The OCGT group, led by Professor Robin Ali and Professor Rachael Pearson, represents a large, coordinated research programme to develop cell- and gene-based therapies for the treatment of retina and neurodegeneration.
Sight-loss affects millions of people worldwide and has severe personal and socioeconomic consequences. We seek to understand the molecular mechanisms that drive retinal development and retinal disease conditions and harness this knowledge to develop new cell- and gene-based therapeutic strategies to restore normal visual function.
The OCGT benefits from recently refurbished laboratory space and state-of-the-art GMP Stem Cell Facilities. Professor Ali also Director of the Gene Therapy Vector Facility.
People
Professor of Human Molecular Genetics
Professor of Developmental Neuroscience
Projects
Photoreceptor transplantation to restore sight
Ocular cell transplantation makes up our flagship programme, underpinned by substantial funding from the Medical Research Council, as well as several sight-loss charities. We have shown proof of principle for the rescue of visual function following the transplantation of murine and human stem cell derived photoreceptors in both progressive and advanced retinal degeneration (MacLaren, Pearson et al., Nature 2006; Pearson et al., Nature, 2012; Gonzalez-Cordero et al., Nature Biotechnology; Ribeiro, Procyk et al., Cell Reports, 2021). We continue to expand this and are now undertaking the development work required, including transition to GMP manufacturing, to move into clinical trials for photoreceptor replacement therapy. We utilise a wide range of techniques including viral vector design and manufacturing, human and murine stem cell cultures, advanced confocal imaging, retinal electrophysiology, behavioural assessments of vision, and the application of microfluidics and biomaterials.
Modelling human retinal development and disease using human stem cell-derived retinal organoids
We have established protocols for the generation of highly organized retinal organoids from human pluripotent stem cells (hROs) (Gonzalez-Cordero et al., Nature Biotechnology, 2013; Gonzalez-Cordero et al., Stem Cell Reports, 2017; West et al., Stem Cell Reports, 2022). By undertaking fundamental research into human and murine retinal development (Aghaizu et al., 2021; multiple manuscripts in preparation) and combining advanced imaging, stem cell culture and transcriptomics, we are creating increasingly advanced hRO-based models of both early human retinal development and retinal degeneration. In collaboration with biomaterials experts, we are working to create more complex structures that encompass tissues and structures beyond the neural retina. These improved hRO models can be for disease modelling, as well as therapeutic development of small molecules and gene correction therapies.
Synaptic connectivity in degeneration and repair
Establishing robust synaptic connectivity between donor and host neurons is fundamental for all neuronal replacement strategies. We are developing strategies to maximise the efficiency of photoreceptor replacement therapy by addressing several aspects: i) by having a better understanding of the diseased retinal environment, the barriers it may present to regenerative therapies and how we might overcome these (e.g. Barber et al., PNAS, 2013; Hippert et al., GLIA, 2021), ii) by improving our understanding of synaptic remodelling in disease and after repair, and iii) by identifying signals that promote synaptic connectivity in normal development and repurposing them in regeneration (Matsuyama et al., 2021; multiple manuscripts in preparation). We utilise a wide range of techniques, including live imaging of the developing retina (Aghaizu et al., Cell Reports, 2021), synaptic tracing and transplantation (Ribeiro et al., Cell Reports, 2021; Kalargyrou et al., EMBO Reports, 2021) as well as microfluidics to generate model synaptic circuits.
Gene therapy for inherited retinal dystrophy
Over the past 2 decades, we have shown that AAV-mediated gene delivery to the retina of mice with various forms of retinal dystrophy can successfully prevent the disease or stop its progression after onset. Leber Congenital Amaurosis (LCA) caused by AIPL1 mutations is a severe, childhood-onset retinal dystrophy that leads to full blindness within the first decade of life. In collaboration with UCL and Great Ormond Street Hospital, we are running a study assessing gene therapy treatment of young children with this condition, and we hope to publish the results of this work soon.
Gene therapy for neuronal ceroid lipofuscinosis (Batten disease)
Neuronal ceroid lipofuscinoses (NCL) are a group of inherited conditions that are characterised by neuronal degeneration in the brain and retina. In collaboration with colleagues at UCL, we have shown that AAV-mediated gene supplementation to both the brain and retina can preserve survival and function of the neurons for various forms of the condition, including CLN2, CLN3, CLN5 and CLN6. With the support of KCL’s Gene Therapy Vector Facility, we are in the process of preparing for a clinical trial to assess whether a therapeutic vector is efficacious in Batten disease patients.
Publications
Activities
Externally focused events:
Both senior and junior members of the group regularly present at international conferences, including Association for Research in Vision and Ophthalmology (ARVO), International Society for Stem Cell Research (ISSCR), Society for Neuroscience.
