Preserving the Precious Gift of Sight

Richard L. Hurwitz, MD

WILSON RESEARCH PROJECT

Department of Pediatrics, Hematology and Oncology Service

Texas Children’s Hospital

Baylor College of Medicine

Houston, TX

 

Dr. Hurwitz’ Research Project

Immune Consequences of Gene Therapy for Ocular Disorders
 

Current Research Interests

Retinoblastoma (Rb), an ocular cancer that affects young children, can be caused either by spontaneous growth of a tumor in one eye or by an inherited mutation that often causes tumors in both eyes. Removal of the eye (enucleation) with the tumor is often curative but ophthalmologists are opting for local therapies to control small tumors or systemic chemotherapy to control larger tumors. Sometimes small pieces of tumor break off to form vitreous seeds. Developing alternative treatments that could potentially preserve vision and reduce the risk of developing other cancers is important.

Dr. Hurwitz has completed the first clinical trial using suicide gene therapy (a method of forcing the tumor cells to produce a protein that converts a drug to a locally toxic agent) to treat children with advanced Rb. The successful reduction of vitreous seeds has encouraged him to continue his laboratory initiatives to improve this innovative therapy. Additionally he would like to better understand the differences between invasive and non-invasive tumors and to identify and characterize the Rb tumor stem cell. He is also interested in developing gene therapy options for retinal degenerative disorders such as Stargardt Disease. His strategy for either application of gene therapy uses a special nonpathogenic virus to deliver the correct genetic material to selected cells in the eye.

Progress in 2016

Dr. Hurwitz has developed novel, non-invasive microwafers that can deliver nanoparticles containing drugs or gene-expressing plasmids to the posterior chamber of the eye including to the retina. He hypothesizes that this system would be ideal for treating Rb. These microwafers are small, flexible discs similar to contact lenses, containing wells on one surface that can be filled with nanoparticles that carry a drug or gene of the doctor’s choice. Preliminary in vitro studies using nanoparticles that deliver doxorubicin demonstrate that nanoparticles can deliver this chemotherapeutic agent to Y79 Rb cells and cause cell death in a dose-dependent manner.

Plans for 2017

Continue his investigation of the use of adenoviral vectors to transfer therapeutic genes to the ocular environment; to examine the immune response as it pertains to gene therapy. 1) The vector systems that his laboratory has developed for suicide gene therapy for Rb and for gene replacement approaches for the treatment of Stargardt Disease will be used to explore mechanisms of adenoviral-mediated transgene expression unique to the ocular environment. 2) The origin of Rb tumor cells and the mechanisms of retina-derived cell proliferation will be explored. 3) The immune response to adenoviral-mediated gene therapy for children with Rb was monitored and shown to be dose dependent. Innovative methods to reduce the dose of viral vector required to achieve therapeutic effect are being developed.

Progress in 2015

1) Preliminary results are consistent with the hypothesis that the hyaluronan-binding proteoglycan versican is the component of vitreous that enhances adenoviral-mediated transgene expression. 2) Preliminary data shows that when expression of the protein SKAP2 is decreased, the proliferation of Rb cells increases. 3) Dr. Hurwitz has found that inhibition of Src kinase activity in vitro can decrease the amount of viral vector necessary to kill retinoblastoma cells.

Progress in 2014

1) Dr. Hurwitz has previously reported that hyaluronan (HA), a major component of vitreous, enhances adenoviral-mediated transgene expression through interactions with its receptor CD44. Dr. Hurwitz is currently exploring whether versican, a complex protein, can explain the hyaluronan-CD44 interaction that he has previously observed. 2) Dr. Hurwitz has isolated approximately 30 primary cell lines from children who presented with Rb, and he has determined the exact RB1 mutations that resulted in their disease for most of these children. 3) Dr. Hurwitz determined the dose of vector that achieved 50% killing of the tumor cells.

