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Designing the Next Generation of Gene Therapy Treatments

The Ocular Gene Therapy Laboratory (OGTL) founded by Daniel M. Lipinski, DPhil, is dedicated to the development of novel therapies to prevent human blindness. Occupying over 1,000 square feet of research space within the Medical College of Wisconsin Eye Institute, OGTL provides the expertise and infrastructure to design the next generation of gene therapy treatments aimed at preventing retinal cell death or dysfunction.
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Development of gene therapy treatments to prevent vascular dysfunction in diabetic retinopathy

Dysfunction of the retinal vasculature underlies development of sight-threatening complications in patients with both type I and Type II diabetes, leading to abnormal growth of new blood vessels (neovascularization) across the surface of the retina which subsequently leak (hemorrhage) blood into the vitreous, causing inflammation, scarring and ultimately vision loss. One of the major problems preventing the development of an effective gene therapy treatment aimed at preventing vascular dysfunction is our inability to efficiently deliver new genetic material to cells of blood vessels within the eye. As part of a research project grant (R01EY027767) awarded to Dr Lipinski (PI) from the National Eye Institute (NEI), the ocular gene therapy laboratory (OGTL) is currently developing recombinant adeno-associated virus (rAAV) vector technologies capable of delivering genetic material to vascular endothelial cells and retinal pericytes, two therapeutic targets that are critical for controlling proper vascular function. Complementary to this research, we are also developing novel imaging modalities to non-invasively assess vascular function in the living eye for use as both a biomarker of disease progression and as an outcome measure of therapeutic efficacy in response to the gene therapy treatments we develop.  
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Development of gene therapy technologies for the treatment of primary open angle glaucoma (POAG)

POAG is one of the leading causes of blindness in the working-age population, affecting approximately 57.5 million worldwide. In the majority of glaucoma patients, an imbalance between the amount of fluid (aqueous) entering and leaving the eye causes increased intra-ocular pressure (IOP) and the death of retinal ganglion cells, specialized neurons within the eye that make up the optic nerve and are responsible for transmitting visual information from the retina to the brain. Whilst existing pharmacological and surgical treatments aimed at lowering IOP can be extremely effective, they place a high medical burden on the patient, usually requiring adherence to a life-long daily treatment regimen of eye drops to relieve pressure. The OGTL is currently pursuing an exciting alternative strategy to traditional pharmacological approaches capable of permanently and safely lowering IOP in glaucomatous eyes following a single gene therapy treatment; the early pre-clinical stages of this work have shown promising dose-dependent reduction in pressure and have been generously supported through intra-mural funding from the MCW Office of Technology and Development (OTD). 

In addition to developing long-acting treatments for glaucoma we are investigating methodologies to non-invasively deliver new genetic material to cells of the cornea using a contact lens-based delivery system in work supported but a Shaffer Award to Dr Lipinski (PI) from the Glaucoma Research Foundation (GRF). 

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Evaluation of gene therapy treatments for rare inherited retinal disease

Inherited retinal diseases collectively affect 1 in 4000 individuals worldwide and are characterized by a progressive loss of photoreceptor cells, leading to blindness that is both irreversible and untreatable. In the majority of patients, rod photoreceptors, which provide for nighttime vision, degenerate first due to an underlying genetic abnormality, followed by the secondary loss of genetically normal cone photoreceptors. The OGTL, funded through a Foundation for Fighting Blindness Individual Investigator Award (TA-NMT-0618-0739) to Dr Lipinski (PI) is investigating whether over-expression of a group of proteins called proteolysis inhibitors is able to physically prevent cone photoreceptors from being broken down in degenerative disease. 

In addition to working on the development of a gene-independent strategies to protect against cone photoreceptor degeneration, we are also working on collaborative projects aimed at developing gene-specific therapies for hyper-rare systemic diseases that have an ocular phenotype, including Farber lipogranulomatosis (Collaborator: Dr Jeffery Medin, MCW) and gyrate atrophy (Collaborators: Drs Mandeep Singh and David Valle, Johns Hopkins), conditions with fewer than 500 reported cases between them. 

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Generation and characterization of novel models of inherited retinal disease

The generation and characterization of animal models that accurately reflect the progression and symptoms of human retinal disease is critical for the development of safe and effective therapeutics to prevent blindness or restore vision. As part of two broad collaborative projects led by Drs Jacque Duncan and Joseph Carroll (MPI) and supported through a Foundation for Fighting Blindness (FFB) program project award (PPA-0617-0718-USCF) and National Eye Institute (NEI) Audacious Goals Initiative grant (U24EY029891), the OGTL is working help develop novel models of recessive retinal diseases, such as Usher syndrome, that can be utilized by investigators nationwide to advance vision research.