Archive for the ‘Stem Cell Research’ Category

Roche is teaming up with the Massachusetts General Hospital and Harvard University to develop new stem cell-based cell lines as disease models for early drug candidate testing. The 3–5 year partnership will initially focus on metabolic disorders and cardiovascular disease and will expand to cover a range of other diseases.

The collaboration aims to develop cell lines that can be used to evaluate the potential efficacy, safety, and toxicology profiles of new drugs pulled from Roche’s compound library. The company says that the cell lines will be derived from the tissues of both healthy volunteers and patients with a range of diseases.

Roche will provide research funding over the term of the agreement and will have access to cell lines, protocols, data, and materials. The firm will also pay clinical development milestones for drug candidates discovered through stem cell disease models.

The ultimate goal is to use stem cells for discovering new treatment approaches and bridging the gap between the laboratory and the clinic. “This technology is like having a disease in a test tube and being able to test possible effects of drugs on virtual patients—translational medicine at its best,” states Jacques Garaud, global head of pharma research and early development at Roche.

Roche has forged a number of collaborations focused on evaluating stem cell-based approaches for drug discovery. In June 2009, the firm signed a €7.5 million (about $10.36 million), two-year collaboration with I-STEM (Institute for Stem Cell Therapy and Exploration of Monogenic Diseases) focused on the use of I-STEM’s neuronal stem cell proliferation technologies in the screening of Roche’s compounds for potential new candidates against neurodegenerative diseases.

In 2008, Roche partnered with U.K.-based stem cell consortium SC4SM (Stem Cells 4 Safer Medicines) to generate a repository of stem cells suitable for toxicology testing in high-throughput platforms. The initiative is being fund primarily by the U.K. Government, with Roche and two other pharmaceutical companies also contributing. During the same year the firm signed an agreement with Cellular Dynamics to test a number of its drug compounds for cardiotoxicity.

source: genengnews.com

A team led by scientists from The Scripps Research Institute has developed a method that dramatically improves the efficiency of creating stem cells from human adult tissue, without the use of embryonic cells. The research makes great strides in addressing a major practical challenge in the development of stem-cell-based medicine.

The findings were published in an advance, online issue of the journal Nature Methods on October 18, 2009.

The new technique, which uses three small drug-like chemicals, is 200 times more efficient and twice as fast as conventional methods for transforming adult human cells into stem cells (in this case called “induced pluripotent stem cells” or “iPS cells”).

“Both in terms of speed and efficiency, we achieved major improvements over conventional conditions,” said Scripps Research Associate Professor Sheng Ding, Ph.D., who led the study. “This is the first example in human cells of how reprogramming speed can be accelerated. I believe that the field will quickly adopt this method, accelerating iPS cell research significantly.”

In addition to its significant practical advantages, the development of the technique deepens the understanding of the biology behind the transformation of adult human cells into stem cells.

Tackling Major Challenges

The hope of most researchers in the field is that one day it will be possible to use stem cells – which possess the ability to develop into many other distinct cell types, such as nerve, heart, or lung cells – to repair damaged tissue from any number of diseases, from Type 1 diabetes to Parkinson’s disease, as well as from injuries. The creation of iPS cells from adult cells sidesteps ethical concerns associated with the use of embryonic stem cells, and allows the generation of stem cells matched to a patient’s own immune system, avoiding the problem of tissue rejection.

The creation of human iPS cells was first announced in December 2007 by two labs, one in Japan and another in Wisconsin. In both cases, the teams used viruses to insert multiple copies of four genes (eg. c-Myc, Oct4, Sox2, Klf4) into the genome of skin cells. These four genes then produced transcription factors turning on and off other genes, and pushing the cell to “dedifferentiate” into stem cells.

