Gentamicin Therapy for Recessive Dystrophic Epidermolysis Bullosa (RDEB) Nonsense Mutation Patients

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Brief Title

Gentamicin Therapy for Recessive Dystrophic Epidermolysis Bullosa (RDEB) Nonsense Mutation Patients


Brief Summary

      Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable, devastating, inherited
      skin disease for which there is only supportive care. RDEB is due to mutations in COL7A1 gene
      that encodes for type VII collagen (C7), the major component of anchoring fibrils (AFs)
      mediating epidermal-dermal adherence. Approximately 20% of COL7A1 mutations are nonsense
      mutations leading to premature stop codons and a truncated C7 with diminished function. The
      investigators demonstrated that aminoglycosides such as gentamicin readily induce premature
      termination codon (PTC) "read through" and produce biologically functional C7 in 22 reported
      COL7A1 nonsense mutations. Importantly, aminoglycoside-induced C7 reversed the abnormal RDEB
      cell phenotype and incorporated into the dermal-epidermal junction. Herein, the investigators
      propose the first clinical trial of gentamicin (topical and intradermal) in RDEB patients
      with nonsense mutations that the investigators have fully characterized. The milestones
      include increased C7 and AFs at the patients' dermal-epidermal junction and absence of
      significant gentamicin side effects.
    

Detailed Description

      Evaluate C7 and AF expression with topical and intradermal gentamicin treatment Topical
      application of gentamicin to skin lesion: We will apply commercially available gentamicin
      0.1% ointment three times a day under Tegaderm occlusion for two weeks to a target RDEB skin
      erosion. Likewise, we will apply the ointment control vehicle three times a day to a
      similarly sized RDEB erosion. This dosage schedule is based on the successful clinical trial
      in CF patients that resulted in clinical efficacy without side effects.19 In our in vitro
      cell culture studies, we showed that a single dose of gentamicin (400 ug/ml) induced C7
      expression at a level of 20-40% of that seen in normal cells (Figure 1A and 1B).23 In our
      clinical trial, the experimental ointment will contain 1 milligram of gentamicin per
      milliliter of ointment vehicle.

      Injection of gentamicin into the high dermis of RDEB patient skin: In addition, we will
      identify target 2.0 cm x 2.0 cm areas of unwounded intact skin within areas prone to blister
      formation and intradermally inject commercially available sterile gentamicin solution (40
      mg/ml in saline). A similar control area will be injected with equal volumes of saline. We
      will inject 200 ul (8 milligrams) into each site once on day 0 and once again on day 1. A
      single injection will be administered to the site on each of the two days. The total dose
      will be 16 milligrams injected into the upper dermis where it will contact the patient's
      dermal fibroblasts and basal keratinocytes. In our published in vitro read-through study,
      each 1 cm2 of cultured cells was exposed to 400 ugs/ml of gentamicin that showed read-through
      activity with no cytoxocity. For the proposed intradermal study, we will be using a total
      dose approximately 5-fold greater than the in vitro dose.

      Initial and follow-up Parameters: Prior to any treatment, the RDEB patients will be subjected
      to a 9 mm shave biopsy of intact skin that will be divided into 3 parts and evaluated for H&E
      histology, transmission electron microscopy and direct immunofluorescence for C7 expression.
      At 1 and 3 months after gentamicin treatment of RDEB erosions or intact skin in blister prone
      areas, we will biopsy the treated sites and repeat the histological, ultrastructural and C7
      expression evaluations. For the assessment of C7 expression at the DEJ by immunofluorescence
      (IF), 5 micron cryosections will be probed with anti-C7 polyclonal antibodies to the NC1 and
      NC2 domains of C7. The increased expression of the NC2 domain of C7 at the DEJ of
      gentamicin-treated skin or erosions will serve as one major "milestone" in this study since
      it would indicate PTC read-through and restoration of a full-length C7. The third part of the
      biopsy will be evaluated ultrastructurally, and AFs will be enumerated by computer-assisted
      morphometry. These studies will assess if there is restoration of normal AFs. Skin sections
      from normal human subjects will serve as positive controls, while skin sections from the
      vehicle control site will serve as negative controls.

