Category Archives: Transhuman News

PUBLIC RELEASE DATE:

30-Sep-2014

Contact: Garth Sundem garth.sundem@ucdenver.edu University of Colorado Denver @CUDenver

The New England Journal of Medicine reports positive results of a phase 1 clinical trial of the drug crizotinib against the subset of lung cancer marked by rearrangement of the gene ROS1. In this multi-center study of 50 patients with advanced non-small cell lung cancer testing positive for ROS1 gene rearrangement, the response rate was 72 percent, with 3 complete responses and 33 partial responses. Median progression-free survival the time it takes for the disease to resume its growth after being slowed by treatment is estimated at 19.2 months with exactly half of patients remaining on observation for disease progression that has not yet occurred.

Over 200,000 people in the United States are diagnosed with lung cancer annually and advanced stage lung cancer has a 5-year survival rate of only about 2 percent. ROS1 rearrangements are found in approximately 1 percent of lung cancer patients, the majority of whom have never smoked.

"This is a major advance for the clinical treatment of lung cancer," says Robert C. Doebele, MD, PhD, investigator at the University of Colorado Cancer Center, associate professor of Medical Oncology at the CU School of Medicine, and one of the study authors. Doebele was involved primarily in the characterization of ROS1 gene rearrangements. Additional CU Cancer Center researchers involved in the project include Marileila Varella-Garcia, PhD, who developed a test for the ROS1 rearrangement in patient tumor samples, and Ross Camidge, MD, PhD, who was involved in the clinical testing of crizotinib against both ALK-positive and now ROS1-positive lung cancers.

In fact, current results follow similar activity seen earlier for the drug against lung cancers marked by rearrangement of the gene ALK. Crizotinib earned FDA approval for treatment of ALK-positive lung cancer in 2011. Both ALK and ROS1 are proteins in the family of tyrosine kinases that normally control the behavior of cells; in the case of these rearrangements, the altered genes continuously signal cells to improperly grow, spread and survive, making the cells act cancerous.

As in the case of ALK-positive lung cancer, in which the gene ALK improperly fuses with the nearby gene EML4, in this newly studied subtype of lung cancer, the gene ROS1 fuses with a nearby partner. Tumor samples studied in the current study showed 5 known gene partners for ROS1 fusion and 2 new partners. The most commonly rearrangement was of ROS1 with the gene CD74, but no matter the ROS1 partner, all rearrangements were equally susceptible to treatment with crizotinib.

"This is ongoing work in which the primary goal of this phase one study was to characterize the safety of the drug. Not only was the safety profile promising, but we saw anti-cancer activity that makes us extremely optimistic for future trials," Doebele says.

In fact, and though it will need to be confirmed by future trials, crizotinib may have an even more durable action against ROS1-positive lung cancer than it does against ALK-positive lung cancer, the disease for which the drug was initially developed and approved. Specifically, median progression free survival for crizotinib against ROS1-positive lung cancer is just more than double the progression free survival for the drug against ALK-positive lung cancer.

Read more:
NEJM: Crizotinib effective in Phase 1 trial against ROS1 lung cancer

PHILADELPHIA In the second of two papers outlining new gene-therapy approaches to treat a rare disease called MPS I, researchers from Perelman School of Medicine at the University of Pennsylvania examined systemic delivery of a vector to replace the enzyme IDUA, which is deficient in patients with this disorder. The second paper, which is published online in the Proceedings of the National Academy of Sciences this week, describes how an injection of a vector expressing the IDUA enzyme to the liver can prevent most of the systemic manifestations of the disease, including those found in the heart.

The first paper, published in Molecular Therapy, describes the use of an adeno-associated viral (AAV) vector to introduce normal IDUA to glial and neuronal cells in the brain and spinal cord in a feline model. The aim of that study was to directly treat the central nervous system manifestations of MPS while the more recent study aims to treat all other manifestations of the disease outside of the nervous system.

This family of diseases comprises about 50 rare inherited disorders marked by defects in the lysosomes, compartments within cells filled with enzymes to digest large molecules. If one of these enzymes is mutated, molecules that would normally be degraded by the lysosome accumulate within the cell and their fragments are not recycled. Many of the MPS disorders can share symptoms, such as speech and hearing problems, hernias, and heart problems. Patient groups estimate that in the United States 1 in 25,000 births will result in some form of MPS. Life expectancy varies significantly for people with MPS I.

The two main treatments for MPS I are bone marrow transplantation and intravenous enzyme replacement therapy (ERT), but these are only marginally effective or clinically impractical, and have significant drawbacks for patient safety and quality of life and do not effectively address some of the most critical clinical symptoms, such as life-threatening cardiac valve impairments.

Both of these papers are the first proof-of-principle demonstrations for the efficacy and practicality for gene therapies to be translated into the clinic for lysosomal storage diseases, says lead author James M. Wilson, MD, PhD, professor of Pathology and Laboratory Medicine and director of the Penn Gene Therapy Program. This approach may likely turn out to be better than ERT and compete with or replace ERT. We are especially excited about the use of this approach in treating the many MPS I patients who do not have access to ERT due to cost or inadequate health delivery systems to support repeated protein infusions, such as in China, Eastern Europe, India, and parts of South America.

Patients with mucopolysaccharidosis type I (MPS I), accumulate compounds called glycosaminoglycans in tissues, with resulting diverse clinical symptoms, including neurological, eye, skeletal, and cardiac disease.

Using a naturally occurring feline model of MPS I, the team tested liver-directed gene therapy via a single intravenous infusion as a means of establishing long-term systemic IDUA presence throughout the body.

The team treated four MPS I cats at three to five months of age with an AAV serotype 8 vector expressing feline IDUA. We observed sustained serum enzyme activity for six months at approximately 30 percent of normal levels in one animal and in excess of normal levels in the other three animals, says Wilson.

Remarkably, treated animals not only demonstrated reductions in glycosaminoglycans storage in most tissues, but most also exhibited complete resolution of aortic valve lesions, an effect which has not been previously observed in this animal model or in MPS I patients treated with current therapies.

Critical to the evaluation of these novel therapies is the feline model of MPS I, which was provided through coauthor Mark E. Haskins, School of Veterinary Medicine at Penn. Haskins and his colleagues maintain a variety of canine and feline models of human genetic diseases that have been instrumental in establishing proof of concept for a number of novel therapeutics, including the current enzyme replacement therapy.

Excerpt from:
Gene Therapy Targeting Liver Corrects Cardiovascular Symptoms in Animal Model of Rare Enzyme Deficiency Disease