| Dr Subhadra Dravida |
The pharmaceutical trade splurges over billions per year on research and development (R&D) of new medicines/ molecules globally. Between 2008 and 2010 there were 55 terminations of projects in the western market that had already reached the final phase III stage of clinical testing, more than double the level of 2005-07, reflecting the growing difficulty of developing new drugs. The industry is subjected to a variety of laws and regulations regarding the testing and ensuring safety, efficacy and marketing of drugs.
One of the key intentions for the pharma industry is a reduction in inefficiencies and high costs associated with taking compounds through to final stage of drug discovery and development. In the course of this tedious and draining efforts, many drugs fail due to deplorable safety profiles. More than half of US drug safety studies never see the light of day. An average clinical phase time period of eight years is unchanged in recent years to bring new drugs to market. In that 70 per cent of the lag phase is on testing the safety profiles in various animal models, the data of which will be obsolete for a simple reason of species non-compatibility.
New tool to evalute risk
Availability of validated human cell-based in vitro toxicity screens may facilitate earlier attrition of compounds with unacceptable safety profiles, and therefore, also reduce the use of animals. The predictivity of in vitro screens is dependent on the appropriateness of biological modelling, which is limited otherwise. Stem cells are master cells that have the self renewing and differentiation capabilities with battery of stage and stemness specific genes expressed that are identified. Human originated harvested stem cells can be expanded sometimes indefinitely, while retaining the stem cell specific characteristics. Significant potential added value to the pharma industry from stem cell technology is multi-fold: a reliable, consistent and unlimited source of cells for screening, avoiding sporadic and limited availability of human tissue, and enabling a closer phenotypic match than animal material.
The discovery of both embryonic and adult multi/pluripotent stem cells and their ability to differentiate into diverse cell types has created ideas and avenues to alter the way new drugs are evaluated for risk to human health. Some typical cell based in vitro cytotoxicity assays make use of either transformed, immortalised cell lines or primary cells that are isolated directly from animal tissues. Although easily maintained and readily available, transformed cells exhibit abnormal behaviours, are usually aneuploid, and do not ideally recapitulate the phenotypes and mechanisms that would be observed in their normal cell counterparts. Primary cells, on the other hand, offer a more relevant model system for predicting toxicology and other cellular activities but are limited in quantity and suffer from batch-to-batch variation, as cells must continuously be isolated from whole animals or tissues for further study. Adult stem cells and their derivatives represent a promising opportunity for developing in vitro, human cell assays that would ultimately replace or enhance, or the current models that are used for predictive toxicology.
Unprecedented opportunities
There are currently no methods to predict individual susceptibility to a particular drug in trials. Conceivably, the most powerful models of predictive tailor made toxicology could be achieved using stem cells derived from either embryonic or adult tissues of human origin. Cell types that these referred stem cells have been shown to differentiate into in vitro or in vivo include osteoblasts, chondrocytes, myocytes, adipocytes, and neuronal, beta-pancreatic islets cells, cardiac and hepatocytes owing to their multi/pluripotency. Some of the adult sources of stem cells are bone marrow, adipose tissue, placenta, umbilical cord blood, dental pulp while embryos derived are totipotent in nature with induced pluripotent cells (iPS) discovered and isolated from skin source.
Benefits to patients, trial volunteers
Improved drug safety profiles predicted with the stem cell line models will also provide tangible benefits for patients and trial volunteers. The proposed avant-garde change to current systems of screening the drug safety doses and efficacy will be significant and can be exploited in emerging technologies focusing on the initial development of characterised tools for early decision-making in discovery research as only compounds that have a positive in vitro safety profile will proceed to the in vivo stage.
Initiatives so far
There are couple of proposals and initiatives involving the academia, corporate and regulatory bodies who teamed up to develop embryonic stem cell based predictive toxicology assays in Europe and US since 2005. The role of regulatory bodies is framed with embryonic source while the supply and credibility of the cells proposed play crucial for scientific acceptance. The short term objectives of these initiatives have been developing the cell based toxicology assays for acute toxicity, carcinogenicity, dermal, neural, reproductive toxicity effects. The global market for cell-based assays for drug discovery validating drug targets and lead profiling assays was valued at $6.2 billion in 2010. This sphere is projected to increase at an 11.6 per cent compound annual growth rate (CAGR) to reach nearly $10.8 billion in 2015. With stem cell based predictive toxicity assays developed, the projections in increase of sales is expected to be doubled.
Regulations
Stem cell laws are the law, rules, and policy governance concerning not just the treatment using stem cells in humans but also the sources and research involved. These laws have been the source of much controversy for embryonic source and vary significantly by country. Laws and legislations in this sector are required to be clarified to avoid misinterpretations and conflicts with respect to the restrictions on sources and types of stem cell research.
In the European Union, stem cell research using the human embryo is permitted in Sweden, Finland, Belgium, Greece, Britain, Denmark and the Netherlands; however, it is illegal in Germany, Austria, Ireland, Italy, and Portugal. The embryonic stem cell research has similarly divided the US, with some states enforcing a complete ban and others giving financial support while Japan, India, Iran, Israel, South Korea, China, and Australia are supportive. However, New Zealand, most of Africa (except South Africa), and most of South America (except Brazil) are restrictive.
Centre for Biologics Evaluation and Research (CBER) of the Food and Drug Administration (FDA), US, Indian Council of Medical Research (ICMR) with National Apex Committee registration (2012) in India and the European Union Tissues and Cells Directive 2004 (EUTCD), Human Tissue Act 2004 (“2004 Act”) for Europe are some of the country specific regulatory bodies evolved for stem cell research for both clinical and non-clinical research based applications. Adult stem cell research is proven morally non-controversial for applications in the midst of active research globally.
(The author Dr Subhadra Dravida is the CEO of Tran-Scell Biologics, a stem cell bank and research centre at Hyderabad, India. The company with it’s diverse and integrated stem cell specific therapeutic and non-therapeutic initiatives, plans to foray into this cell based predictive toxicology business by developing stem cell lines suitable for predictive toxicology assays for commercial application by 2014.)
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