Fight for Sight
Professor Pearson’s Fight for Sight funded project, to develop macular-like structures from pluripotent stem cells, was featured in the charity’s Christmas 2020 fundraising campaign and was their most successful campaign to date.
People
Professor of Human Molecular Genetics
Professor of Developmental Neuroscience
Projects
Photoreceptor transplantation to restore sight
Ocular cell transplantation makes up our flagship programme, underpinned by substantial funding from the Medical Research Council, as well as several sight-loss charities. We have shown proof of principle for the rescue of visual function following the transplantation of murine and human stem cell derived photoreceptors in both progressive and advanced retinal degeneration (MacLaren, Pearson et al., Nature 2006; Pearson et al., Nature, 2012; Gonzalez-Cordero et al., Nature Biotechnology; Ribeiro, Procyk et al., Cell Reports, 2021). We continue to expand this and are now undertaking the development work required, including transition to GMP manufacturing, to move into clinical trials for photoreceptor replacement therapy. We utilise a wide range of techniques including viral vector design and manufacturing, human and murine stem cell cultures, advanced confocal imaging, retinal electrophysiology, behavioural assessments of vision, and the application of microfluidics and biomaterials.
Modelling human retinal development and disease using human stem cell-derived retinal organoids
We have established protocols for the generation of highly organized retinal organoids from human pluripotent stem cells (hROs) (Gonzalez-Cordero et al., Nature Biotechnology, 2013; Gonzalez-Cordero et al., Stem Cell Reports, 2017; West et al., Stem Cell Reports, 2022). By undertaking fundamental research into human and murine retinal development (Aghaizu et al., 2021; multiple manuscripts in preparation) and combining advanced imaging, stem cell culture and transcriptomics, we are creating increasingly advanced hRO-based models of both early human retinal development and retinal degeneration. In collaboration with biomaterials experts, we are working to create more complex structures that encompass tissues and structures beyond the neural retina. These improved hRO models can be for disease modelling, as well as therapeutic development of small molecules and gene correction therapies.
Synaptic connectivity in degeneration and repair
Establishing robust synaptic connectivity between donor and host neurons is fundamental for all neuronal replacement strategies. We are developing strategies to maximise the efficiency of photoreceptor replacement therapy by addressing several aspects: i) by having a better understanding of the diseased retinal environment, the barriers it may present to regenerative therapies and how we might overcome these (e.g. Barber et al., PNAS, 2013; Hippert et al., GLIA, 2021), ii) by improving our understanding of synaptic remodelling in disease and after repair, and iii) by identifying signals that promote synaptic connectivity in normal development and repurposing them in regeneration (Matsuyama et al., 2021; multiple manuscripts in preparation). We utilise a wide range of techniques, including live imaging of the developing retina (Aghaizu et al., Cell Reports, 2021), synaptic tracing and transplantation (Ribeiro et al., Cell Reports, 2021; Kalargyrou et al., EMBO Reports, 2021) as well as microfluidics to generate model synaptic circuits.
Gene therapy for inherited retinal dystrophy
Over the past 2 decades, we have shown that AAV-mediated gene delivery to the retina of mice with various forms of retinal dystrophy can successfully prevent the disease or stop its progression after onset. Leber Congenital Amaurosis (LCA) caused by AIPL1 mutations is a severe, childhood-onset retinal dystrophy that leads to full blindness within the first decade of life. In collaboration with UCL and Great Ormond Street Hospital, we are running a study assessing gene therapy treatment of young children with this condition, and we hope to publish the results of this work soon.
Gene therapy for neuronal ceroid lipofuscinosis (Batten disease)
Neuronal ceroid lipofuscinoses (NCL) are a group of inherited conditions that are characterised by neuronal degeneration in the brain and retina. In collaboration with colleagues at UCL, we have shown that AAV-mediated gene supplementation to both the brain and retina can preserve survival and function of the neurons for various forms of the condition, including CLN2, CLN3, CLN5 and CLN6. With the support of KCL’s Gene Therapy Vector Facility, we are in the process of preparing for a clinical trial to assess whether a therapeutic vector is efficacious in Batten disease patients.
Publications
Activities
Externally focused events:
Both senior and junior members of the group regularly present at international conferences, including Association for Research in Vision and Ophthalmology (ARVO), International Society for Stem Cell Research (ISSCR), Society for Neuroscience.
Fight for Sight
Professor Pearson’s Fight for Sight funded project, to develop macular-like structures from pluripotent stem cells, was featured in the charity’s Christmas 2020 fundraising campaign and was their most successful campaign to date.
Our Partners
European Research Council
Guy's and St Thomas' Charity
Group leads
Professor of Human Molecular Genetics
Professor of Developmental Neuroscience