LUXTURNA Proves Effectiveness of Single Gene Therapy To Cure Rare Cause of Blindness

MedicalResearch.com Interview with:

Dr. Stephen M. Rose, PhD Chief Research Officer Foundation Fighting Blindness

Foundation Fighting Blindness

Dr. Stephen Rose PhD
Chief Research Officer
Foundation Fighting Blindness (FFB)

Dr. Rose comments on the announcement of the FDA approval of voretigene neparvovec (LUXTURNA™) gene therapy for inherited blindness due to mutations in the RPE65 gene.

What is the background for this announcement? What were the main findings from the study?

Response: While it has been 30 years since the RPE65 gene was identified as causing Leber’s Congenital Amaurosis, this shows that it is possible to have an effective gene therapy for an inherited disease. As the first gene therapy for the eye or for an inherited disease, LUXTURNA is a historic milestone in the search for cures for all inherited retinal diseases (IRDs). As a one-time gene therapy, LUXTURNA will not only be life-changing for patients with vision loss due to mutations in the RPE65 gene, it also provides critical momentum for gene therapies – for the eye and other diseases – now in the clinic.  Continue reading

Viral Vector Delivered Gene Therapy That Reversed Diabetes in Mice

MedicalResearch.com Interview with:
Xiangwei Xiao, M.D., Ph.D.
Assistant Professor of Department of Surgery,
Children’s Hospital of Pittsburgh
University of Pittsburgh School of Medicine,
Pittsburgh, PA

MedicalResearch.com: What is the background for this study?

Response: Diabetes is a prevalent chronic disease characterized by persistently high blood glucose. Diabetes has two main subtypes, type 1 diabetes and type 2 diabetes. In type 1 diabetes, the immune system attacks and destroys insulin-producing beta cells in the pancreas, resulting in high blood levels of glucose. In type 2 diabetes, the beta cells do not produce enough insulin or the body is not able to use insulin effectively.

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FDA Advisory Committee Recommended Approval of First Gene Therapy For Inherited Eye Disease

MedicalResearch.com Interview with:
Dr. Stephen M. Rose, PhD Chief Research Officer Foundation Fighting BlindnessDr. Stephen M. Rose, PhD
Chief Research Officer
Foundation Fighting Blindness

Dr. Rose discusses the FDA advisory panel unanimously recommended approval of Spark Therapeutics’ Gene Therapy Luxturna  for the treatment of patients with vision loss due to confirmed biallelic RPE65-mediated inherited retinal dystrophies, a group of rare blinding conditions caused by one of more than 220 different genes.

MedicalResearch.com: Would you tell us a little about IRD? Whom does it affect and how?  How common is this disorder?

Response: The retina at the back of the eye is responsible for collecting light and turning it into signals that are transmitted to the brain and interpreted as vision. Think of the retina as the film in a camera, or more recently the sensor at the back of a digital camera. Inherited rare retinal degenerations are when the retina at the back of the eye deteriorates and loses its ability to capture light, thereby leading to blindness.

iRDs can affect anyone, no matter race or ethnicity. These are inherited conditions that are passed down from parents to children, if a parent or both parents are either affected already or are carriers for a variant in any of the over 250 genes responsible for retinal degeneration.

There are over 15 different types of iRDs, with retinitis pigmentosa being the most common with a US affected population around 100,000. The rest of the iRDs make up another approximately 100,000 affected individuals in the US, so there are about 200,000 total affected individuals in the US. Worldwide these iRDs affect somewhere around one to two million individuals.

