Stem Cells

Gene Editing Technologies

CRISPR-Cas9 was first described as a gene editing tool in 2012. In just a few years, the technology has exploded in popularity thanks to its promise of making genome editing much faster, cheaper and easier than ever before.CRISPR has changed the way scientists do research, but what everyone is expecting, either with excitement or fear, is its use in humans. In theory, CRISPR technology could let us edit any mutation at will and cure the disease it causes.

Potential applications of CRISPR are:

• Cancer
• Blood disorders
• Blindness
• AIDS
• Cystic fybrosis
• Muscular dystrophy
• Huntington’s disease

However, CRISPR-Cas9 is not without risks.

Limitations can occur by variation of the genome-editing efficiency and or “off-target effects,” where DNA is cut at sites other than the intended target. This can lead to the introduction of unintended mutations.

The high potential number of applications raise questions about the ethical merits and consequences of tampering with genomes.

“To better inform future public conversations recommended by the Napa meeting, research is needed to understand and manage risks arising from the use of the CRISPR-Cas9 technology. Considerations include the possibility of off-target alterations, as well as on-target events that have unintended consequences. It is critical to implement appropriate and standardized benchmarking methods to determine the frequency of off-target effects and to assess the physiology of cells and tissues that have undergone genome editing. At present, the potential safety and efficacy issues arising from the use of this technology must be thoroughly investigated and understood before any attempts at human engineering are sanctioned, if ever, for clinical testing. As with any therapeutic strategy, higher risks can be tolerated when the reward of success is high, but such risks also demand higher confidence in their likely efficacy. And, for countries whose regulatory agencies focus on safety and efficacy but not on broader social and ethical concerns, another venue is needed to facilitate public conversation.

Given the speed with which the genome engineering field is evolving, the Napa meeting concluded that there is an urgent need for open discussion of the merits and risks of human genome modification by a broad cohort of scientists, clinicians, social scientists, the general public, and relevant public entities and interest groups.

In the near term, we recommend that steps be taken to:

• Strongly discourage, even in those countries with lax jurisdictions where it might be permitted, any attempts at germline genome modification for clinical application in humans, while societal, environmental, and ethical implications of such activity are discussed among scientific and governmental organizations. (In countries with a highly developed bioscience capacity, germline genome modification in humans is currently illegal or tightly regulated.) This will enable pathways to responsible uses of this technology, if any, to be identified.
• Create forums in which experts from the scientific and bioethics communities can provide information and education about this new era of human biology, the issues accompanying the risks and rewards of using such powerful technology for a wide variety of applications including the potential to treat or cure human genetic disease, and the attendant ethical, social, and legal implications of genome modification.
• Encourage and support transparent research to evaluate the efficacy and specificity of CRISPR-Cas9 genome engineering technology in human and nonhuman model systems relevant to its potential applications for germline gene therapy. Such research is essential to inform deliberations about what clinical applications, if any, might in the future be deemed permissible.
• Convene a globally representative group of developers and users of genome engineering technology and experts in genetics, law, and bioethics, as well as members of the scientific community, the public, and relevant government agencies and interest groups—to further consider these important issues, and where appropriate, recommend policies.“ (David Baltimore et al. Science. 2015 Apr 3; 348(6230): 36–38)

HuIPScell lines

Since their introduction in 2007 (Takahashi et al., 2007) hiPSC have been rapidly and broadly incorporated into research to understand their potential for disease. This has substantiated interest to incorporate this resource into drug discovery pipelines, prospective patient stratifica- tion, recruitment for clinical trials and post-clinical drug assessment of safety issues following rare event reporting“(P.A. De Sousa et al. / Stem Cell Research 20 (2017) 105–114 )

Induced pluripotent stem cells (iPSC) are tissue or organ derived cells that have been manipulated or reprogrammed to an embryonic stem cell-like state by being forced to express genes and factors important for maintaining the defining properties of embryonic stem cells. A key feature and defining characteristic of pluripotent stem cells is their ability to be propagated indefinitely whilst maintaining stable properties in tissue culture. As an established iPSC line, each reagent becomes a powerful tool to study biology of normal development and disease specific processes in the laboratory.

Mouse iPSCs were first reported in 2006, and human iPSCs in late 2007. Mouse iPSCs demonstrate important characteristics of pluripotent stem cells, including expressing stem cell markers, forming cells of the three principal (primary) tissue layers in organisms (ectoderm, mesoderm & endoderm) and being able to contribute cells to many different tissues when transplanted at a very early stage in development. Human iPSCs also express stem cell markers and are capable of generating cells of the three primary tissue layers.

The discovery of how to induce the pluripotent state via “de-differentiation” in cells whose developmental fates had been previously assumed to be determined, has opened up several new avenues of applied research. Crucially the method has now made research into how the behaviour of our various cells and tissues are affected by our genes, much more possible and medical research into the causation and eventual treatment of disease can now be performed with greater accuracy. The TESCT Society believes that human iPSC will be used in transplantation medicine, either as the source of the therapy itself or as the basis of a test for predicting safety of novel cell based medicines. The combination of Gene Editing and iPSC-Technology will boost the possibility to cure any genetic disease.

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• Stem Cell Research
• Gene Editing Technologies
• HuIPScell lines
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