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Jean Bennett is the F. M. Kirby Professor of Ophthalmology in the Perelman School of Medicine at the University of Pennsylvania. Her research focuses on gene therapy for retinal diseases. Her laboratory developed the first FDA approved gene therapy for use in humans, which treats a rare form of blindness. She was elected a member of the National Academy of Sciences in 2022. [1]
Bennett graduated with honors from Yale University in 1976, with a bachelor of science in biology. Her father, William R. Bennett Jr., was a member of the faculty there. In 1980, she obtained a Doctorate of Philosophy in Zoology; Cell And Development Biology from the University of California, Berkeley. Bennett continued on to Harvard University to receive her Doctor of Medicine (MD) in 1986.
Bennett received her PhD in Zoology from the University of California, Berkeley in 1980 under Dr. Daniel Mazia. Her graduate research focused on the early development of sea urchin embryos. She moved on to postdoctoral work at the University of California, San Francisco under the guide of Dr. Roger Pedersen. As a postdoctoral student, she collaborated with Dr. William French Anderson developing molecular techniques for gene editing. In 1982, she left this position to attend medical school at Harvard University. [2]
At Harvard, Bennett studied human genetics with Leon Rosenberg and Wayne Fenton (Yale), and she also investigated Down's syndrome and Alzheimer's disease with John Gearhart, Mary Lou Oster-Granite, and Roger Reeves (Johns Hopkins). From this work, she was awarded a career development grant from the Foundation Fighting Blindness to begin research on gene therapy for retinitis pigmentosa (genetic blindness).
To develop an effective gene therapy in the retina, Bennett started by investigating adenoviruses and adeno-associated viruses (AAV) for gene editing in mice and non-human primates at the Institute for Human Gene Therapy at the University of Pennsylvania. [3] [4] [5] [6] The field of gene therapy was stymied after the death of Jesse Gelsinger during 1999 in a clinical trial for gene editing. [7] However, Bennett pushed forward and demonstrated that AAV-mediated delivery of a functional RPE65 gene significantly improved sight in near-blind dogs. [8]
Based on their pre-clinical data, Bennett's team pursued clinical trials in children with a defective form of the RPE65 gene. Their initial trials showed a stark improvement in light sensitivity and visual function in these children. [9] [10] [11] [12] Based on this, the therapy, marketed as LUXTURNA®, was approved by the FDA for use in humans. Currently, her laboratory is investigating gene therapy approaches for other retinal diseases. [13] [14] [15]
Gene therapy is a medical technology which aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells.
The retina is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then processes that image within the retina and sends nerve impulses along the optic nerve to the visual cortex to create visual perception. The retina serves a function which is in many ways analogous to that of the film or image sensor in a camera.
Virotherapy is a treatment using biotechnology to convert viruses into therapeutic agents by reprogramming viruses to treat diseases. There are three main branches of virotherapy: anti-cancer oncolytic viruses, viral vectors for gene therapy and viral immunotherapy. These branches use three different types of treatment methods: gene overexpression, gene knockout, and suicide gene delivery. Gene overexpression adds genetic sequences that compensate for low to zero levels of needed gene expression. Gene knockout uses RNA methods to silence or reduce expression of disease-causing genes. Suicide gene delivery introduces genetic sequences that induce an apoptotic response in cells, usually to kill cancerous growths. In a slightly different context, virotherapy can also refer more broadly to the use of viruses to treat certain medical conditions by killing pathogens.
Adeno-associated viruses (AAV) are small viruses that infect humans and some other primate species. They belong to the genus Dependoparvovirus, which in turn belongs to the family Parvoviridae. They are small replication-defective, nonenveloped viruses and have linear single-stranded DNA (ssDNA) genome of approximately 4.8 kilobases (kb).
Leber congenital amaurosis (LCA) is a rare inherited eye disease that appears at birth or in the first few months of life.
Choroideremia is a rare, X-linked recessive form of hereditary retinal degeneration that affects roughly 1 in 50,000 males. The disease causes a gradual loss of vision, starting with childhood night blindness, followed by peripheral vision loss and progressing to loss of central vision later in life. Progression continues throughout the individual's life, but both the rate of change and the degree of visual loss are variable among those affected, even within the same family.
Viral vectors are tools commonly used by molecular biologists to deliver genetic material into cells. This process can be performed inside a living organism or in cell culture. Viruses have evolved specialized molecular mechanisms to efficiently transport their genomes inside the cells they infect. Delivery of genes or other genetic material by a vector is termed transduction and the infected cells are described as transduced. Molecular biologists first harnessed this machinery in the 1970s. Paul Berg used a modified SV40 virus containing DNA from the bacteriophage λ to infect monkey kidney cells maintained in culture.
