Category Archives: Transhuman News

PUBLIC RELEASE DATE:

29-Sep-2014

Contact: Karen Kreeger karen.kreeger@uphs.upenn.edu 215-349-5658 University of Pennsylvania School of Medicine @PennMedNews

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.

Read this article:
Liver gene therapy corrects heart symptoms in model of rare enzyme disorder

Treatment with the targeted therapy drug crizotinib effectively halts the growth of lung tumors driven by rearrangements of the ROS1 gene. In an article receiving Online First publication in the New England Journal of Medicine to coincide with a presentation at the European Society for Medical Oncology meeting, an international research team reports that crizotinib treatment led to significant tumor shrinkage in 36 of 50 study participants and suppressed tumor growth in another 9.

"Prior to this study, there were a handful of reports describing marked responses to crizotinib in individual patients with ROS1-positive lung tumors," says Alice Shaw, MD, PhD, of the Massachusetts General Hospital (MGH) Cancer Center, lead author of the NEJM report. "This is the first definitive study to establish crizotinib's activity in a large group of patients with ROS1-positive lung cancer and to confirm that ROS1 is a bona fide therapeutic target in those patients."

Crizotinib currently is FDA-approved to treat non-small-cell lung cancers (NSCLC) driven by rearrangments in the ALK gene, which make up around 4 percent of cases. An MGH Cancer Center report published in 2012 reported that 1 to 2 percent of NSCLCs are driven by rearrangements in ROS1, which encodes a protein with significant structural similarities to that encoded by the ALK gene.

The current study, an expansion of the original phase 1 crizotinib trial, enrolled 50 patients with ROS1-positive NSCLC, beginning in late 2010. Patients received twice daily doses of crizotinib. As noted above, tumor size was significantly reduced in 72 percent of patients and tumor growth was halted in an additional 18 percent. The average duration of response was over 17 months. At the end of the study, 25 of the 50 patients were still receiving crizotinib with no evidence of tumor progression.

As with other targeted cancer therapy drugs, treatment resistance developed in a number of participants, but the effectiveness of crizotinib appeared to last longer in ROS1-positive patients than in patients with ALK-positive tumors. "Almost all patients treated with targeted therapies eventually develop resistance," explains Shaw, an associate professor of Medicine at Harvard Medical School (HMS). "Fortunately, the remissions induced by crizotinib in ROS1-positive patients are quite prolonged, and resistance appears to emerge much later, on average, than what we have seen with other targeted therapies for lung cancer and melanoma."

The authors note that development of efficient laboratory diagnostics has been critical to identification of ROS1 rearrangements and of other genetic alterations that drive tumor growth. John Iafrate, MD, PhD, medical director of the MGH Center for Integrated Diagnostics and associate professor of Pathology at HMS, who is senior author of the study comments, "This is a great example of success in personalized medicine. While NSCLC patients with ROS1 fusions are rare, if you devote the diagnostic laboratory resources to find that 1 to 2 percent of patients, you will make a real difference."

While crizotinib's FDA approval currently covers only ALK-positive NSCLC, Shaw notes that National Comprehensive Cancer Network guidelines recommend that patients with advanced lung cancer be considered for ROS1 testing and that crizotinib should be used to treat ROS1-positive patients.

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The above story is based on materials provided by Massachusetts General Hospital. Note: Materials may be edited for content and length.

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Crizotinib treatment effective against ROS1-positive lung cancer, study suggests