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- July 2013 -'Big leap' towards curing blindness in stem cell study
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Meet the research team
The main focus of my
research is the development of gene and stem cell therapy with the
primary aim of developing novel treatments for eye disease. Over the
past ten years we have been optimising gene transfer to the eye. We are
engaged in a comprehensive programme of work to develop gene therapy for
eye disease and in particular for disorders affecting the retina,
including inherited retinal degeneration as well as complex diseases
such as those associated with retinal and choroidal neovascularisation
and posterior uveitis.
My research has utilised a variety of viral vectors, but my main interest is in the development of vector systems based on either adeno-associated virus (AAV) or lentiviruses. We have demonstrated the utility of these systems for gene transfer to the eye. A major aspect of our research is the development and use of a wide variety of genetic and experimental animal models of retinal disorders, including large animal models, in order to assess novel therapeutic approaches. We are engaged in a broad programme of work to demonstrate proof of concept for a number of alternative strategies, including gene replacement therapy and/or delivery of siRNA to treat animal models of inherited retinal degeneration and delivery of genes encoding angiostatic, anti-apoptotic, immunomodulatory or neurotrophic molecules to treat a variety of animal models. We are now also investigating the potential of stem or progenitor cell transplantation to repair degenerating retinae. A recent key discovery is that transplantation of rod precursor cells at a specific stage of development results in their integration and subsequent differentiation into rod photoreceptors that form synaptic connections and improve visual function in mouse models of retinal degeneration. Conversely, transplantation of progenitor or stem cells that are not at this precise ontogentic stage do not show this property and fail to integrate. We are now combining gene therapy approaches with that of stem cell transplantation and using viral vectors carrying genes encoding a variety of transcription factors in order to generate appropriate cells for transplantation from either embryonic or adult-derived stem cells.
In order to deliver new treatments, we have now established a programme of translational research. My research group includes a number of clinicians (clinical training fellows as well as senior clinican/scientists) and we have strong links with a number of biotechnology companies. We have recently established a Department of Health funded clinical trial of gene therapy for a form of severe childhood-onset retinal dystrophy due to mutations in the gene encoding RPE65. This condition is likely to be particularly amenable to effective treatment and the trial should facilitate future trials and underpin the programme of development of treatments for other retinal disorders. The first patients were enrolled in early 2007 and the first results from the trial were published in the New England Journal of Medicine in May 2008.
I am a surgeon-scientist at the NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and UCL Institute of Ophthalmology. My programme of research extends from the laboratory investigation of mechanisms of disease in experimental models of sight loss to clinical trials of new medical and surgical interventions.
Since 2007 I have been the lead clinician in the world's first gene therapy trial for inherited blindness, demonstrating proof of-concept that offers hope for people with inherited retinal degeneration. I also lead Europe's first clinical trial using human embryonic stem cells, a first-in-human study to test the potential of retinal cell transplantation in macular degeneration. In 2011 I was appointed to the Chair of Retinal Studies at UCL, and in 2012 to a NIHR Research Professorship.
Retinal degenerations culminating in photoreceptor (PR) loss are the leading causes of untreatable blindness in the Western world. Clinical treatments are of limited efficacy, at best slowing disease progression. As such, there is a clear need for new therapeutic approaches.
Gene therapy is effective in the treatment of inherited retinal disease. However, such strategies will be ineffective once degeneration has occurred. PR transplantation offers a complementary approach that could not only halt the progression of blindness but also potentially reverse it.
In two landmark studies, we have demonstrated that, by using donor cells from early postnatal retina, PR cell transplantation is possible. The adult retina is capable of integrating transplanted cells & these cells develop unambiguous characteristics of mature PRs. Moreover, we demonstrated that the cells that possess this capacity to migrate & functionally integrate are post-mitotic PR precursors, rather than stem or progenitor cells (MacLaren & Pearson et al., Nature, 2006).
Most importantly, we now have definitive evidence of restoration of rod-mediated visually guided behaviour in rod-deficient mice following transplantation (Pearson et al., Nature, 2012). Of critical importance was the finding that the amount of vision restored is critically dependent upon the number of cells that correctly integrated.
Together, these establish a major proof-of-concept; that PR transplantation has the potential to improve not only retinal function but actually restore vision and provide strong justification for the continued research into photoreceptor transplantation strategies for the treatment of blindness. They also increase the need to find appropriate donor cells from non-fetal sources.
