Periodic Reporting for period 3 - UshTher (Clinical trial of gene therapy with dual AAV vectors for retinitis pigmentosa in patients with Usher syndrome type IB)
Période du rapport: 2021-01-01 au 2021-12-31
Usher syndrome (USH) is the most common combination of deafness and blindness due to retinitis pigmentosa. USHIB caused by mutations in the large MYO7A gene, is among the most severe and frequent forms of USH. While deafness can be improved with cochlear implants, blindness remains untreatable. The overall goal of UshTher is to develop a phase I/II, first-in-human, clinical trial of gene therapy for USHIB retinitis pigmentosa based on dual AAV. It would be the first time the dual AAV vector approach is tested in humans. Towards this ambitious objective, UshTher has assembled a very competitive consortium with leaders in the fields of retinal gene therapy from bench to bedside including SMEs with expertise in the development of gene therapy products.
The planned activities span from manufacturing of clinical –grade dual AAV vectors to non clinical safety, biodistribution and expression studies performed under good laboratory practices up to performing a multicenter, multinational clinical trial which envisages subretinal administrations of dual AAV vectors in twelve USHIB patients.
The planned activities span from manufacturing of clinical –grade dual AAV vectors to non clinical safety, biodistribution and expression studies performed under good laboratory practices up to performing a multicenter, multinational clinical trial which envisages subretinal administrations of dual AAV vectors in twelve USHIB patients.
The Partners planned the production of the clinical vector under GMP conditions for use as an Investigational Medicinal Product (IMP) and provide a safety report for regulatory authorities. During the reporting period, we performed long-term stability studies on: dual AAV8-MYO7A GMP-like lot (Tox Lot), and GMP dual AAV8-MYO7A Drug Product and AAV8.Myo7A Buffer Diluent. In addition, an Investigational Medicinal Product Dossier (IMPD) is in preparation.
We proposed to conduct non-clinical safety studies for dual AAV8-MYO7A in macaques given the similarity with the human retina. GMP-like dual AAV8-MYO7A vectors used in non-clinical safety studies will be representative of that to be administered in the clinical study. During the reporting period, we performed vector biodistribution, shedding and germline transmission analysis on low- and high-dose macaques injected in the subretinal region of the right eye. The dual vector was most importantly detected in tissues of animals that received the highest dose, and in tissues of the eye as well as in some anatomical parts directly linked to the optic tract. It was not detected in large organs (heart, kidney, lung) and sporadically measured in the liver and quantified in pancreas and spleen of some animals. Importantly, dual vector was not found in epididymis, testis and ovaries, thus excluding the risk of germline transmission at both doses.
The main goal of this project is the design and performance of: a natural history observational study of USHIB retinitis pigmentosa, and the gene therapy clinical trial with subretinal administrations of dual AAV8-MYO7A in USHIB patients. Importantly, we must demonstrate that subretinal administrations of dual AAV8-MYO7A are safe and effective in USHIB patients. Clinical sites from Italy, Spain and The Netherlands are conducting a natural history study to further characterize the USHIB patients’ population and disease progression. During the reporting period, the main results are the completion of 2 years follow-up in almost all patients enrolled in the natural history study, despite the COVID-19 restrictions. UNICAMP performed all the examinations for the baseline visits, expected by the protocol, in 32 enrolled patients, 3 of them have been excluded because only one mutation in MYO7A gene was identified. Moreover, UNICAMP performed the first annual follow-up visits in all the 29 included patients and the second annual follow-up visits in 21 patients. The remaining visits are planned for the next month of 2022. The phase I/II clinical trial start has been postponed because of the delay in dual AAV8.MYO7A GMP-like lot production and pre-clinical development.
We are also involved in the production and filing of the regulatory documents necessary to perform the UshTher gene therapy clinical trial. During the reporting period, the clinical protocol has been updated on the basis of the novel evidences in the field of ocular gene therapy (i.e. Voretigene Neparvovec treatment), and the preliminary findings of the natural history study. Furthermore, the documentation required by AIFA to start a phase I clinical trial at an Italian Centre (i.e. UNICAMP) was drafted, including quality manual and standard operating procedures.
In order to ensure that the clinical study will be performed according to the highest ethical standards and to organize study monitoring throughout the project, we established an Ethics Advisory Group (EAG) constituted by internationally known medical ethicists with experience in clinical trials and members of patient organizations including the Italian, Spanish, and Dutch Societies. In addition, during the reporting period, we carried out the dissemination of UshTher results at several meeting organized by patient organizations, including national and international conferences.
The management team created and currently maintains the project website to disseminate project results and keeps running record of project progresses. The team takes also care of the communication of the project results, using different media, in order to reach the expert of the field and the lay public. Communication within the Consortium was always open and
consistent. During the reporting period, we have made important efforts to disseminate and transfer all the results, participating to a total of 35 events, even during the pandemic.
Importantly, in 2021, two peer-reviewed articles have been published:
- Stemerdink M, García-Bohórquez B, Schellens R, Garcia-Garcia G, Van Wijk E, Millan JM. Genetics, pathogenesis and therapeutic developments for Usher syndrome type 2. Hum Genet. 2021 Jul 30. doi: 10.1007/s00439-021-02324-w. PMID: 34331125.
- Galbis-Martínez L, Blanco-Kelly F, García-García G, Ávila-Fernández A, Jaijo T, Fuster-García C, Perea-Romero I, Zurita-Muñoz O, Jimenez-Rolando B, Carreño E, García-Sandoval B, Millán JM, Ayuso C. Genotype-phenotype correlation in patients with Usher syndrome and pathogenic variants in MYO7A: implications for future clinical trials. Acta Ophthalmol. 2021. Dec;99(8):922-930. doi: 10.1111/aos.14795. PMID: 33576163.
