Netherton SyndromePhase 1NCT01545323
Gene Therapy for Netherton Syndrome
A Phase 1 study testing One 20cm2/10cm2 autologous skin sheet graft in people with Netherton Syndrome, run by Great Ormond Street Hospital for Children NHS Foundation Trust at 2 sites in United Kingdom.
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). Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Netherton Syndrome
- What is being tested?
- One 20cm2/10cm2 autologous skin sheet graft
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 2 sitesUnited Kingdom
- Study dates
- Apr 2014to Apr 2018
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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 locations and contacts
2 sites in 1 country.
United Kingdom2 sites, 2 recruiting
- Recruiting
Guy's and St Thomas NHS Trust
London, SE1 9RT
Jemima Mellerio, Dr, jemima.mellerio@kcl.ac.uk
John McGrath, Prof, john.mcgrath@kcl.ac.uk
- Not yet recruiting
Great Ormond Street Hospital for Children NHS Trust
London, WC1N 3JH
Jemima Mellerio, Dr, jemima.mellerio@kcl.ac.uk
Wei-Li Di, Dr, w.di@ucl.ac.uk
About this study
Official title: 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.
Read the 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
- Being tested
- One 20cm2/10cm2 autologous skin sheet graft
- Keywords
- Netherton syndrome, Gene therapy, SPINK5
- Medical subject headings
- Netherton Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Genetic: One 20cm2/10cm2 autologous skin sheet graft |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 1 year
Secondary outcomes (2)
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.
Measured: 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.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Mar 2012 (estimated)
- Study startApr 2014
- Primary completionApr 2018 (estimated)
- Study completionApr 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Netherton SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 5 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Great Ormond Street Hospital for Children NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jemima Mellerio, Dr, Principal investigator, Great Ormond Street Hospital for Children NHS Foundation TrustJemima Mellerio, Dr, Principal investigator, Guy's and St thomas Hospital NHS Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01545323
- Sponsor's protocol ID
- 10MI30
- Status last verified
- Oct 2016
- First submitted
- 1 Mar 2012
- Last updated
- 19 Oct 2016
- Results posted
- No
- Data monitoring committee
- Yes
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.
PubMed 12915442Chavanas 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.
PubMed 10835624Di 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.
PubMed 24329107
Study at a glance
From the registry record, last updated by the sponsor on 19 Oct 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Study of Ex-vivo Lentiviral Gene Therapy for the Inherited Skin Disease Netherton Syndrome
- ClinicalTrials.gov ID
- NCT01545323
- Acronym / sponsor ID
- 10MI30
- Conditions
- Netherton Syndrome
- Keywords
- Netherton syndrome, Gene therapy, SPINK5
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 5 participants (estimated)
- Lead sponsor
- Great Ormond Street Hospital for Children NHS Foundation TrustUniversity, hospital or other
- Study start
- Apr 2014
- Primary completion
- Apr 2018 (estimated)
- Study completion
- Apr 2018 (estimated)
- First posted
- 6 Mar 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| One 20cm2/10cm2 autologous skin sheet graft | Experimental | Genetic: One 20cm2/10cm2 autologous skin sheet graftAdults 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 |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (4 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| One 20cm2/10cm2 autologous skin sheet graftAdults 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 |
Primary outcome
Safety of gene modified grafts
Time frame: 1 year
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.
Histological evidence of correction of graft skin architecture
Time frame: 1 year
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.
2 secondary outcomes
Detection of increased LEKT1 staining at site outside the graft
Time frame: 1 year
Immune response to graft/transgene
Time frame: 1 year
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Oct 2016.
- Background: PubMed 12915442Bitoun 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.
- Background: PubMed 10835624Chavanas 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.
- Derived from this study: PubMed 24329107Di 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.
Related trials for Netherton Syndrome
RecruitingPhase 2/3
Phase 2/3 Clinical Study of QRX003 Lotion in Subjects With Netherton Syndrome
Netherton Syndrome
RecruitingPhase 2/3
Clinical Study of QRX003 Lotion in Subjects With Netherton Syndrome
Netherton Syndrome
RecruitingPhase 2/3
Open Label, Safety and Efficacy Study of QRX003 Lotion in Subjects With Netherton Syndrome
Netherton Syndrome
RecruitingPhase 1
A Study of the Safety, Tolerability, Pharmacokinetics, and Immunogenicity of BCX17725
Netherton Syndrome
RecruitingObservational study
Study of Skin and Gut Microbiome in a Skin Condition Involving Skin Barrier Impairment and Allergic Symptoms: Netherton Syndrome
Netherton Syndrome
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jemima Mellerio, Dr principal investigator
Great Ormond Street Hospital for Children NHS Foundation Trust
Jemima Mellerio, Dr principal investigator
Guy's and St thomas Hospital NHS Trust
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing One 20cm2/10cm2 autologous skin sheet graft in people with Netherton Syndrome, run by Great Ormond Street Hospital for Children NHS Foundation Trust at 2 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 19 Oct 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Waseem Qasim, Dr (00442079052764 ext. 2794, w.qasim@ucl.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety of gene modified grafts (time frame: 1 year). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01545323, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Oct 2016.