Recent advances in stem cell technology have demonstrated the potential to generate photoreceptor precursor donor cells. In a remarkable recent study, Eiraku et al., have demonstrated that it is possible to essentially grow a retina in a culture dish. We have recently started to generate transplantation-competent rod precursors from ES cells (West et al., Stem Cells, 2012; Gonzalez et al., in prep).
I am interested in retinal diseases, particularly in research aimed at
improving the care and long-term outcomes for these patients. Since my MD degree (2002-2004; Cone and Central Receptor Dystrophies – A
Clinical and Molecular Genetic Investigation), this research interest
has increasingly taken on a translational aspect - I now focus on
studies that link clinical research with laboratory findings, especially
in the form of clinical trials for novel gene and cell therapy for
This requires a broad approach, including:
- Establishing a molecular genetic diagnosis in the majority of patients with retinal disease, helping to improve counselling, advice on prognosis, and provide a cohort of patients with molecularly proven disease who may be eligible for current and future treatment trials.
- Identifying the patients/genetic subtypes and time-points that may be most appropriate for interventions, and identify reliable and sensitive outcome measures.
- Assisting in the development of gene- and cell therapies to either significantly slow or halt disease progression - or ideally improve visual function and subsequently being the clinical lead in undertaking rigorous clinical trials to ascertain their efficacy.
In July 2010 I was appointed as a Consultant Ophthalmologist at Moorfields Eye Hospital in the departments of Medical Retina, Inherited Eye Disease and Paediatric Ophthalmology; and as a Clinical Senior Lecturer at the UCL Institute of Ophthalmology. These posts are partly funded by a prestigious and highly competitive Department of Health ‘New Blood’ Senior Lectureship Award. Prior to my appointment I have undertaken a medical retina and genetics clinical fellowship at Moorfields Eye Hospital, and a combined genetics and paediatric ophthalmology clinical and research fellowship at Casey Eye Institute, Portland, USA.
During my time at Casey I was in receipt of an International Guest Scholarship from the American College of Surgeons which primarily enabled me to foster continuing collaborations with the ocular genetics department at Casey Eye Institute and to strengthen collaborations with Professor Joe Carroll and his team at the Medical College of Wisconsin, working on advanced ocular imaging technologies such as adaptive optics.
FORMER MEMBERS OF THE GROUP INCLUDE:
Name: Dr. Jonathan Aboshiha
Research interests: I am a clinician undertaking a PhD looking at various inherited retinal dystrophies both at a clinical and laboratory-based level, focusing on the potential for gene-based and stem-cell based therapeutic interventions for such diseases.
Name: Mr. Dominic Aghaizu
Research interests:As shown by our group, the transplantation of donor photoreceptor cells into recipient retinae is a viable strategy that allows restoration of visual function. The success of this approach critically depends upon the number of donor photoreceptors that correctly migrate and integrate into the recipient retina.
My goal is to determine how and why these transplanted cells can migrate and integrate as well as to identify ways to increase this migration. I will use multi-photon microscopy to follow the movement of these cells in real time. I further aim to characterise the gene expression profile of transplanted photoreceptors and the recipient retina to identify genes involved in the migratory process. This will provide targets for manipulation with the aim of increasing the migration and integration of transplanted photoreceptors.
Name: Dr. Stuart Beattie
Email address: email@example.com
Title of current project: Public and patient engagement with gene and cell therapy for sight loss.
Research Interests: My role is to co-ordinate our team's engagement with patients and members of the public, explaining our work in an accessible way and ensuring that patients and the public are involved in the design, implementation and dissemination of our research. I developed and maintain this website, and our growing social media presence, as well as organising awareness and engagement events.
Email address: firstname.lastname@example.org
Title of current project: Gene therapy and novel treatments for inherited retinal cone dystrophies
Research Interests: My main project has focused on the use of gene replacement therapy to demonstrate total visual functional recovery in the Cngb3 mouse model of achromatopsia, a devastating disease in humans which leads to complete colour blindness and loss of visual acuity. My research interests also include understanding the biological mechanism behind cone degeneration and developing novel therapies in different mouse models of inherited cone degeneration like the Cnga3, Pde6c, Gcap1 and RetGC.
Email address: email@example.com
Title of current project: Gene therapy for uveitis
Research Interests: Intraocular inflammatory disease remains a significant cause of visual loss, even with current immunosuppressive therapy. Following the success of clinical trials for monogenic retinal disorders, I am investigating the application of similar viral gene therapy to the treatment of uveitis. This approach offers the possibility of potent, self-regulating, long-term disease control following a single treatment and without systemic side effects.
