EB-101 for Epidermolysis Bullosa
Recruiting in Palo Alto (17 mi)
+1 other location
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Abeona Therapeutics, Inc
Must be taking: Pain medications
Must not be taking: Investigational therapies
Disqualifiers: HIV, Hepatitis B, Hepatitis C, others
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?To evaluate and further characterize the safety of EB-101 (LZRSE-Col7A1 gene-corrected keratinocyte sheets with type VII collagen \[C7\] expression) for the treatment of large, chronic RDEB wounds in new and previously EB-101 treated patients 12 months and older.
Will I have to stop taking my current medications?
The trial requires that you stay on a stable pain medication regimen for at least 30 days before starting and throughout the study. Other medications are not specifically mentioned, so it's best to discuss with the trial team.
What data supports the effectiveness of the treatment EB-101 for Epidermolysis Bullosa?
Research on similar gene therapies for Epidermolysis Bullosa shows promise, with studies demonstrating long-term restoration of type VII collagen, which is crucial for skin integrity, in preclinical models. These findings suggest that gene delivery methods, like those used in EB-101, can effectively correct genetic defects in skin tissue, potentially improving symptoms in patients.
12345Is EB-101 safe for use in humans?
The treatment involving gene-modified cells, similar to EB-101, was well tolerated in a study with no serious adverse reactions or autoimmune responses observed, suggesting it is generally safe in humans.
12345How is the treatment EB-101 unique for epidermolysis bullosa?
EB-101 is unique because it involves using a patient's own skin cells that are genetically modified to correct the COL7A1 gene mutation, which is responsible for the skin fragility in epidermolysis bullosa. This ex-vivo gene therapy approach aims to restore the production of type VII collagen, a key structural protein, directly addressing the root cause of the condition rather than just alleviating symptoms.
13467Eligibility Criteria
This trial is for patients aged 6 and older with Recessive Dystrophic Epidermolysis Bullosa (RDEB) who have stable pain medication regimens and at least one wound larger than 20 cm2 that's been present for over six months. Participants must not be pregnant, use reliable birth control, and cannot have a history of certain allergies or recent investigational therapies.Inclusion Criteria
I have two confirmed RDEB C7 mutations inherited recessively.
I have a wound larger than 20 cm2, present for over 6 months, and it's a stage 2 wound.
I am using reliable birth control and have a negative pregnancy test.
+6 more
Exclusion Criteria
I have severe symptoms or lab results, but common issues like throat tightness, low iron, low protein, or pain/itch won't disqualify me.
I am too unwell to travel for treatment or participate in the study.
You are currently addicted to drugs or alcohol.
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
5 weeks
1 visit (in-person), 1 phone call
Treatment
One-time surgical application of up to 12 autologous, gene-corrected keratinocyte sheets
1 week
Inpatient stay for up to 7 days
Follow-up
Participants are monitored for safety and effectiveness after treatment
24 weeks
Phone call on Day 14; telehealth visits on Weeks 4, 8, and 18; clinic visits on Weeks 12 and 24
Participant Groups
The trial tests EB-101, which are engineered skin sheets applied surgically to treat wounds caused by RDEB. It aims to assess the safety of this treatment in both new patients and those previously treated with EB-101.
1Treatment groups
Experimental Treatment
Group I: EB-101 Surgical application of RDEB woundsExperimental Treatment1 Intervention
New or Previously Treated RDEB Patients
EB-101 is already approved in United States for the following indications:
🇺🇸 Approved in United States as Prademagene zamikeracel for:
- Recessive dystrophic epidermolysis bullosa (RDEB)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Stanford UniversityRedwood City, CA
University of Massachusetts Medical SchoolWorcester, MA
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Who Is Running the Clinical Trial?
