Gene Therapy for Netherton Syndrome

NCT ID: NCT01545323

Last Updated: 2016-10-19

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-04-30
• Study Completion Date: 2018-04-30

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.

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.

Conditions

Netherton Syndrome

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

One 20cm2/10cm2 autologous skin sheet graft

Intervention Type: GENETIC

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

Interventions

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

Intervention Type: GENETIC

Eligibility 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

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Great Ormond Street Hospital for Children NHS Foundation Trust

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jemima Mellerio, Dr

Role: PRINCIPAL_INVESTIGATOR

Great Ormond Street Hospital for Children NHS Foundation Trust

Jemima Mellerio, Dr

Role: PRINCIPAL_INVESTIGATOR

Guy's and St thomas Hospital NHS Trust

Locations

Guy's and St Thomas NHS Trust

London, , United Kingdom

Site Status: RECRUITING

Great Ormond Street Hospital for Children NHS Trust

London, , United Kingdom

Site Status: NOT_YET_RECRUITING

Countries

United Kingdom

Central Contacts

Waseem Qasim, Dr

Role: CONTACT

w.qasim@ucl.ac.uk

00442079052764 ext. 2794

Anne-Marie McNicol, Dr

Role: CONTACT

anne-marie.mcnicol@ucl.ac.uk

00442079052292 ext. 2292

Facility Contacts

Jemima Mellerio, Dr

Role: primary

jemima.mellerio@kcl.ac.uk

John McGrath, Prof

Role: backup

john.mcgrath@kcl.ac.uk

Jemima Mellerio, Dr

Role: primary

jemima.mellerio@kcl.ac.uk

Wei-Li Di, Dr

Role: backup

w.di@ucl.ac.uk

References

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.

Reference Type: BACKGROUND

PMID: 12915442 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 10835624 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24329107 (View on PubMed)

Other Identifiers

10MI30

Identifier Type: -

Identifier Source: org_study_id