While the work was a major breakthrough, it left two major challenges for the field to solve before iPS cell therapy could be considered of any potential practical use. The first involved safety, since the technique relied on potentially harmful genetic manipulation, and worse yet, the insertion of two known cancer-causing genes (c-Myc and Oct4). The second problem was the length and inefficiency of the iPS cell process, which had a success rate of roughly one in 10,000 cells and took about four weeks from start to finish.

Ding and colleagues essentially solved the first problem, the reliance on genetic manipulation, earlier this year in a paper published in Cell Stem Cell (Volume 4, Issue 5, May 8, 2009). In the paper, the researchers demonstrated that they could use purified proteins to transform adult cells all the way back to the most primitive embryonic-like cells, avoiding the problems associated with inserting genes.

In the current paper, the team makes major strides in solving the second problem, efficiency.

A Focus on Natural Processes

In developing the improved method, Ding drew on his knowledge of biology. He decided he would focus his efforts on manipulating a naturally occurring process in cells, in particular in a type of adult cell called fibroblasts, which give rise to connective tissue.

This naturally occurring process – called MET (mesenchymal to ephithelial cell transition) – pushes fibroblasts closer to a stem-cell-like state. If he could manipulate such a fundamental process to encourage MET and the formation of stem cells, Ding reasoned, such a method would be both safer and more direct than hijacking other aspects of biology, for example those directly involved in cancer.

“People have studied this mechanism for 10 to 20 years,” said Ding. “It is a fundamental mechanism.”

Ding and colleagues tested a number of drug-like molecules, looking for those that inhibited the TGFb (transforming growth factor beta) and the MEK (mitogen-activated protein kinase) pathways, which are known to be involved in the MET process. The researchers identified the most active compounds, then looked at their effects on stem cell creation when used singly and in combination.

The researchers found two chemicals – ALK5 inhibitor SB43142 and MEK inhibitor PD0325901 – used in combination were highly effective in promoting the transformation of fibroblasts into stem cells.

“This method is the first in human cells that is mechanism-specific for the reprogramming process,” said Ding.

And the two-chemical technique bested the efficiency of the classic genetic method by 100 times.

Efficient, Fast, Safe

But the researchers thought they might be able to do even better.

Attempting to increase the efficiency of the process even further, the team decided to enlist another natural pathway, the cell survival pathway. After screening a library of compounds targeting this pathway, the team focused on a novel compound called Thiazovivin.

The researchers found that a technique using Thiazovivin in combination with the two previously selected chemicals, SB43142 and PD0325901, beat the efficiency of the classic method by 200 times.

In addition, while the classic method required four weeks to complete, the new method took two weeks.

In addition to its virtues of speed and efficiency, Ding emphasizes that the safety profile of the new method is highly promising. Not only is the method based on natural biological processes, he said, but also the type of molecules used have all been tested in humans. – Scripps Research Institute

PARSIPPANY, N.J. – (Business Wire) Arno Therapeutics, Inc., a clinical-stage biopharmaceutical company focused on oncology therapeutics, today announced the presentation of a poster at the annual American Society of Hematology (ASH) meeting that describes the preclinical activity of Arno’s drug candidate AR-42 against leukemia stem cells (LSCs). AR-42 is a broad spectrum inhibitor of both histone and non-histone deacetylation proteins that demonstrated potent activity against Acute Myeloid Leukemia (AML) stem cells. The poster, entitled “Identification of the Histone Deacetylase Inhibitor (HDACi), AR-42, as a Novel Anti-Leukemia Stem Cell Agent in Acute Myeloid Leukemia (AML)” was presented at the 51st ASH Annual Meeting and Exposition held December 5-8, 2009 in New Orleans, LA. LSCs are believed to be able to initiate and perpetuate AML while displaying resistance to standard chemotherapies. The ability to target these cells with therapeutic compounds may help improve patient outcomes. The poster’s findings show that AR-42 preferentially targets LSCs compared to normal healthy cells. The research also suggests that AR-42 is active through a mechanism that differentiates it from other compounds with preclinical anti-LSC activity.

