By Salih Sanlioglu VMD, PhD

Recurrent pancreatic cancer is a lethal disease with a median survival rate of less than 6 months. Rexin-G (Retroviral Expression Vector bearing an Inhibitory Gene) being a replication-incompetent retroviral vector derived from Moloney Murine Leukemia Virus (MoMLV) encodes dominant negative mutant form of human cyclin G1 involved in cell cycle regulation and therefore, has a broad spectrum of antineoplastic activity. In addition, surface modified nanosized particles of interest with von Willebrand Factor derived collagen binding motif selectively accumulate in metastatic lesions seeking out to destroy cancer cells following systemic gene delivery.

In 2003, Rexin G finally became the world's first targeted injectable vector approved by the FDA and is granted orphan drug designation against pancreatic cancer. Rexin G has also demonstrated significant anti-tumor activity against chemotherapy resistant squamous cell carcinoma, hormone refractory prostate cancer, breast cancer, ovarian cancer and some hematologic malignancies such as B cell lymphoma.

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By Ahter D. Sanlioglu PhD

Type 1 Diabetes (T1D) is characterized by T-cell mediated autoimmune destruction of the pancreatic beta cells. TRAIL is thought to play an important role in development of T1D, as a significant component of the immune system. However, the role of TRAIL in T1D development is still controversial.

In a study conducted by our group, high TRAIL expression levels in human pancreas were correlated with higher apoptosis rates. Yet another recent study by our group used TRAIL overexpression by adenoviral vectors as a strategy to increase its expression levels in the allotransplanted beta islets to diabetic rats. This approach provided a higher protection for the islets against the infiltrating leukocytes, reflected by decreased severity of insulitis, prolonged allograft longevity, and greater function.

Furthermore, our group detected specific alterations in TRAIL ligand and receptor expressions in the pancreatic beta islets of Non-Obese Diabetic (NOD) mice treated with the diabetes inducing/accelerating agents streptozotocin or cyclophosphamide.

Whether TRAIL plays a protective or destructive role in T1D development will be discussed in the light of these studies.

The potential of treating or preventing disease by modifying the expression of one's genes has captured the imagination of the scientific community ever since the discovery of DNA.

This therapeutic concept, called gene therapy, emerged as a very literal clinical application of modern day molecular biology. While the concept may seem simple, its translation into effective therapies has been challenging. The events that led up to this impending revolution are summarized below.

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Researchers in Oxford have treated a man with an advanced gene therapy technique to prevent him from losing his sight.

It is the first time that anyone has tried to correct a genetic defect in the light-sensing cells that line the back of the eye.

The president of the Academy of Medical Sciences said the widespread use of gene therapy of this treatment will be soon be possible.

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Genevolve Vision Diagnostics developed a noninvasive molecular diagnostic for all major forms of congenital color blindness, for use by ophthalmologists and optometrists.

The test, marketed under the Eyedox™ brand, involves using a noninvasive buccal epithelial cell collector to pick up skin cells sloughed daily from the lining of the mouth.The DNA goes to a CLIA-certified laboratory where the color genes are identified and classified for inherited color vision deficiency, and a treatment plan and family history are developed.

While gene therapy has been shown to cure some forms of congenital blindness, better diagnostics will be critical for identifying patients for current and future gene therapies.

The U.K. CF Gene Therapy Consortium, funded by the Cystic Fibrosis Trust, seeks to raise €6 million for a gene therapy trial.

As of October 6, supporters raised €700,000 toward funding the multidose clinical trial, which calls for more than 100 people with cystic fibrosis in Edinburgh and London to be given either a healthy gene, the gene transfer agent, and the promoter or a placebo, once a month for a year.

If patient lung function shows improvement, the consortium has said it will pursue a pharmaceutical partner to take the product into a Phase III clinical trial starting in 2015.

University of Pennsylvania researchers reported sustained remissions of up to a year among a small group of advanced chronic lymphocytic leukemia patients treated with genetically engineered versions of their own T cells.

Carl June, M.D., led a team from the Abramson Cancer Center and Perelman School of Medicine in removing patients' cells, modifying them in UPenn's vaccine production facility, then infusing the new cells back into patients' bodies after chemotherapy.

The findings, published simultaneously in the New England Journal of Medicine and Science Translational Medicine, are the first demonstration of gene transfer therapy to create "serial killer" T cells aimed at cancerous tumors, a possible roadmap for treating other cancers.

U.S. and British researchers identified a highly undifferentiated stem-cell-like T cell within a patient's immune system that can continually refresh itself for long periods of time, possibly permanently.

Writing in Nature Medicine, the researchers from NCI, NIAID, NIH, UPenn, and Cardiff University School of Medicine discussed how they isolated a tiny fraction of highly undifferentiated T cells showing the first changes in gene expression that occur when T cells "remember" antigens they have seen previously, and prepare to react quickly.

NCI's Nicholas P. Restifo, M.D., and his team hope to regenerate younger T cells from older ones by manipulating certain genes.

An FDA advisory panel identified three challenges to development of cellular and gene therapies for retinal disorders in adult and pediatric populations.

FDA's Cellular, Tissue, and Gene Therapies Advisory Committee pinpointed the challenges as: 1)Selection of efficacy endpoints for clinical trials, especially for trials intended to study rare retinal disorders and disorders in very young children; 2)Treatment of the contralateral eye and repeat administration of the product; and 3)Identifying methods to confirm accurate delivery of the intended dose into the target site, in both preclinical and clinical studies.

No cell or gene therapy products are licensed for ophthalmic indications in the U.S., but several such products are in development.

Christopher Reid and his family are celebrating 10 years since he became the first child in England to receive gene replacement therapy for severe combined immuno-deficiency (SCID), a genetic condition that meant he had no natural immune system and was forced to live in a protective "bubble".

He was diagnosed with SCID at eight months of age, and given three months to live. But in December 2001, Christopher underwent an operation in which an artificially created gene was mixed with his bone marrow, and injected into his body.

Gene therapy is now considered a cure for SCID, as reported in Science Translational Medicine in August.

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