Name: Dr. Oliver Comyn
Email address: firstname.lastname@example.org
Title of current project: Investigating VEGF inhibition in diabetic eye disease
Research Interests: Drugs can now be given into the eye to block the action of VEGF, a signalling molecule that contributes to the growth of abnormal new blood vessels in diabetic eye disease. It also causes blood vessels to leak fluid into the macula, the central part of the retina used for fine vision (diabetic macular oedema). Blocking the action of VEGF can reduce the fluid and improve vision. My research involves carrying out clinical trials to investigate in detail the effect on the retina of the drug ranibizumab in diabetic macular oedema, and to establish its usefulness prior to surgery for the complications of proliferative diabetic retinopathy. As a clinician I am interested in improving the treatments available to patients in the NHS and working to address a disease that is a major cause of sight loss.
Email address: email@example.com
Title of current project: 1) Innate immunity in retinal aging and disease. 2) Phenotyping and genotyping patients with Achromotopsia in preparation for gene therapy trials.
Research interests: I am currently working on two main projects within the Gene Therapy group. The first is investigating the role of the alternative complement pathway in age related macular degeneration; the second involves genotyping patients for mutations in CNGA3 and CNGB3 to identify suitable individuals for inclusion in gene therapy trials. Previous research interests have included: characterising the KCNV2 gene, mutations in which cause a rare cone dystrophy exhibiting supernormal rod response; genotyping patients for mutations in AIPL1, a cause of Leber’s Congenital Amaurosis; the genetics of vertebrate colour vision and spectral tuning of visual pigments.
Email address: firstname.lastname@example.org
Title of current project: Oxyge-sensing mechanisms in eye development and disease
Research interests: Oxygen-sensing mechanisms are fundamental for numerous physiological and pathological events in various tissues. The retina is the most metabolically demanding structure in the body and it is extremely sensitive to low oxygen conditions. Correct retinal development and maintenance depends strictly on constant monitoring of oxygen tension: hypoxic conditions are usually required in developmental angiogenesis but they also represent an exacerbating factor in various retinal degenerative disorders, like age-related macular degeneration.
My work investigates the role of retina-specific oxgen-sensing mechanisms, both in eye development and in the progression of ischaemic vasoproliferative retinal diseases. The relevance and involvement of hypoxia-inducible factors (HIFs) expressed in the retinal pigmented epithelium (RPE) is now being evaluated, with the ultimate aim of identifying novel therapeutic endogenous targets potentially able to stop the detrimental effects of low O2 conditions as an alternative to classic anti-angiogenic therapies.
Email address: email@example.com
Title of current project:
Virally-mediated RNA interference for the treatment of dominant retinal degenerations.
I have been working in gene therapy research for more than a decade concentrating on viral gene therapy for the treatment of retinal degeneration. I’m currently concentrating on the use of AAV or lentiviral vectors as RNA interference mediators for allele-specific and allele non-specific knockdown of dominant gene mutations in the retina causing retinitis pigmentosa and macular degeneration.
In addition, I’m interested in studying the miRNA transcriptome in the human and murine retina as well as utilising miRNA-based technology to improve viral targeting in retinal neurons.
I’m also involved in the optimisation of our AAV clinical trial vectors for treating patients with Leber’s congenital amaurosis.
Email address: firstname.lastname@example.org
Title of current project: Retinal repair utilizing ES cell-derived photoreceptor precursors.
Research Interests: Retinal degeneration is a leading cause of irreversible blindness in the developed world. The differentiation of retinal cells, including photoreceptors, from both mouse and human ES and iPS cells, potentially provides a renewable source of cells for retinal transplantation. The aim of my PhD project is to assess the extent to which mouse ES cell differentiation recapitulates retinal development, and also to evaluate differentiation and integration of ES cell-derived photoreceptors following transplantation.
Name: Ms. Sneha Haria
As a Clinical Trial Coordinator, I am responsible for ensuring that clinical trials conducted by the department are in compliance with Good Clinical Practice and the relevent EU directives.
Email address: email@example.com
Title of current project:
Local dysregulation of the complement pathway in the retinal pigment epithelium (RPE) as a model for age-related macular degeneration.
Age related macular degeneration (AMD) is the most common cause of vision loss amongst the elderly in industrialised countries. Immunological processes, particularly the complement system, are crucial for the development of AMD. The aim of my project is to investigate the consequences of local dysregulation of the main components of the alternative complement pathway.
