Autologous Adipose-Derived Adult Stem Cell Implantation for Corneal Diseases (ADASCs-CT-CD)
Condition: Ophthalmological Disorder; Corneal Dystrophy; Treatment; Therapy; Keratoconus
MeSH terms: Keratoconus; Corneal Dystrophies, Hereditary; Corneal Diseases; Eye Diseases
Study type: Interventional
Phase: Phase 2

Summary: 
      Cellular therapy of the corneal stroma with implantation of mesenchymal stem cells derived
      from autologous adipose tissue with or without a carrier (scaffold) composed by
      decellularized human donor corneal stroma is used in patients with corneal diseases such as
      corneal dystrophies, and keratoconus.

      For this purpose, the study planned to assess the enhancement of visual acuity, pachymetric,
      and aberrometric parameters with implantation of autologous mesenchymal adipose
      tissue-derived adult stem cells (ADASCs) alone, 120 µm thickness of decellularized or
      recellularized laminas with ADASCs. Three groups will be included in the study: (1)
      Implantation of a single dose of ADASCs alone without scaffold. (2) Implantation of
      decellularized human corneal lamina without ADASCs. (3) Implantation of the recellularized
      human corneal lamina with ADASCs.
    

Detailed description: 
      Different types of stem cells have been used in various ways in several research projects to
      find the optimal procedure to regenerate the human corneal stroma. It included several
      approaches which can be classified as intrastromal implantation of stem cells (1) alone, (2)
      together with a biodegradable scaffold, (3) with a non-biodegradable scaffold, or (4) with a
      decellularized corneal stromal scaffold. The complex structure of the corneal stroma has not
      been yet replicated, and there are well-known drawbacks to the use of synthetic
      scaffold-based designs. Recently, several corneal decellularization techniques have been
      described, which provide an acellular corneal extracellular matrix (ECM). These scaffolds
      have gained attention in the last few years. The scaffold provides a more natural environment
      for the growth and differentiation of cells when compared with synthetic scaffolds. In
      addition, components of the ECM are generally conserved among species and are tolerated well
      even by xenogeneic recipients. Keratocytes are essential for remodeling the corneal stroma
      and for normal epithelial physiology. This highlights the importance of transplanting a
      cellular substitute together with the structural support (acellular ECM) to undertake these
      critical functions in corneal homeostasis. To the best of the investigators' knowledge, all
      attempts to repopulate decellularized corneal scaffolds have used corneal cells, but these
      cells have major drawbacks that preclude their autologous use in clinical practice (damage of
      the donor tissue, lack of cells, and inefficient cell subcultures), thus the efforts to find
      an extraocular source of autologous cells. A recent study by the investigators has shown a
      perfect bio integration of human decellularized corneal stromal laminas (100 µm thickness)
      with and without h-ADASCs colonization inside the rabbit cornea in vivo, without observing
      any rejection response despite the graft being xenogeneic. The investigators also
      demonstrated the differentiation of h-ADASCs into functional keratocytes inside these
      implants in vivo, which then achieved their proper biofunctionalization. According to the
      investigator's opinion, the transplant of stem cells together with decellularized corneal ECM
      would be the best technique to effectively restore the thickness of a diseased human cornea,
      like in keratoconus. Through this technique, and using extraocular mesenchymal stem cells
      from patients, it is possible to transform allergenic grafts into functional autologous
      grafts, theoretically avoiding the risk of rejection.

      The process flow is defined as following: (1) the file study: which start by receiving the
      file of the patient, the file will be forwarded to appointed physicians coordinators for
      review and submission of medical report, then the medical report will be evaluated within the
      cell therapy committee and the patient will be asked for clinical examination, and after
      consultation a reply to the patient with medical decision will follow with an approval or not
      to be recruited and if yes, a brief report about the procedure will be submitted and
      explained in details to the patient, a consent form must be signed if the patient agree to be
      included in the study, (2) the patient admission: which may start by completion of the
      procedure forms and doing the pre-op evaluation (initial work up defined as a clinical and
      biological assessment upon C.A.S which may include unaided and best spectacle corrected
      visual acuity, refraction, slit lamp examination, intraocular pressure, fundoscopy, corneal
      topography, aberrometry, endothelial cell count (specular microscopy), corneal confocal
      microscopy, as well as blood tests), all this tests should be effectuated by an specialist
      and reviewed by an ophthalmologist. Then, a lipoaspiration of the subcutaneous adipose tissue
      to be performed by a plastic surgeon, sample processing at a cGMP facility for isolation and
      characterization of the stromal vascular fraction enriched with ADASCs as well as laminas
      preparing (the quality control assessment will be realized before and after all the steps of
      the procedure starting from the ADASCs collection to implantation including cell culture,
      cell quiescence, decellularization of human corneal lamina, recellularization of the laminas
      with ADASCs, and implantation; the assessment will include cell viability, cell number, cell
      apoptosis, immunophenotyping, infection, inflammation by analyzing the secreted cytokines
      from ADASCs, lamina cutting, lamina thickness, immunostaining, confocal microscopy, etc.);
      (3) the delivery (implantation) which starts by a peribulbar or retrobulbar anesthesia where
      the patient is placed under operating microscope, followed by a femtosecond laser-assisted
      mid-stromal lamellar dissection, then the autologous ADASCs or laminas or recellularized
      laminas will be placed within the pocket, and finally closed by a superior incision closure.
      The patient will be put under antibiotic/steroids for a defined period and followed by the
      team at 1 week, 2 weeks, 1 month, 3 months, 6 months.

      This protocol of cell therapy will be applied exclusively at VISSUM (Alicante-Spain),
      Barraquer Ophthalmology Center (Barcelona-Spain), Ramon y Cajal Hospital (Madrid-Spain),
      Asturias Prince Hospital (Madrid-Spain), and Murcia Hospital (Murcia-Spain), in affiliation
      with Miguel Hernandez of Elche University (Elche-Spain).

      The patient's recruitment will take place: for the lipoaspiration, processing, preparing the
      cellularized laminas and quality control assessments in VISSUM (Alicante-Spain), Barraquer
      Ophthalmology Center (Barcelona-Spain), Ramon y Cajal Hospital (Madrid-Spain), and Murcia
      Hospital (Murcia-Spain). All these steps are managed by VISSUM (Prof. J. ALIO).
    

Intervention name(s): Implantation; Lipoaspiration
Intervention type(s): Procedure; Procedure
Intervention description(s): Procedure: Implantation The ophthalmologist will carry out the implantation of the ADASCs cells with or without scaffold in the intrastromal cornea of the patient; Procedure: Lipoaspiration The patient will have a liposuction surgery from which the autologous ADASCs implant in the cornea will be obtained.
Procedure: Implantation The ophthalmologist will carry out the implantation of the ADASCs with or without scaffold in the intrastromal cornea of the patient
Other intervention name(s): corneal implantation; corneal implantation
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: In this study, 15 evaluable patients affected by corneal stromal dystrophies of any type (particularly keratoconus) will be included in 3 different groups. Ten patients will be included in the two experimental groups and five in the control group with cell-free treatment (5 patients per group and a total of 3 groups)
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Regenerative medicine; Corneal bioengineering; Stem cell therapy; Keratoconus; Adipose-derived adult stem cells (ADASCs); Keratocytes; Corneal confocal microscopy; Advanced corneal therapy