NCT01545323

Brief Summary

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.

Trial Health

43
At Risk

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date
Enrollment
5

participants targeted

Target at below P25 for phase_1

Timeline
Completed

Started Apr 2014

Longer than P75 for phase_1

Geographic Reach
1 country

2 active sites

Status
unknown

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

March 1, 2012

Completed
5 days until next milestone

First Posted

Study publicly available on registry

March 6, 2012

Completed
2.1 years until next milestone

Study Start

First participant enrolled

April 1, 2014

Completed
4 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

April 1, 2018

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

April 1, 2018

Completed
Last Updated

October 19, 2016

Status Verified

October 1, 2016

Enrollment Period

4 years

First QC Date

March 1, 2012

Last Update Submit

October 18, 2016

Conditions

Netherton Syndrome

Keywords

Netherton syndromeGene therapySPINK5

Outcome Measures

Primary Outcomes (2)

  • Safety of gene modified grafts

    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.

    1 year

  • Histological evidence of correction of graft skin architecture

    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.

    1 year

Secondary Outcomes (2)

  • Detection of increased LEKT1 staining at site outside the graft

    1 year

  • Immune response to graft/transgene

    1 year

Study Arms (1)

One 20cm2/10cm2 autologous skin sheet graft

EXPERIMENTAL

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

Interventions

One 20cm2/10cm2 autologous skin sheet graftGENETIC

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

One 20cm2/10cm2 autologous skin sheet graft

Eligibility Criteria

Sexall
Healthy VolunteersNo
Age GroupsChild (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

  • 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

You may not qualify if:

  • 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

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (2)

Guy's and St Thomas NHS Trust

London, SE1 9RT, United Kingdom

RECRUITING

Great Ormond Street Hospital for Children NHS Trust

London, WC1N 3JH, United Kingdom

NOT YET RECRUITING

Related Publications (3)

  • Bitoun E, Micheloni A, Lamant L, Bonnart C, Tartaglia-Polcini A, Cobbold C, Al Saati T, Mariotti F, Mazereeuw-Hautier J, Boralevi F, Hohl D, Harper J, Bodemer C, D'Alessio M, Hovnanian A. LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. Hum Mol Genet. 2003 Oct 1;12(19):2417-30. doi: 10.1093/hmg/ddg247. Epub 2003 Jul 29.

    PMID: 12915442BACKGROUND

  • Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD, Bonafe JL, Wilkinson J, Taieb A, Barrandon Y, Harper JI, de Prost Y, Hovnanian A. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet. 2000 Jun;25(2):141-2. doi: 10.1038/75977.

    PMID: 10835624BACKGROUND

  • Di WL, Mellerio JE, Bernadis C, Harper J, Abdul-Wahab A, Ghani S, Chan L, Martinez-Queipo M, Hara H, McNicol AM, Farzaneh F, McGrath J, Thrasher A, Qasim W. Phase I study protocol for ex vivo lentiviral gene therapy for the inherited skin disease, Netherton syndrome. Hum Gene Ther Clin Dev. 2013 Dec;24(4):182-90. doi: 10.1089/humc.2013.195.

    PMID: 24329107DERIVED

MeSH Terms

Conditions

Netherton Syndrome

Condition Hierarchy (Ancestors)

Abnormalities, MultipleCongenital AbnormalitiesCongenital, Hereditary, and Neonatal Diseases and AbnormalitiesIchthyosiform Erythroderma, CongenitalIchthyosisSkin AbnormalitiesSkin Diseases, GeneticGenetic Diseases, InbornInfant, Newborn, DiseasesKeratosisSkin DiseasesSkin and Connective Tissue Diseases

Study Officials

  • 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

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Waseem Qasim, Dr

CONTACT

00442079052764w.qasim@ucl.ac.uk

Anne-Marie McNicol, Dr

CONTACT

00442079052292anne-marie.mcnicol@ucl.ac.uk

Study Design

Study Type
interventional
Phase
phase 1
Allocation
NA
Masking
NONE
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

March 1, 2012

First Posted

March 6, 2012

Study Start

April 1, 2014

Primary Completion

April 1, 2018

Study Completion

April 1, 2018

Last Updated

October 19, 2016

Record last verified: 2016-10

Locations

GB(2)