      Patient clinical assessment: Skin Erosion Sites: Patients will be blinded to the gentamicin
      and vehicle treatments of the Experimental Site and Control Site. Each week, the patients
      will assess the sites and grade their healing as follows: - 1 = enlargement of the erosion
      compared to its initial size; 0 = no change in the size of the erosion; +1 = partial healing
      and a smaller erosion than its initial size, and +2 = complete closure of the wound.

      Secondly, baseline photographs of the erosions will be generated and the area of the erosions
      calculated by computer-assisted planimetry. Identical assessments will be made at 1 and 3
      months post treatment. Therefore, a second "milestone" for this study will be decreased
      surface areas of gentamicin-treated erosions compared with vehicle control-treated erosions.

      Evaluation of RDEB intact skin treated by intradermal injections of gentamicin: Patients and
      Investigators will be blinded to the treatments of the Experimental Area and Control Area.
      Each week, the patient will evaluate the areas and grade them as follows: - 1 = new blister
      or erosion formation in the site, and +1 = no new blisters or erosions. At USC visits at 1
      and 3 months, biopsies will be obtained from the sites and evaluated as above for the
      expression of C7 at the DEJ and enumeration of AFs.

      Evaluation of Patients' Safety: Patients will have baseline histories, review of systems
      (ROS), vital signs (including weight) and physical examinations on Day 0 before treatment,
      and at Day 1 (one day after treatment) and then at 1 and 3 months during their visits to USC.
      At these same time points, blood tests will be performed and include a complete blood count,
      electrolytes, liver enzymes, erythrocyte sedimentation rate, creatinine, and BUN. Creatinine
      clearances will be also calculated, and the patient's treatment sites will be evaluated for
      erythema, edema, blistering and erosions. At Day 0, 1 month and 3 months after treatment,
      audiometry evaluations will be done. Patients will complete a ROS questionnaire daily at
      home, and be telephoned weekly by a USC study member inquiring about any new signs, symptoms,
      or ROS changes.

      E. Characterization of Immune Responses to Gentamicin-Induced C7: Our study patients all
      express lower levels of C7 including the NC1 domain, which is the most antigenic domain of
      C7. Therefore, with the exception of patient B, we doubt that reading through the patient's
      PTC will induce a protein that is viewed as antigenic by the patient's immune system.
      Nevertheless, we hope that gentamicin will generate a functional, rather than non-functional,
      species of C7. To evaluate if this change triggers an immune response and generates anti-C7
      antibodies, patient serum will be obtained at baseline, 1 month, and 3 months for evaluation
      of anti-C7 antibodies by salt-split IIF and ELISA. If a patient develops antibodies to C7, we
      will then examine their skin for C7 antibody deposits by DIF.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Restoration of Full-length Type VII Collagen as Assessed by Immunofluorescence.


Condition

Recessive Dystrophic Epidermolysis Bullosa

Intervention

Gentamicin

Study Arms / Comparison Groups

 Gentamicin
Description:  Gentamicin antibiotic

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

5

Start Date

February 25, 2016

Completion Date

June 30, 2017

Primary Completion Date

March 31, 2017

Eligibility Criteria

        Inclusion Criteria:

        (i) RDEB patients with a nonsense mutation in COL7A1 in either one or two alleles (ii) An
        absence or decrease in C7 expression at their DEJ when compared to that of normal human
        skin.

        Exclusion Criteria:

        (i) Pre-existing renal or auditory impairment (ii) Allergies to aminoglycosides or sulfate
        compounds (iii) Pregnancy (iv) Exposure to gentamicin within the past 6 weeks.
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

David Woodley, MD, , 



Administrative Informations


NCT ID

NCT02698735

Organization ID

HS-15-00821


Responsible Party

Principal Investigator

Study Sponsor

University of Southern California


Study Sponsor

David Woodley, MD, Principal Investigator, University of Southern California Department of Dermatology


Verification Date

October 2019