Gene Therapy for Netherton Syndrome

Netherton Syndrome Clinical Trial

Official title:

Phase I Study of Ex-vivo Lentiviral Gene Therapy for the Inherited Skin Disease Netherton Syndrome

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01545323
• Other study ID #: 10MI30
• Status: Recruiting
• Phase: Phase 1
• First received: March 1, 2012
• Last updated: October 18, 2016
• Start date: April 2014
• Est. completion date: April 2018

Study information

• Verified date: October 2016
• Source: Great Ormond Street Hospital for Children NHS Foundation Trust
• Contact: Waseem Qasim, Dr
• Phone: 00442079052764
• Email: w.qasim[@]ucl.ac.uk
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited Kingdom: Research Ethics Committee
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 5
• Est. completion date: April 2018
• Est. primary completion date: April 2018
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

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 Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Netherton Syndrome
• Syndrome

Intervention

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

Locations

Country	Name	City	State
United Kingdom	Great Ormond Street Hospital for Children NHS Trust	London
United Kingdom	Guy's and St Thomas NHS Trust	London

Sponsors (1)

Lead Sponsor	Collaborator
Great Ormond Street Hospital for Children NHS Foundation Trust

Country where clinical trial is conducted

United Kingdom, 

References & Publications (2)

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. Epub 2003 Jul 29. — View Citation

Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD, Bonafé JL, Wilkinson J, Taïeb 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Primary	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	Yes
Secondary	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	No
Secondary	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	Yes