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Single Injection of Klotho Gene Protected Animals From Cognitive Decline

MedicalResearch.com Interview with:

Dr Miguel Chillon PhD Department of Biochemistry and Molecular Biology Universitat Autonoma Barcelona Spain

Dr. Chillon

Dr Miguel Chillon PhD
Department of Biochemistry and Molecular Biology
Universitat Autonoma Barcelona
Spain

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Klotho is a protein with an anti-aging and neuroprotective role. Recent studies show it prevents the development of cognitive problems associated with aging and Alzheimer’s disease. Klotho works mainly by inhibiting the insulin / IGF-1 signaling pathway and decreasing the damage caused by oxidative stress in the brain. One of the latest results revealed that the concentration of Klotho in cerebrospinal fluid is significantly lower in Alzheimer’s patients than in human controls of the same age; and it is lower in the elderly with respect to young adults.

Our study used a gene therapy strategy to introduce the Klotho gene into the Central Nervous System of adult animals. With just a single injection of the Klotho gene, young adult animals were protected over time from the cognitive decline associated with aging in old animals. These exciting results pave the way to further advances in research and the development of a neuroprotective therapy based on Klotho.

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Novel Viral Vector Allows Gene Transfer To Correct Hearing Loss

MedicalResearch.com Interview with:

Lukas Landegger MD Molecular Neurotology Laboratory (PI Konstantina Stankovic) Massachusetts Eye and Ear Infirmary

Dr. Landegger

Lukas Landegger MD
Molecular Neurotology Laboratory (PI Konstantina Stankovic)
Massachusetts Eye and Ear Infirmary

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Genetic hearing loss affects more than 125 million people worldwide and constitutes a major hurdle for language acquisition and child development in general. Technological advances over the last decades, such as cochlear implants, have made it possible for deaf children to partially regain their sense of hearing. However, these devices still have several shortcomings, especially when listeners attempt to understand speech in noise or listen to music.

In establishing Anc80L65 as a reliable vector for gene delivery in the inner ear and releasing the first data demonstrating convincing hearing and vestibular function rescue in mice, we provide a foundation for other researchers interested in assessing the benefits of gene therapy in animal models of human disease.

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Gene Therapy Restores Hearing Down To A Whisper, in Mice

MedicalResearch.com Interview with:

Gwenaelle Geleoc, PhD Assistant Professor Department of Otolaryngology F.M. Kirby Neurobiology Center Children's Hospital and Harvard Medical School Boston, MA

Dr. Gwenaelle Geleoc

Gwenaelle Geleoc, PhD
Assistant Professor
Department of Otolaryngology
F.M. Kirby Neurobiology Center
Children’s Hospital and Harvard Medical School
Boston, MA

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We seek to develop gene therapy to restore auditory and balance function in a mouse model of Usher syndrome. Usher syndrome is a rare genetic disorder which causes deafness, progressive blindness and in some cases balance deficits. We used a novel viral vector developed by Luk Vandenberghe and package gene sequences encoding for Ush1c and applied it to young mice suffering from Usher syndrome. These mice mimic a mutation found in patients of Acadian descent. We assessed recovery of hearing and balance function in young adult mice which had received the treatment. Otherwise deaf and dizzy, we found that the treated mice had recovered hearing down to soft sounds equivalent to a whisper and normal balance function.

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Early Use of Gene Therapy May Stop Plaques of Alzheimer’s Disease

MedicalResearch.com Interview with:

Dr. Magdalena Sastre PhD Faculty of Medicine, Department of Medicine Senior Lecturer Imperial College London

Dr. Magdalena Sastre

Dr. Magdalena Sastre PhD
Faculty of Medicine, Department of Medicine
Senior Lecturer
Imperial College London

MedicalResearch.com: What is the background for this study?

Response: Alzheimer’s disease is the most common neurodegenerative disorder, affecting over 45 million people around the world. Currently, there are no therapies to cure or stop the progression of the disease. Here, we have developed a gene therapy approach whereby we delivered a factor called PGC-1α, which regulates the expression of genes involved in metabolism, inflammation and oxidative stress in the brain of transgenic mice. This factor is also involved in the regulation of energy in the cells, because it controls the genesis of mitochondria and in the generation of amyloid-β, the main component of the neuritic plaques present in the brains of Alzheimer’s disease patients.