Abeona Therapeutics, IncLead Sponsor
References
BP180 gene delivery in junctional epidermolysis bullosa. [2023]Epidermolysis bullosa (EB) comprises a family of inherited blistering skin diseases for which current therapy is only palliative. Junctional EB (JEB) involves dissociation of the dermal-epidermal junction and results from mutations in a number of genes that encode vital structural proteins, including BP180 (type XVII collagen/BPAG2). In order to develop a model of corrective gene delivery for JEB, we produced a retroviral expression vector for wild-type human BP180 and used it to restore BP180 protein expression to primary keratinocytes from BP180-negative patients with generalized atrophic JEB. Restoration of full-length BP180 protein expression was associated with adhesion parameter normalization of primary JEB keratinocytes in vitro. These cells were then used to regenerate human skin on immune-deficient mice. BP180 gene-transduced tissue demonstrated restoration of BP180 gene expression at the dermal-epidermal junction in vivo while untransduced regenerated JEB skin entirely lacked BP180 expression. These findings provide a basis for future efforts to achieve gene delivery in human EB skin tissue.
Long-term type VII collagen restoration to human epidermolysis bullosa skin tissue. [2021]In spite of advances in the molecular diagnosis of recessive dystrophic epidermolysis bullosa (RDEB), an inherited blistering disease due to a deficiency of type VII collagen at the basement membrane zone (BMZ) of stratified epithelium, current therapy is limited to supportive palliation. Gene delivery has shown promise in short-term experiments; however, its long-term sustainability through multiple turnover cycles in human tissue has awaited confirmation. To characterize approaches for long-term genetic correction, retroviral vectors were constructed containing long terminal repeat-driven full-length and epitope-tagged COL7A1 cDNA and evaluated for durability of type VII collagen expression and function in RDEB skin tissue regenerated on immune-deficient mice. Type VII collagen expression was maintained for 1 year in vivo, or over 12 epidermal turnover cycles, with no abnormalities in skin morphology or self-renewal. Type VII collagen restoration led to correction of RDEB disease features, including reestablishment of anchoring fibrils at the BMZ. This approach confirms durably corrective and noninjurious gene delivery to long-lived epidermal progenitors and provides the foundation for a human clinical trial of ex vivo gene delivery in RDEB.
Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa. [2022]BACKGROUNDRecessive dystrophic epidermolysis bullosa (RDEB) is a severe form of skin fragility disorder due to mutations in COL7A1 encoding basement membrane type VII collagen (C7), the main constituent of anchoring fibrils (AFs) in skin. We developed a self-inactivating lentiviral platform encoding a codon-optimized COL7A1 cDNA under the control of a human phosphoglycerate kinase promoter for phase I evaluation.METHODSIn this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 106 cells/cm2 of intact skin) of COL7A1-modified autologous fibroblasts and were followed up for 12 months. The primary outcome was safety, including autoimmune reactions against recombinant C7. Secondary outcomes included C7 expression, AF morphology, and presence of transgene in the injected skin.RESULTSGene-modified fibroblasts were well tolerated, without serious adverse reactions or autoimmune reactions against recombinant C7. Regarding efficacy, there was a significant (P
SIN retroviral vectors expressing COL7A1 under human promoters for ex vivo gene therapy of recessive dystrophic epidermolysis bullosa. [2021]Recessive dystrophic epidermolysis bullosa (RDEB) is caused by loss-of-function mutations in COL7A1 encoding type VII collagen which forms key structures (anchoring fibrils) for dermal-epidermal adherence. Patients suffer since birth from skin blistering, and develop severe local and systemic complications resulting in poor prognosis. We lack a specific treatment for RDEB, but ex vivo gene transfer to epidermal stem cells shows a therapeutic potential. To minimize the risk of oncogenic events, we have developed new minimal self-inactivating (SIN) retroviral vectors in which the COL7A1 complementary DNA (cDNA) is under the control of the human elongation factor 1alpha (EF1alpha) or COL7A1 promoters. We show efficient ex vivo genetic correction of primary RDEB keratinocytes and fibroblasts without antibiotic selection, and use either of these genetically corrected cells to generate human skin equivalents (SEs) which were grafted onto immunodeficient mice. We achieved long-term expression of recombinant type VII collagen with restored dermal-epidermal adherence and anchoring fibril formation, demonstrating in vivo functional correction. In few cases, rearranged proviruses were detected, which were probably generated during the retrotranscription process. Despite this observation which should be taken under consideration for clinical application, this preclinical study paves the way for a therapy based on grafting the most severely affected skin areas of patients with fully autologous SEs genetically corrected using a SIN COL7A1 retroviral vector.