Name: Dr. Claire Hippert
Title of current project: Modulation of gliosis to determine its role in photoreceptor transplantation efficiency
interest: So far, our
lab showed that post-mitotic rod precursor donor cells can migrate, integrate
and differentiate into rod photoreceptors in the recipient retina. In addition,
they can connect to the host retinal circuitry and following successful
transplantation of several thousand cells, restore visual function. Thus far,
the levels of integration we have observed are sufficient to improve some
aspects of visual function in murine models of retinal degeneration. It is
likely that this level can be significantly improved. My work is to investigate the role of
a physical barrier, Gliosis, that may impede cell integration. To modulate
gliosis I will use AAV2/9 vectors expressing shGFAP or/and shvimentin in the
rhodopsin knockout, model of retinal degeneration.
Email address: firstname.lastname@example.org
Title of current project: Regeneration of ocular tissue using gene transfer
Research Interests: Corneal endothelial cells are important in maintaining the clarity of the cornea. Since these cells do not replicate in humans, endothelial cell loss impairs vision and requires corneal transplantation. Our goal is to induce corneal endothelial cell replication by transferring genes or proteins that modify the cell cycle status. We examine the efficacy and safety of new viral vectors delivering plasmid DNA, mRNA, or proteins into human corneas ex vivo and investigate methods for clinical application in donor corneas before transplantation.
These techniques could also be applied other tissues of the eye to induce regeneration, such as the corneal epithelium and retinal pigment epithelium.
Email address: email@example.com
Title of current project: Innate immunity in retinal ageing and disease
Research Interests: In my research program I aim to develop a mechanistic understanding of the role of systemic and local innate immune system dysfunction during normal ageing and in inherited and age-related retinal degenerations.
Specifically, I am interested in the local and systemic responses and interaction of the complement and myeloid cell system in order to understand their relative importance for age-related and pathological processes in the eye. This is of particular interest since one of the common blinding diseases in the western world is age-related macular degeneration (AMD) and many genetic risk factors for this disease affect these two branches of the innate immune system. I aim to understand how identified genetic risk factors contribute to innate immune dysregulation and hyper-activation on the molecular and cellular level and how this might lead to pathological features of the disease at the interface of the retina and the RPE/choroidal complex.
Email address: firstname.lastname@example.org
Title of current project: Human Gene Therapy Clinical Trial for Achromatopsia Patients with CNGB3 mutations
Research Interests: Achromatopsia patients completely lack cone photoreceptor function from birth,suffering significant photophobia and reduced visual acuity as well as total lack of colour vision. Genetic defects in CNGB3 are the major cause of this hereditary disease. Recently, our group and others have shown that visual defects in animal models of achromatopsia with CNGB3 mutations could be effectively reversed by gene therapy. My primary interest is to translate these findings into a clinical setting in order to treat patients with achromatopsia by designing and facilitating a Phase I clinical trial. I am also interested in laboratory-based research aimed to improve the efficiency and safety of gene transfer to retinal cells in order to achieve long-term improvements in vision.
Email address: email@example.com
Email address: firstname.lastname@example.org
Title of project: Determining the migratory capacity and mechanisms used by cone photoreceptor precursors during development and in transplantation
Research interests: Cone mediated vision is critical for useful sight in humans, and the death of these cells in degenerative diseases such as macular degeneration is responsible for the loss of central and high acuity vision. Previous efforts have shown that transplanted cone precursors can integrate into an adult retina and show the particular morphology and gene expression of natural cones. However, major challenges remain in improving the efficiency and success rate of these transplantation efforts.
Initially, I will be looking at the ways in which cone photoreceptors migrate in normal development before applying this to transplanted cell populations. My other aims include identifying suitable genetic markers expressed in all cones at early stages of development in order to find a mouse model capable of supplying cone precursor cell populations for transplantation at a wide range of ages.
Email address: email@example.com
Title of project: Retinal repair using stem cell-derived photoreceptor precursors.
Research interests: Inherited or age-related photoreceptor degeneration is a leading cause of blindness, as once photoreceptors are lost they are unable to regenerate. Stem cell therapy is a novel therapeutic strategy to repair the degenerate retina. We have previously shown that the transplantation of photoreceptor precursors from a specific stage of early postnatal development are able to integrate into the adult retina, form synaptic connections and improve vision in models of visual dysfunction. My previous work has involved investigating and improving donor-derived photoreceptor precursor cell integration into the adult retina. My current research focuses on generating photoreceptor precursors from pluripotent stem cell sources to investigate the use of these cells as a therapeutic source for photoreceptor cell transplantation to repair the degenerate retina. The aim of this work is to determine if stem cell-derived photoreceptor precursors can functionally integrate into the adult degenerate retina and restore visual responses, thereby providing a renewable source of cells for therapeutic application.
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