We have found that the animals with Alzheimer’s pathology treated with PGC-1α develop less amyloid plaques in the brain, perform memory tasks as well as healthy mice and do not have neuronal loss in the brain areas affected by the disease.

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Gene Therapy Delivers Intracellular Antibodies To Attack Abnormal Protein in Huntington’s Disease

MedicalResearch.com Interview with:
Lee Henderson, Ph.D. CEO Vybion, Inc. Ithaca, NY 14852Lee Henderson, Ph.D.
CEO, Vybion, Inc.
Ithaca, NY 14852

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Huntington’s disease (HD) is a progressive and fatal neurodegenerative disease characterized by loss of both cognitive and motor function as a result of neuron loss primarily within the brain striatum. HD is directly caused by the expansion of CAG repeats in the huntingtin gene resulting in an expanded glutamine region (polyQ) near the N-terminus of the protein. Age of disease onset and the rate of progression is directly correlated to the size of the expansion with pathology observable at 35-70 repeats in adults and greater in juvenile onset. During normal turnover and degradation of the huntingtin protein, the N-terminal polyQ-containing fragments drive pathology and aggregate formation in cells. The direct link to progression has been described by several laboratories using cell-based and animal model studies and confirmed in humans as the binding of these N-terminal fragments to DNA and transcription factors that result in widespread gene dysregulation in neurons.

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Gene Therapy to Spinal Cord Offers Potential Hope to Peripheral Nerve Pain Patients

MedicalResearch.com Interview with:

Hui-Lin Pan, MD, PhD Helen T. Hawkins Distinguished Professor  and Deputy Division Head for Research Division of Anesthesiology and Critical Care, Unit 110 The University of Texas MD Anderson Cancer Center Houston, TX

Dr. Hui-Lin Pan

Hui-Lin Pan, MD, PhD
Helen T. Hawkins Distinguished Professor
and Deputy Division Head for Research
Division of Anesthesiology and Critical Care, Unit 110
The University of Texas MD Anderson Cancer Center
Houston, TX

MedicalResearch.com: What is the background for this study?

Dr. Hui-Lin Pan: Chronic nerve pain caused by damage to the peripheral nerve is a debilitating health problem and remains very difficult to treat. Sensory neurons in the spinal cord are normally inhibited by inhibitory neurotransmitters (GABA and glycine) to regulate transmission of painful information. A major feature of nerve injury-induced chronic pain is reduced spinal cord inhibition, resulting from diminished activity of a chloride transporter called KCC2. In this study, we investigated whether increasing KCC2 expression at the spinal level using a lentiviral vector can restore KCC2 activity, thereby reducing chronic nerve pain.

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CRISPR Editing May Lead To Genetic Treatment of Retinitis Pigmentosa

More on Gene Therapy on MedicalResearch.com

Benjamin Bakondi, Ph.D. Postdoctoral Scientist, Eye Program Board of Governors Regenerative Medicine Institute Cedars-Sinai Medical Center; Dept. of Biomedical Sciences Los Angeles, CA 90048

Dr. Benjamin Bakondi

MedicalResearch.com Interview with:
Benjamin Bakondi, Ph.D. Postdoctoral Scientist
Laboratory of: Shaomei Wang, M.D., Ph.D.
Institute Director: Clive N. Svendsen, Ph.D.
Board of Governors Regenerative Medicine Institute
Cedars-Sinai Medical Center;
Dept. of Biomedical Sciences
Los Angeles, CA 90048

Medical Research: What is the background for this study? What are the main findings?

Dr. Bakondi: Retinitis Pigmentosa (RP) is an inherited disease that causes progressive retinal degeneration and continual vision loss. Over 130 mutations have been identified in over 60 genes that cause RP. Gene replacement therapy is being evaluated for the recessive form of RP, in which both inherited alleles are dysfunctional. Retinitis Pigmentosa arising from dominant mutations however, would not benefit from such a strategy, and alternative options have not demonstrated clear efficacy.

