Gene therapy improves vision in patients with congenital retinal disease

In a clinical trial at The Children’s Hospital of Philadelphia, researchers from The University of Pennsylvania have used gene therapy to safely restore vision in three young adults with a rare form of congenital blindness. Although the patients have not achieved normal eyesight, the preliminary results set the stage for further studies of an innovative treatment for this and possibly other retinal diseases.

An international team led by The University of Pennsylvania, The Children’s Hospital of Philadelphia, the Second University of Naples and the Telethon Institute of Genetics and Medicine (both in Italy), and several other American institutions reported their findings today in an online article in the New England Journal of Medicine.

“This is the first gene therapy trial for a nonlethal pediatric condition,” said Albert M. Maguire, M.D., Associate Professor, Department of Ophthalmology, University of Pennsylvania School of Medicine and a physician at The Children’s Hospital of Philadelphia. Maguire, together with his wife, Jean Bennett, M.D., Ph.D., Professor of Ophthalmology at Penn and Senior Investigator at the F.M. Kirby Center for Molecular Ophthalmology at Penn’s Scheie Eye Institute, have been researching inherited retinal degenerations such as Leber congenital amaurosis (LCA), for 18 years. LCA is a group of inherited blinding diseases that damages light receptors in the retina. It usually begins stealing sight in early childhood and causes total blindness during a patient’s twenties or thirties. Currently, there is no treatment for LCA.

“Patients’ vision improved from detecting hand movements to reading lines on an eye chart,” Maguire added. In 2001, Bennett and Maguire were part of a team which reported successfully reversing blindness using gene therapy on dogs affected by the same naturally occurring form of congenital blindness.

The current study is sponsored by the Center for Cellular and Molecular Therapeutics at The Children’s Hospital of Philadelphia, directed by Katherine A. High, M.D. High, a study leader and an Investigator of the Howard Hughes Medical Institute, has been a pioneer in translational and clinical studies of gene therapy for genetic disease, and in 2005 initiated a collaboration with Bennett and her group to translate their exciting animal findings into a clinical study.

The scientists used a vector, a genetically engineered adeno-associated virus, to carry a normal version of the gene, called RPE65, that is mutated in one form of LCA. Three patients, ages 19, 26 and 26, received the gene therapy via a surgical procedure performed by Maguire between October 2007 and January 2008 at The Children’s Hospital of Philadelphia, where the gene vector was manufactured at the hospital’s Center for Cellular and Molecular Therapeutics (CCMT).

Starting two weeks after the injections, all three patients reported improved vision in the injected eye. “Standard vision tests showed significantly improved vision in the patients,” said Alberto Auricchio, M.D., a study leader from the Telethon Institute of Genetics and Medicine and University of Naples Federico II. The researchers also reported that each injected eye became approximately three times more sensitive to light, and each was improved compared to the uninjected, previously better functioning eye.

The LCA gene therapy vector showed no signs of causing inflammation in the retina or other toxic side effects. One of the three patients had an adverse event, a hole in the retina that did not affect eyesight and may have been surgery-related, rather than related to biological effects of the therapeutic gene or the vector used to carry it.

The patients enrolled in the study to date were identified at the Department of Ophthalmology at the Second University of Naples, an institution with long-standing experience in collecting and studying patients with inherited retinal diseases, under the supervision of Francesca Simonelli, M.D.

Testing continued over a period of six months following the gene therapy vector administration. One patient was better able to navigate an obstacle course compared to before the injection. The patients also had less nystagmus, an involuntary movement of the eyes that is common in LCA. In the patient who experienced better vision even in the uninjected eye, the researchers suggest that the reduced nystagmus benefited both eyes.

“The current clinical trial will continue with more patients and with ongoing follow-up to monitor results,” said Bennett. “We expect improvements to be more pronounced if treatment occurs in childhood, before the disease progresses.”

“This result is important for the entire field of gene therapy,” notes High, a past president of the American Society of Gene Therapy. “Gene transfer has been in clinical trials for over 15 years now, and although it has an excellent safety record, examples of therapeutic effect are still relatively few. The results in this study provide objective evidence of improvement in the ability to perceive light, and thus lay the groundwork for future studies in this and other retinal disorders,” said High.

The pace of moving from pre-clinical discoveries into clinical trials has typically been slow in the field of gene therapy due to the breadth of expertise required, ranging from in-depth knowledge of the disorder to detailed understanding of vector design, manufacture, and pre-clinical evaluation. The complexities of regulatory oversight at both the federal and local levels also present challenges. Through the Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia has developed concentrated expertise and substantial resources to facilitate the “bench to bedside” translation of gene therapy.

Source: University of Pennsylvania School of Medicine

Related stories:

Studies spot numerous undiscovered gene alterations in pancreatic and brain cancers
HHMI investigators have detected a multitude of broken, missing, and overactive genes in pancreatic and brain tumors, in the most detailed genetic survey yet of any human tumor. Some of these genetic changes were previously unknown and could provide new leads for improved diagnosis and therapy for these devastating cancers.
International team reveals first prognosticator of survival in aggressive cancer
The tumor suppressor gene pRb2/p130 may provide the first independent prognostic biomarker in cases of soft tissue sarcoma (STS), according to an international collaboration of researchers, including scientists at the Sbarro Institute for Cancer Research and Molecular Medicine at the College of Science and Technology at Temple University in Philadelphia, PA, the Department of Human Pathology and Oncology, University of Siena and the Center of Oncological Research of Mercogliano (CROM) in Avellino, Italy.
New methods identify and manipulate 'newborn' cells in animal model of Parkinson's disease
When cells in the brain are lost through disease or injury, neighboring cells begin to divide and multiply, but only a few areas in the brain are able to produce new neurons. Patients with Parkinson's disease suffer degeneration of certain neurons that reside in an area of the brain called the substantia nigra and project into the striatum. Many of the newborn cells in these areas have not been well described because of limitations of methods used to characterize them.
Researchers piece together gene 'network' linked to schizophrenia
Reporting this week in the Archives of General Psychiatry, researchers at the Johns Hopkins University School of Medicine have uncovered for the first time molecular circuitry associated with schizophrenia that links three previously known, yet unrelated proteins.
Growth factor predicts poor outcome in breast cancer
The response to insulin-like growth factor 1 (IGF-I) in breast cancer cells predicts an aggressive tumor that is less likely to respond to treatment, said researchers at Baylor College of Medicine in a report that appears in the current issue of the Journal of Clinical Oncology. The finding gives impetus to the movement to tailor cancer treatments to attributes of the various tumors.
Variation of normal protein could be key to resistance to common cancer drug
Researchers at the Moores Cancer Center at the University of California, San Diego (UC SD) in La Jolla have found evidence explaining why a common chemotherapy drug, cisplatin, may not always work for every cancer patient. They have shown that when a variant version of a key protein that normally causes cell death is active, patients may be resistant to the cancer-killing drug.
First gene associated with dry macular degeneration found
In a study that underscores the important role that individual genetic profiles will play in the development of new therapies for disease, a multi-institutional research team – led by Kang Zhang, MD, PhD professor of ophthalmology and human genetics at Shiley Eye Center at the University of California, San Diego, School of Medicine – has made two important discoveries related to age-related macular degeneration (AMD), the leading cause of blindness in adults over the age of 60.
Growing new ear hairs that can boost hearing: study
Scientists have used gene therapy on mouse embryos to grow hair cells with the potential to reduce hearing loss in adult animals, according to a study released Wednesday.

News discussion:

Medicine & Health news