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.

Study Overview

• Status: Unknown
• Conditions: Netherton Syndrome
• Intervention / Treatment: Genetic: One 20cm2/10cm2 autologous skin sheet graft

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.

• Study Type: Interventional
• Enrollment (Anticipated): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Detection of increased LEKT1 staining at site outside the graft	A skin biopsy will be taken from the graft area to enable LEKTI staining at time points 1, 3, 6 & 12 months post-grafting.	1 year
Immune response to graft/transgene	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.	1 year

Collaborators and Investigators

• Sponsor: 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

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Anticipated): April 1, 2018
• Study Completion (Anticipated): April 1, 2018

Study Registration Dates

• First Submitted: March 1, 2012
• First Submitted That Met QC Criteria: March 5, 2012
• First Posted (Estimate): March 6, 2012

Study Record Updates

• Last Update Posted (Estimate): October 19, 2016
• Last Update Submitted That Met QC Criteria: October 18, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Gene therapy; Netherton syndrome; SPINK5
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Disease; Congenital Abnormalities; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Skin Diseases, Genetic; Skin Abnormalities; Abnormalities, Multiple; Keratosis; Ichthyosiform Erythroderma, Congenital; Ichthyosis; Syndrome; Netherton Syndrome
• Other Study ID Numbers: 10MI30

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No