An RNA-targeted therapy for dystrophic epidermolysis bullosa. [2018]Functional impairment or complete loss of type VII collagen, caused by mutations within COL7A1, lead to the severe recessive form of the skin blistering disease dystrophic epidermolysis bullosa (RDEB). Here, we successfully demonstrate RNA trans-splicing as an auspicious repair option for mutations located in a wide range of exons by fully converting an RDEB phenotype in an ex vivo pre-clinical mouse model based on xenotransplantation. Via a self-inactivating (SIN) lentiviral vector a 3' RNA trans-splicing molecule, capable of replacing COL7A1 exons 65-118, was delivered into type VII collagen deficient patient keratinocytes, carrying a homozygous mutation in exon 80 (c.6527insC). Following vector integration, protein analysis of an isolated corrected single cell clone showed secretion of the corrected type VII collagen at similar levels compared to normal keratinocytes. To confirm full phenotypic and long-term correction in vivo, patches of skin equivalents expanded from the corrected cell clone were grafted onto immunodeficient mice. Immunolabelling of 12 weeks old skin specimens showed strong expression of human type VII collagen restricted to the basement membrane zone. We demonstrate that the RNA trans-splicing technology combined with a SIN lentiviral vector is suitable for an ex vivo molecular therapy approach and thus adaptable for clinical application.
Gene therapy of epidermolysis bullosa. [2023]Easy access to the organ and identification of underlying mutations in epidermolysis bullosa (EB) facilitated the first cutaneous gene therapy experiments in vitro in the mid-1990s. The leading technology was transduction of the respective cDNA carried by a retroviral vector. Using this approach, the genotypic and phenotypic hallmark features of the recessive forms of junctional EB, which are caused by loss of function of the structural proteins laminin-5 or bullous pemphigoid antigen 2/type XVII collagen of the dermo-epidermal basement membrane zone, have been corrected in vitro and in vivo using xenograft mouse models. Recently, this approach has also been shown to be feasible for the large COL7A1 gene (mutated in dystrophic EB), applying PhiC31 integrase or lentiviral vectors. Neither of these approaches has made it into a successful Phase I study on EB patients. Therefore, alternative approaches to gene correction, including modulation of splicing, are being investigated for gene therapy in EB.
Fibroblasts show more potential as target cells than keratinocytes in COL7A1 gene therapy of dystrophic epidermolysis bullosa. [2012]Dystrophic epidermolysis bullosa (DEB) is an inherited blistering skin disorder caused by mutations in the type VII collagen gene (COL7A1). Therapeutic introduction of COL7A1 into skin cells holds significant promise for the treatment of DEB. The purpose of this study was to establish an efficient retroviral transfer method for COL7A1 into DEB epidermal keratinocytes and dermal fibroblasts, and to determine which gene-transferred cells can most efficiently express collagen VII in the skin. We demonstrated that gene transfer using a combination of G protein of vesicular stomatitis virus-pseudotyped retroviral vector and retronectin introduced COL7A1 into keratinocytes and fibroblasts from a DEB patient with the lack of COL7A1 expression. Real-time polymerase chain reaction analysis of the normal human skin demonstrated that the quantity of COL7A1 expression in the epidermis was significantly higher than that in the dermis. Subsequently, we have produced skin grafts with the gene-transferred or untreated DEB keratinocytes and fibroblasts, and have transplanted them into nude rats. Interestingly, the series of skin graft experiments showed that the gene-transferred fibroblasts supplied higher amount of collagen VII to the new dermal-epidermal junction than the gene-transferred keratinocytes. An ultrastructural study revealed that collagen VII from gene-transferred cells formed proper anchoring fibrils. These results suggest that fibroblasts may be a better gene therapy target of DEB treatment than keratinocytes.