“The ability to target cancer stem cells presents an opportunity to change the way that we treat patients, particularly those stricken with diseases that are currently difficult to cure,” stated Monica Guzman, Ph.D., a co-author of the poster with AR-42 at Weill Cornell Medical College. “Patients with AML are prone to recurrent disease, even if therapies are initially effective. Current evidence suggests that the survival of LSCs after treatment may ultimately contribute to the persistence of this disease and its poor clinical prognosis. Inhibiting LSCs may help treat and prevent recurrence of AML in patients.”

“We identified AR-42 by screening a large number of gene expression profiles from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) for potential anti-LSC agents. We were very excited to see our hypothesis confirmed both in vivo and in vitro, and we look forward to discovering if the same promising activity will be seen in the clinical setting,” said co-author Duane Hassane, Ph.D. of Weill Cornell Medical College.

“Arno is very excited about the results from these recent studies and feels that this data helps to support our belief that AR-42 has the potential to emerge as a meaningful addition to the landscape of cancer therapies,” stated David Tanen, President of Arno.

About AR-42

AR-42 (formerly known as “HDAC-42”) is an orally available, broad spectrum inhibitor of both histone and non-histone deacetylation proteins (“pan-DAC”), which may both be important in cancer progression. Histone deacetylase (“HDAC”) inhibitors are a growing class of compounds that target histone deactylase, a molecule involved in determining which genes are expressed in a particular cell. In preclinical studies, AR-42 has shown activity against a broad spectrum of deacetylation targets and increased potency compared to vorinostat (“SAHA,” or Zolinza^®), the first HDAC inhibitor to obtain FDA approval. Arno currently plans to commence an investigator-initiated Phase I/IIa study with AR-42 in collaboration with an academic institution in the first half of 2010.

About Arno Therapeutics

Arno Therapeutics, Inc. is a clinical-stage biopharmaceutical company that develops and commercializes innovative products for the treatment of cancer patients. Arno’s lead clinical compound, AR-12 (formerly known as “OSU-03012”), is a potentially first-in-class, orally available, targeted anti-cancer agent that inhibits PDK-1, a protein in the PI3K/Akt pathway, and also causes cell death through the induction of endoplasmic reticulum stress. Arno is developing two additional drug candidates, AR-67 and AR-42. AR-67 is a novel, third-generation camptothecin analogue that inhibits topoisomerase I activity. AR-67 has demonstrated activity and an excellent safety profile in clinical studies as well as improved pharmacokinetic properties when compared to approved second-generation products Hycamtin^® (topotecan) and Camptosar^® (irinotecan). Arno is conducting a Phase II study of AR-67 in patients with Myelodysplastic Syndrome (MDS) who have failed prior therapies and anticipates commencing a Phase II study in patients with glioblastoma multiforme (GBM), a highly aggressive form of brain cancer by the end of this year.

For more information on Arno please visit www.arnothera.com.

Forward Looking Statements

This press release contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, included in this press release regarding the timing, progress and anticipated results of the clinical development, regulatory processes, potential clinical trial initiations, potential IND and NDA filings, as well as our strategy, future operations, outlook, milestones, the success of Arno’s product development, future financial position, future financial results, plans and objectives of management, are forward-looking statements. We may not actually achieve these plans, intentions or expectations and Arno cautions investors not to place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. Various important factors could cause actual results or events to differ materially from the forward-looking statements that we make. Such factors include, among others, risks that the results of clinical trials will not support our claims or beliefs concerning the effectiveness of our product candidates, our ability to finance the development of our product candidates, regulatory risks, and our reliance on third party researchers and other collaborators. Arno is providing this information as of the date of this presentation and does not undertake any obligation to update any forward-looking statements as a result of new information, future events or otherwise.

Arno Therapeutics, Inc.
Brian Lenz, CPA, 862-703-7175
Chief Financial Officer
bl@arnothera.com

source: earthtimes.org