We proposed to conduct non-clinical safety studies for dual AAV8-MYO7A in macaques given the similarity with the human retina. GMP-like dual AAV8-MYO7A vectors used in non-clinical safety studies will be representative of that to be administered in the clinical study. During the reporting period, we performed vector biodistribution, shedding and germline transmission analysis on low- and high-dose macaques injected in the subretinal region of the right eye. The dual vector was most importantly detected in tissues of animals that received the highest dose, and in tissues of the eye as well as in some anatomical parts directly linked to the optic tract. It was not detected in large organs (heart, kidney, lung) and sporadically measured in the liver and quantified in pancreas and spleen of some animals. Importantly, dual vector was not found in epididymis, testis and ovaries, thus excluding the risk of germline transmission at both doses.
The main goal of this project is the design and performance of: a natural history observational study of USHIB retinitis pigmentosa, and the gene therapy clinical trial with subretinal administrations of dual AAV8-MYO7A in USHIB patients. Importantly, we must demonstrate that subretinal administrations of dual AAV8-MYO7A are safe and effective in USHIB patients. Clinical sites from Italy, Spain and The Netherlands are conducting a natural history study to further characterize the USHIB patients’ population and disease progression. During the reporting period, the main results are the completion of 2 years follow-up in almost all patients enrolled in the natural history study, despite the COVID-19 restrictions. UNICAMP performed all the examinations for the baseline visits, expected by the protocol, in 32 enrolled patients, 3 of them have been excluded because only one mutation in MYO7A gene was identified. Moreover, UNICAMP performed the first annual follow-up visits in all the 29 included patients and the second annual follow-up visits in 21 patients. The remaining visits are planned for the next month of 2022. The phase I/II clinical trial start has been postponed because of the delay in dual AAV8.MYO7A GMP-like lot production and pre-clinical development.
We are also involved in the production and filing of the regulatory documents necessary to perform the UshTher gene therapy clinical trial. During the reporting period, the clinical protocol has been updated on the basis of the novel evidences in the field of ocular gene therapy (i.e. Voretigene Neparvovec treatment), and the preliminary findings of the natural history study. Furthermore, the documentation required by AIFA to start a phase I clinical trial at an Italian Centre (i.e. UNICAMP) was drafted, including quality manual and standard operating procedures.
In order to ensure that the clinical study will be performed according to the highest ethical standards and to organize study monitoring throughout the project, we established an Ethics Advisory Group (EAG) constituted by internationally known medical ethicists with experience in clinical trials and members of patient organizations including the Italian, Spanish, and Dutch Societies. In addition, during the reporting period, we carried out the dissemination of UshTher results at several meeting organized by patient organizations, including national and international conferences.
The management team created and currently maintains the project website to disseminate project results and keeps running record of project progresses. The team takes also care of the communication of the project results, using different media, in order to reach the expert of the field and the lay public. Communication within the Consortium was always open and
consistent. During the reporting period, we have made important efforts to disseminate and transfer all the results, participating to a total of 35 events, even during the pandemic.
Importantly, in 2021, two peer-reviewed articles have been published:
- Stemerdink M, García-Bohórquez B, Schellens R, Garcia-Garcia G, Van Wijk E, Millan JM. Genetics, pathogenesis and therapeutic developments for Usher syndrome type 2. Hum Genet. 2021 Jul 30. doi: 10.1007/s00439-021-02324-w. PMID: 34331125.
- Galbis-Martínez L, Blanco-Kelly F, García-García G, Ávila-Fernández A, Jaijo T, Fuster-García C, Perea-Romero I, Zurita-Muñoz O, Jimenez-Rolando B, Carreño E, García-Sandoval B, Millán JM, Ayuso C. Genotype-phenotype correlation in patients with Usher syndrome and pathogenic variants in MYO7A: implications for future clinical trials. Acta Ophthalmol. 2021. Dec;99(8):922-930. doi: 10.1111/aos.14795. PMID: 33576163.
If successful, UshTher will provide the first proof-of-concept in humans that gene therapy for USHIB with dual AAV8 vectors is both safe and effective.
In terms of general impact to improve the socio-economic welfare of EU citizens, UshTher will impact specifically those connected with Usher syndrome via familial or professional (medical, educational or social) links. In addition to USHIB there are a number of other inherited retinal diseases that would benefit from the proof-of-concept provided through UshTher that subretinal administration of dual AAV vectors is safe and effective.
In addition, UshTher includes two SMEs that are new to Usher syndrome and retinal degenerations and will benefit from their novel technological approaches and already demonstrated commitment to achieve new innovative therapies for rare diseases. The resulting expansion of the contact base will foster new introductions and collaborations in rare disease. The SMEs will benefit from participation by expanding the number of diseases that they are involved in, leading to further new IP, commercial growth by an expanded project base, new jobs and increased revenues.
In terms of general impact to improve the socio-economic welfare of EU citizens, UshTher will impact specifically those connected with Usher syndrome via familial or professional (medical, educational or social) links. In addition to USHIB there are a number of other inherited retinal diseases that would benefit from the proof-of-concept provided through UshTher that subretinal administration of dual AAV vectors is safe and effective.
In addition, UshTher includes two SMEs that are new to Usher syndrome and retinal degenerations and will benefit from their novel technological approaches and already demonstrated commitment to achieve new innovative therapies for rare diseases. The resulting expansion of the contact base will foster new introductions and collaborations in rare disease. The SMEs will benefit from participation by expanding the number of diseases that they are involved in, leading to further new IP, commercial growth by an expanded project base, new jobs and increased revenues.