin Disease Netherton Syndrome

Resource links provided by NLM:


Further study details as provided by Great Ormond Street Hospital for Children NHS Foundation Trust:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Estimated Enrollment: 5
Study Start Date: July 2012
Estimated Study Completion Date: July 2016
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
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

Detailed Description:

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.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01545323

Contacts
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

Locations
United Kingdom
Great Ormond Street Hospital for Children NHS Trust Not yet recruiting
London, United Kingdom, WC1N 3JH
Contact: Jemima Mellerio, Dr       jemima.mellerio@kcl.ac.uk   
Contact: Wei-Li Di, Dr       w.di@ucl.ac.uk   
Principal Investigator: Jemima Mellerio, Dr         
Guy's and St Thomas NHS Trust Not yet recruiting
London, United Kingdom, SE1 9RT
Contact: Jemima Mellerio, Dr       jemima.mellerio@kcl.ac.uk   
Contact: John McGrath, Prof       john.mcgrath@kcl.ac.uk   
Principal Investigator: Jemima Mellerio, Dr         
Sponsors and Collaborators
Great Ormond Street Hospital for Children NHS Foundation Trust
Investigators
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
  More Information

Publications:
Responsible Party: Great Ormond Street Hospital for Children NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT01545323     History of Changes
Other Study ID Numbers: 10MI30
Study First Received: March 1, 2012
Last Updated: October 17, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: Research Ethics Committee

Keywords provided by Great Ormond Street Hospital for Children NHS Foundation Trust:
Netherton syndrome
Gene therapy
SPINK5

Additional relevant MeSH terms:
Syndrome
Netherton Syndrome
Disease
Pathologic Processes
Abnormalities, Multiple
Congenital Abnormalities
Ichthyosiform Erythroderma, Congenital
Ichthyosis
Skin Abnormalities
Skin Diseases, Genetic
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Keratosis
Skin Diseases

ClinicalTrials.gov processed this record on September 22, 2014