Abstract
Regulatory Wire
FDA Seeks Injunction Against Stem Cell Company
The FDA is pursuing a federal injunction against a Colorado-based company, Regenerative Sciences, citing violations of current good manufacturing practice (cGMP) that cause its cultured cell product to be contaminated. The product is also misbranded due to the lack of adequate directions for use and the failure to bear the “Rx only” symbol.
The company is actually a Colorado medical clinic that uses a stem cell procedure in its treatment of orthopedic disorders. The company extracts patient bone marrow and then cultures cells, which it mixes with drugs. The treatment — administered in hopes of avoiding surgery — is then injected into the patient. Regenerative Sciences' cultured cell product is not approved by the FDA, and no adequate and well-controlled studies have been done to demonstrate its safety or effectiveness for any indication.
“FDA recognizes the importance of the development of novel and promising new therapies,” said Karen Midthun, M.D., acting director of FDA's Center for Biologics Evaluation and Research. “However, when companies like Regenerative Sciences fail to comply with FDA laws and regulations, they put the public's health at risk 1 .”
Regenerative Sciences says that the FDA is not distinguishing between a stem cell treatment and a manufactured drug, that it is trying to apply good manufacturing practices to the production of stem cells. It likens its process, from a regulatory perspective, to in vitro fertilization, with stem cells taking the place of fertilized eggs. “What we're doing is no different, in principle,” says John Schultz, a clinic founder, in a statement
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NIH Announces New Program to Develop Therapeutics for Rare and Neglected Diseases: A Potential Opportunity for Gene Therapy
In May 2009, the National Institutes of Health launched a $24 million trans-NIH initiative called the Therapeutics for Rare and Neglected Diseases program (TRND). This program is the nation's first integrated, drug development pipeline specifically charged with producing new treatments for rare and neglected diseases. According to the NIH, a rare disease is one that affects fewer than 200,000 Americans. NIH estimates that, a collection of over 6,800 rare diseases afflict more than 25 million Americans. However, effective pharmacologic treatments exist for only about 200 of these illnesses.
Five pilot projects were selected this spring by TRND. They include drug development programs targeting sickle-cell disease, chronic lymphocytic leukemia, Niemann-Pick Type C, hereditary inclusion body myopathy, and the parasitic diseases schistosomiasis and hookworm.
The projects are in various stages of development and were selected because they illustrate a range of problems and issues in the effort to drive drug development. Some of the problems include the high cost of studies in animals to determine if a drug is too toxic to give to humans, the challenges of meeting regulatory requirements before the Food and Drug Administration allows clinical trials to begin, and the sheer amount of coordination that goes into getting a new drug to market.
For most new drugs, these issues are handled by a pharmaceutical company. Because rare diseases represent a small market, many pharmaceutical companies are reluctant to take on the risks and expense of trying to develop new drugs for these conditions. Therefore, TRND is assigning project managers with experience in drug development to the pilot projects to help identify the necessary steps to get to clinical trials.
Half of TRND's budget this year is going to fund the five pilot projects. The other half of the budget is committed to TRND infrastructure. The program plans to solicit additional projects in September. Yet, according to TRND's director, Dr. Christopher Austin, “we have to succeed with these pilot projects, and if we don't, the program won't continue
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Science Wire
GWAS Identifies Novel Genes Involved in Heart Disease
Scanning the genomes of more than 100,000 people from all over the world, scientists report the largest set of genes discovered to date underlying high cholesterol and high triglycerides — the major risk factors for coronary heart disease. Taken together, the gene variants explain 10–12% of the total variance (representing 25–30% of the genetic variance) observed in blood levels of cholesterol and triglyceride. The research, representing scientists from 17 countries, appeared in two articles in the August 5 issue of Nature 1,2 .
Genome-wide association studies, or GWAS, analyze DNA across populations to pinpoint hard-to-find genetic hotspots for common diseases that are thought to have many causes, both genetic and environmental. Previous gene-scanning approaches have turned up hints about the nature of inherited heart disease risk. The new results take the science well beyond what was previously known, and pinpoint research directions to elucidate the molecular and cellular mechanisms by which genetic variants contribute to disease.
The research team found 95 genetic variants that contribute to changes in blood cholesterol and triglyceride levels in women and men of many ethnic backgrounds 1 . Of the genetic variants, 59 had not been known and thus provide new clues for developing effective medicines to combat heart disease. Some of the 59 new loci contain genes of clear biological and clinical importance—among them LDLRAP1 (responsible for autosomal recessive hypercholesterolemia), SCARB1 (receptor for selective uptake of high density lipoprotein cholesterol, HDL-C), NPC1L1 (established drug target), MYLIP (recently characterized regulator of low density lipoprotein cholesterol, LDL-C), and PPP1R3B (newly characterized regulator of HDL-C).
A highlight of the article by Teslovich et al. is their analysis of the biological significance of several of the genes and loci they identified, including a systematic evaluation of the effects of the associated variants on gene expression in the liver and in fat tissue. The authors used an AAV8 vector platform to validate the role of three of the gene variants. Of the three genes they investigated further, one, GALNT2, which encodes a member of the N-acetylgalactosamine-transferase enzyme family, was not previously known to be involved in lipid metabolism. Decreasing the expression of Galnt2, using an AAV8 encoding small hairpin RNA (shRNA), in mouse liver significantly decreased levels of HDL-cholesterol.
One locus identified in the study by Teslovich et al. as being associated with both plasma low-density lipoprotein cholesterol and coronary artery disease forms the focus of the second paper appearing in the August 5 issue of Nature 2 . The locus, on chromosome 1p13, is shown to create a binding site for C/EBP transcription factors and to alter SORT1 gene expression in the liver. Modulating Sort1 levels in mouse liver, using AAV8 over-expression or shRNA knockdown, was shown to alter plasma lipoprotein levels. These findings potentially explain why variation at this locus is associated with heart disease. This finding identifies the sortilin pathway as a possible target for therapeutic intervention. Collectively, these two studies illustrate how GWAS results can be used as a production line for drug and gene therapy targets. (sk)
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