Gene therapy using lentiviral vectors was being explored in early stage trials as of 2009.
Gene therapy for color blindness is an experimental gene therapy of the human retina aiming to grant typical trichromatic color vision to individuals with congenital color blindness by introducing typical alleles for opsin genes. Animal testing for gene therapy began in 2007 with a 2009 breakthrough in squirrel monkeys suggesting an imminent gene therapy in humans. While the research into gene therapy for red-green colorblindness has lagged since then, successful human trials are ongoing for achromatopsia. Congenital color vision deficiency affects upwards of 200 million people in the world, which represents a large demand for this gene therapy.
Retinal gene therapy holds a promise in treating different forms of non-inherited and inherited blindness.
Gene therapy for osteoarthritis is the application of gene therapy to treat osteoarthritis (OA). Unlike pharmacological treatments which are administered locally or systemically as a series of interventions, gene therapy aims to establish sustained therapeutic effect after a single, local injection.
Alipogene tiparvovec, sold under the brand name Glybera, is a gene therapy treatment designed to reverse lipoprotein lipase deficiency (LPLD), a rare recessive disorder, due to mutations in LPL, which can cause severe pancreatitis. It was recommended for approval by the European Medicines Agency in July 2012 and approved by the European Commission in November of the same year. It was the first marketing authorisation for a gene therapy treatment in either Europe or the United States.
James M. Wilson is a biomedical researcher with expertise in gene therapy. Wilson graduated from Albion College and the University of Michigan . He completed residency training in Internal Medicine at the Massachusetts General Hospital followed by a postdoctoral fellowship at the Whitehead Institute.
Katherine A. High is an American doctor-scientist who is an emeritus professor at the Perelman School of Medicine at the University of Pennsylvania. She was the co-founder, president, and chief scientific officer of Spark Therapeutics and currently serves as President of Therapeutics at AskBio. Her career has focused on pioneering work in the area of gene therapy, with many accomplishments in basic, translational, and clinical investigation in gene therapy.
Voretigene neparvovec, sold under the brand name Luxturna, is a gene therapy medication for the treatment of Leber congenital amaurosis.
Adeno-associated virus (AAV) has been researched as a viral vector in gene therapy for cancer treatment as an Oncolytic Virus. Currently there are not any FDA approved AAV cancer treatments, as the first FDA approved AAV treatment was approved December 2017. However, there are many Oncolytic AAV applications that are in development and have been researched.
Occult macular dystrophy (OMD) is a rare inherited degradation of the retina, characterized by progressive loss of function in the most sensitive part of the central retina (macula), the location of the highest concentration of light-sensitive cells (photoreceptors) but presenting no visible abnormality. "Occult" refers to the degradation in the fundus being difficult to discern. The disorder is called "dystrophy" instead of "degradation" to distinguish its genetic origin from other causes, such as age. OMD was first reported by Y. Miyake et al. in 1989.
Paul A. Sieving is a former director of the National Eye Institute, part of the U.S. National Institutes of Health. Prior to joining the NIH in 2001, he served on the faculty of the University of Michigan Medical School as the Paul R. Lichter Professor of Ophthalmic Genetics. He also was the founding director of the Center for Retinal and Macular Degeneration in the university's Department of Ophthalmology and Visual Sciences.
Congenital blindness refers to blindness present at birth. Congenital blindness is sometimes used interchangeably with "Childhood Blindness." However, current literature has various definitions of both terms. Childhood blindness encompasses multiple diseases and conditions present in ages up to 16 years old, which can result in permanent blindness or severe visual impairment over time. Congenital blindness is a hereditary disease and can be treated by gene therapy. Visual loss in children or infants can occur either at the prenatal stage or postnatal stage. There are multiple possible causes of congenital blindness. In general, 60% of congenital blindness cases are contributed from prenatal stage and 40% are contributed from inherited disease. However, most of the congenital blindness cases show that it can be avoidable or preventable with early treatment.
Mavis Agbandje-McKenna was a Nigerian-born British medical biophysicist, structural virologist, and a professor of structural biology, as well as the director of the Center for Structural Biology at the University of Florida in Gainesville, Florida. Agbandje-McKenna studied parvovirus structures using X-ray crystallography and cryogenic electron microscopy and did much of the initial work to elucidate the basic structure and function of adeno-associated viruses (AAVs). Her viral characterization and elucidation of antibody binding sites on AAV capsids has led to the development of viral capsid development and gene therapy approaches that evade immune detection and can be used to treat human diseases such as muscular dystrophies. Agbandje-McKenna was recognized with the 2020 American Society of Gene and Cell Therapy Outstanding Achievement Award for her contributions to the field. She died in 2021 from amyotrophic lateral sclerosis.
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