Stanford study finds Induced pluripotent stem cells match embryonic stem cells in modeling human disease


Investigators from Stanford University School of Medicine have shown that induced Pluripotent Stem cells (iPSCs), which are made from adult cells through genetic engineering techniques, are a possible alternative to human embryonic stem cells when it comes to modeling those defects caused by a particular genetic condition. The example used in this study was Marfan syndrome, and in this study, iPSCs modeled the disease as well as embryonic stem cells (ESCs). Thus, iPSCs could be used to examine the molecular aspects of Marfan on a personalized basis. Embryonic stem cells, on the other hand, can’t do this because their genetic contents are those of the donated embryo are not the same as the patient’s.

Marfan syndrome is an inherited connective-tissue disorder that occurs in one in 10,000 to one in 20,000 individuals. It results from a large number of defects in one gene called “fibrillarin.” People with Marfan syndrome tend to be very tall and thin, and also tend to suffer from osteopenia, or poor bone mineralization. Medical experts have speculated that Abraham Lincoln, for example, suffered from this disorder. Marfan can also profoundly affect the eyes and cardiovascular system.

This proof-of-principle study, with regards to the utility of iPSCs also has more universal significance; it advances the credibility of using iPSCs to model a broad range of human diseases. iPSCs, unlike ESCs, are easily obtained from virtually anyone and possess a genetic background identical to the patient from which they were derived. Moreover, they carry none of the ethical controversy associated with the necessity of destroying embryos.

“Our in vitro findings strongly point to the underlying mechanisms that may explain the clinical manifestations of Marfan syndrome,” said Michael Longaker, MD, professor of surgery and senior author of the study, which will be published online Dec. 12 in Proceedings of the National Academy of Sciences. Longaker is the Dean P. and Louise Mitchell Professor in the School of Medicine and co-director of the school’s Institute for Stem Cell Biology and Regenerative Medicine. The study’s first author is Natalina Quarto, PhD, a senior research scientist in Longaker’s laboratory.

In this study, both iPSCs and ESCs, and embryonic stem cells that carried a mutation that causes Marfan syndrome showed impaired ability to form bone, and all too readily formed cartilage. These aberrations mirror the most prominent clinical manifestation of the disease.

iPSCs were discovered in 2006, and are derived from fully differentiated tissues such as the skin. However, they harbor the same capacity as embryonic stem cells; namely to differentiate into all the tissues of the body, and replicate for indefinite periods in a cell culture dish. Because iPSCs offer an ethically uncomplicated alternative to ESCs, IPSCs have fueled the hope that they can replace ESCs in scientists’ efforts to analyze, in a dish, those cellular defects ultimately responsible for diseases ranging from diabetes to Parkinson’s and even such complex conditions as cardiovascular disease and autism.

One hope for iPSCs is to be able to differentiate them in a dish into tissues of interest and then study these cells and their characteristics. This would help scientists better understand diseases in a patient-specific way, which would be impossible to do with ESCs unless ESCs were made from donated human eggs that were modified by cloning procedures. Cloning human embryos to the blastocyst stage has yet to occur, which makes this option technically impossible at the present time.

While scientists want to us iPSCs to develop therapeutic applications for regenerative medicine. This strategy, however, is technically more difficult, since scientists will have to develop the capacity first to repair genetic defects within cells before they can be used for regenerative medicine. iPSCs in theory might be a better bet because they are derived from patients’ own cells and, therefore, are less likely to provoke graft rejection than similar tissues produced using a donor embryo’s ESCs.

Unfortunately, several studies have reported subtle differences between iPSCs and ESCs, and these differences imply that the two cell types may not be equivalent. Stem cell experts have wondered whether these differences may render iPSCs inadequate substitutes for ESCs in modeling disease states, but this Stanford study suggests otherwise.

Geron Corporation Announces Phase II Trial for Brain-Specific Anticancer Drug GNR1005


After a successful completion of a Phase I study, Geron Corporation announces the initiation of a phase II trial for its GRN1005 anticancer drug. This drug was designed to specifically treat tumors that have metastasized (spread) to the brain from the lung. This clinical trial is called GRABM-L, which stands for GRN1005 Against Brain Metastases – Lung cancer). This phase II trial is designed to determine the efficacy of GRN1005 in patients with brain metastases arising from non-small cell lung cancer (NSCLC).

GRN1005 is a novel cancer drug that consists of three molecules of the anticancer drug paclitaxel linked to a 19 amino acid peptide (Angiopep-2). This 19-amino acid peptide binds to a receptor called the “lipoprotein receptor-related protein 1” (LRP1), which is one of the most highly expressed receptors on the surface of the blood-brain barrier (BBB). Brain tumor treatment is exceedingly difficult because the central nervous system is surrounded by the BBB. The BBB prevents molecules from entering the brain unless they can bind specific receptors. When GRN1005 binds to the LRP1 receptor, the binding facilitates “receptor-mediated transport,” or transcytosis, across the BBB into the brain tissue. Conveniently, LRP1 is also very heavily expressed in many tumors. Therefore, once GRN1005 enters the brain, it can gain entry into tumor cells. GRN1005 is a “prodrug,” which means that the form that the patient takes is inactive, but the drug becomes active once it enters cells and is cleaved by enzymes called “esterases” to release active paclitaxel from the peptide.

Geron’s Executive Vice President, Head of R&D and Chief Medical Officer, Stephen M. Kelsey, M.D., said: “With the treatment of the first patient in the GRABM-L study, we have initiated both of the planned Phase 2 clinical trials of GRN1005 in patients with cancer metastases in the brain, a significant unmet medical need for which there are currently no approved drug therapies. We have been encouraged by the preliminary evidence of anti-tumor activity against brain metastases observed in the Phase 1 study of GRN1005, and we hope to confirm these results in our Phase 2 trials.”

The purpose of GRABM-L Phase 2 study is to determine the efficacy, safety and tolerability of GRN1005 in patients with brain metastases from Non-Small Cell Lung Cancer. The trial plans to enroll 50 patients, who will receive one intravenous dose of GRN1005 every three weeks (650 mg/m2). The primary efficacy endpoint for the trial is the response of the tumors to the drug during the course of treatment.

Patients with brain cancer, particularly secondary tumors that are the result of metastases, currently have few options. The reason for this treatment dead-end is the difficulty in getting antitumor drugs to effectively cross the blood-brain barrier and enter the tumor. Preclinical and Phase 1 data indicate that GRN1005 not only transports paclitaxel into tumors inside the brain through LRP1-mediated transport, but also has activity against tumors outside the brain.

Data on safety and tolerability, and preliminary evidence of anti-tumor activity of GRN1005 were documented in two separate Phase 1 multi-center, open-label, dose escalation clinical trials, conducted by Angiochem, Inc. In these trials, patients with heavily pre-treated progressing, advance-stage solid tumors and brain metastases (n=56; including NSCLC) and patients with recurrent or progressive malignant glioma (n=63) were treated with GRN1005. Final data were presented at the 2011 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in November. The data were encouraging. In patients with brain metastases from solid tumors, overall response rate was 20% (4/20) by one-dimensional assessment when treated with a dose of 650 mg/m2 of GRN1005 administered as single-agent therapy once every three weeks. Anti-tumor activity was observed against metastases inside the brain and in organs outside the brain, such as the liver, lung and lymph nodes.

Geron’s clinical development plan for GRN1005 includes two Phase 2 clinical trials in patients with brain metastases arising from either breast cancer (GRABM-B) or non-small cell lung cancer (GRABM-L). Top-line data from both studies are expected to be available by the end of the second quarter of 2013.