Gene Therapy for Netherton Syndrome

NHS Foundation Trust

Status and phase: Unknown; Phase 1

Conditions: Netherton Syndrome

Treatments: Genetic: One 20cm2/10cm2 autologous skin sheet graft

Study type: Interventional

Funder types: Other

Identifiers

NCT01545323

10MI30

Details and patient eligibility

About

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.

Full 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.

Enrollment: 5 estimated patients

Sex: All

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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5 participants in 1 patient group

One 20cm2/10cm2 autologous skin sheet graft

Experimental group

Description:

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

Treatment:

Genetic: One 20cm2/10cm2 autologous skin sheet graft