The idea for a therapeutic based on our approach is to use CRISPR/Cas9 to ablate the mutant copy of an allele and leave the wild-type copy unaffected. Barring haploinsufficiency, the wild-type allele should restore function and prevent retinal degeneration at levels commensurate with Cas9 cleavage efficiency. Our experimental findings provide proof-of-principle that a single DNA nucleotide difference in the genomic sequence between mutant and wild-type genes is enough to distinguish the mutant transcript for Cas9 cleavage with high fidelity. Eliminating production of the mutant rhodopsin protein prevented retinal degeneration and preserved vision. While Cas9/gRNA delivery improvement is underway, it should be noted that translational applicability of this approach is restricted to dominant mutations, not all of which may be targetable for ablation therapy.

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Gene Therapy with Leptin Induces Weight Loss

Urszula T. Iwaniec, Ph.D. Associate Professor Skeletal Biology Laboratory School of Biological and Population Health Sciences Oregon State University Corvallis, OR 97331MedicalResearch.com Interview with:
Urszula T. Iwaniec, Ph.D.
Associate Professor
Skeletal Biology Laboratory
School of Biological and Population Health Sciences
Oregon State University
Corvallis, OR 97331

Medical Research: What is the background for this study? What are the main findings?

Dr. Iwaniec: Excessive weight gain in adults is associated with a variety of negative health outcomes. Unfortunately, dieting, exercise, and pharmacological interventions have had limited long-term success in weight control and can result in detrimental side effects, including accelerating age-related bone loss.  Leptin, a hormone produced by fat cells plays an essential role in weight regulation. Delivery of leptin directly into the hypothalamus by gene therapy normalizes body weight. We investigated the efficacy of using hypothalamic leptin gene therapy as an alternative method for reducing weight in skeletally-mature female rats and determined the impact of leptin-induced weight loss on bone. Our findings show that hypothalamic leptin gene therapy reduced body weight with minimal effects on bone mass or microarchitecture.

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Study: Gene therapy causes breast cancer stem cells to self-destruct

Targeted agent avoids healthy cells, blocks proteins that prevent cell death in tumors

HOUSTON — Gene therapy delivered directly to a particularly stubborn type of breast cancer cell causes the cells to self-destruct, lowers chance of recurrence and helps increase the effectiveness of some types of chemotherapy, researchers at The University of Texas MD Anderson Cancer Center reported in the Sept. 13 edition of Cancer Cell.

In cellular and mouse studies, scientists found the gene mutation BikDD significantly reduced treatment-resistant breast-cancer initiating cells (BCICs), also known as breast cancer stem cells, by blocking the activity of three proteins in the Bcl-2 family. This genetic approach increased the benefits of lapatinib, one of the most common chemotherapy drugs for breast cancer.

“There are no effective methods to target BCICs, and they’re urgently needed, especially for relapsed breast cancer patients,” said senior author Mien-Chie Hung, Ph.D., vice president for basic research, professor and chair of MD Anderson’s Department of Molecular and Cellular Oncology. “This research suggests a potential therapeutic approach to breast cancer stem cells that will minimize recurrence and drug resistance.”

Special delivery system targets cells

Gene therapy was deposited directly into breast cancer cells with an innovative delivery system called VISA, short for versatile expression vector, which was developed at MD Anderson. It includes a targeting agent, also called a promoter, two components that boost gene expression in the target tissue and a payload — a Bik mutant gene called BikDD known to kill cancer cells. It’s all packaged in a fatty ball called a liposome and delivered intravenously.

This system has been successfully applied in pancreatic, lung, liver and ovarian cancer preclinical models. MD Anderson clinical researchers are preparing a phase I clinical trial for pancreatic cancer.

Stem cells frequently stymie treatment

Breast cancer stem cells, often resistant to chemotherapy and radiotherapy, are a major obstacle for breast cancer treatment, Hung said. If any of these cells remain after treatment, a new tumor often forms. Although lapatinib, known commercially as Tykerb®, can stabilize the level of these cells, no drugs are available to reduce them.