Progress in 2013

Dr. Hurwitz has completed the first clinical trial that used suicide gene therapy (a method of forcing the tumor cells to produce a protein that converts a drug to a locally toxic agent) to treat children with advanced Rb. The successful reduction of vitreous seeds has encouraged him to continue his laboratory initiatives to improve this innovative therapy. Additionally, he would like to better understand the differences between invasive and non-invasive tumors and to identify and characterize the Rb tumor stem cell. Dr. Hurwitz is also interested in developing gene therapy options for retinal degenerative disorders such as Stargardt Disease. His strategy for either application of gene therapy uses a special nonpathogenic virus to deliver the correct genetic material to selected cells in the eye.

Progress in 2012

Dr. Hurwitz has completed the first clinical trial that used suicide gene therapy (a method of forcing the tumor cells to produce a protein that converts a drug to an agent that is toxic to the tumor cells) to treat children with advanced Rb and the successful results have encouraged him to continue his laboratory initiatives to improve this innovative therapy.

Retinoblastoma (Rb), an ocular cancer that affects young children, can be caused either by spontaneous growth of a tumor in one eye or by an inherited mutation that often causes tumors in both eyes. Removal of the eye with the tumor is often curative, but ophthalmologists are opting for laser, cryo- or radiation therapies to control small local tumors or systemic chemotherapy to control larger tumors with the goal of saving vision. However, children treated with chemotherapy or radiation therapy have a significantly increased risk of developing other types of cancer later in life.

Some disorders that cause retinal degeneration and blindness such as Stargardt Disease are also associated with errors in genetic material. These defects are manifest in the abnormal structure or function of proteins responsible for normal vision. If the mutation(s) in the affected gene is known, replacing the defective gene with a normally functioning gene could slow or even halt the degeneration.

Dr. Hurwitz’s laboratory continued their investigations of the use of adenoviral vectors to transfer therapeutic genes to the ocular environment and to examine the immune response as it pertains to gene therapy.

1. The vector systems that they have developed for suicide gene therapy for retinoblastoma and for gene replacement approaches for the treatment of Stargardt Disease are used to explore mechanisms of adenoviral-mediated transgene expression unique to the ocular environment.

2. To better target these vectors to retina cells and the retinoblastoma tumors derived from them, the origin of retinoblastoma tumor cells and the mechanisms of retina-derived cell proliferation are being explored.

3. The immune response to adenoviral-mediated gene therapy for children with retinoblastoma was monitored and shown to be dose dependent. Innovative methods to reduce the dose of viral vector required to achieve therapeutic effect are being developed.

Progress in 2011

The vector systems that Dr. Hurwitz has developed for suicide gene therapy for retinoblastoma and for gene replacement approaches for the treatment of Stargardt Disease are being used to explore mechanisms of adenoviral-mediated transgene expression unique to the ocular environment.

Dr. Hurwitz studies the potential use of gene therapy for the treatment of ocular diseases. He has shown that a novel treatment for retinoblastoma using suicide gene therapy is safe and possibly effective in children. The mechanism of adenoviral-mediated transgene expression in the ocular environment is being explored with goals of providing future molecular targets to modulate adenoviral-mediated gene therapy for both retinoblastoma and retinal degenerative diseases and possibly of controlling adenovirus infection in general.

Dr. Hurwitz is studying the cellular origin of retinoblastoma and the differences between invasive and non-invasive forms of this disease. Dr. Hurwitz has demonstrated that an embryonic mouse model of retinoblastoma, a cancer of the eye that occurs in children, can be created. This model conclusively shows that proliferating, undifferentiated retinal cells can form tumors.  A small percentage of cells that express the neural stem cell related protein CD133 can be isolated from a cell line that was created from this murine tumor.

These CD133 positive cells can preferentially recreate the retinal tumor in mice and this tumor appears identical to primary retinoblastoma tumors in both mice and children.  Therefore, a proliferating tumor cell that expresses the neural stem cell marker CD133 is responsible for retinoblastoma tumor initiation in a mouse model of the disease.

 

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Mission of RRF

The mission of the Retina Research Foundation is to reduce retinal blindness worldwide by funding programs in research and education. As a public charity, RRF raises funds from the private sector and the investment of its endowment funds.

RRF’s 48th Anniversary

October 1, 2017