The Bcl-2 family of proteins – especially the subtypes Bcl-2, Bcl-xL and Mcl-1 — is essential for breast cancer tumor growth and treatment resistance. If too many of these three proteins are present, they can cause poor prognosis and resistance to chemotherapy drugs including lapatinib, as well as paclitaxel, doxorubicin and cisplatin.

This study shows that Bcl-2 proteins help breast cancer stem cells survive, causing resistance to treatment and likelihood of recurrence. However, using VISA to deliver BikDD can block the three key Bcl-2 proteins, eliminating the stem cells.

VISA-claudin4-BikDD cuts tumor burden

The researchers engineered a VISA that contained claudin4, a protein over-expressed in breast cancer, as a targeting agent to preferentially express BikDD in breast cancer cells. This process silenced the three Bcl-2 proteins and caused the cancer cells to self-destruct. Since the VISA focused the BikDD on cancer cells, normal cells were not affected.

Treating mice with the VISA-claudin4-BikDD therapy reduced tumor volume by 75 percent compared to control mice.

They also compared VISA-claudin4-BikDD therapy to BikDD packaged with a non-specific strong promoter from cytomegalovirus. Both versions reduced tumor burden and extended survival of mice, but tumor volume in mice treated with VISA-claudin4-BikDD was half that of the CMV-BikDD-treated mice. In a safety study using an unusually high dose, 60 percent of mice treated with CMV-BikDD survived after three days; all mice treated with VISA-Claudin4-BikDD survived for the duration of the 14-day safety profile study.

In cell line experiments, the CMV-BikDD also invaded and destroyed normal cells, while the VISA-Claudin4-BikDD did not.

Agent energizes lapatinib, other drugs

BikDD made HER2-positive breast cancer cells more sensitive to lapatinib when all three Bcl-2 proteins were inhibited but not when they were inhibited separately. HER2-positive breast cancer is a particularly aggressive type that makes too much human epidermal growth factor 2; it accounts for about 20 percent of breast cancers. BikDD also sensitized EGFR+ (epidermal growth factor positive) breast cancer cells to lapatinib and several other breast cancer cells lines to paclitaxel.

Moving discovery forward

Hung said this approach is promising for breast cancer treatment, especially recurrent disease.

“VISA-claudin4-BikDD gene therapy may provide an effective strategy to inhibit breast tumor growth,” he said. “It demonstrates virtually no toxicity in normal cells and produces a profound killing effect in multiple breast cancer cell lines and synergy with other agents.”

Hung said the next step is to move VISA-claudin4-BikDD into a Phase I clinical trial to test its effect on patients with breast cancer.

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This work was supported by grants from the National Cancer Institute, including MD Anderson’s Specialized Program in Research Excellence grant, the MD Anderson/China Medical University Hospital Sister Institution Fund, the Breast Cancer Research Foundation, National Breast Cancer Foundation, Inc., Patel Memorial Breast Cancer Research Fund, MD Anderson’s Center for Biological Pathways and NCI Cancer Center Support Grant, and the Taiwan Department of Health Cancer Center Research of Excellence Grant.

In addition to Hung, MD Anderson researchers include first author Jing-Yu Lang, Ph.D., first author, Jennifer Hsu, Ph.D., Chun-Ju Chang, Ph.D., Qingfei Wang, Ph.D., Xiaoming Xie, Ph.D., Yi Bao, Ph.D., Hirohito Yamaguchi, Ph.D. and Dihua Yu, M.D., Ph.D., Department of Molecular and Cellular Oncology; Funda Meric-Bernstam, M.D., Department of Surgical Oncology; Wendy Woodward, M.D., Ph.D., Department of Radiation Oncology; and Gabriel Hortobagyi, M.D., Department of Breast Medical Oncology.

Hung and Hsu hold joint appointments at China Medical University and Asia University, Taichung, Taiwan. Xie holds an appointment at Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China.