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Human gene editing continues to hold a major fascination within a biomedical and biopharmaceutical industries. It’s extraordinary potential is now being realized but important questions as to who will be the beneficiaries of such breakthrough technologies remained to be answered. The session will discuss whether gene editing technologies can alleviate some of the most challenging unmet medical needs. We will discuss how research advances often never reach minority communities and how diverse patient populations will gain access to such breakthrough technologies. It is widely recognize that there are patient voids in the population and we will explore how community health centers might fill this void to ensure that state-of-the-art technologies can reach the forgotten patient groups . We also will touch ethical questions surrounding germline editing and how such research and development could impact the community at large.

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CRISPR’s Unwanted off-target effects: Need for safety study designs with Gene-Editing

Reporter: Stephen J. Williams, Ph.D.

From CafePharma at https://www.statnews.com/2016/07/18/crispr-off-target-effects/

Do CRISPR enthusiasts have their head in the sand about the safety of gene editing?

WASHINGTON — At scientific meetings on genome-editing, you’d expect researchers to show pretty slides of the ribbony 3-D structure of the CRISPR-Cas9 molecules neatly snipping out disease-causing genes in order to, everyone hopes, cure illnesses from cancer to muscular dystrophy. Less expected: slides of someone kneeling on a beach with his head in the sand.

Yet that is what Dr. J. Keith Joung of Massachusetts General Hospital showed at the American Society of Hematology’s workshop on genome-editing last week in Washington. While the 150 experts from industry, academia, the National Institutes of Health, and the Food and Drug Administration were upbeat about the possibility of using genome-editing to treat and even cure sickle cell disease, leukemia, HIV/AIDS, and other blood disorders, there was a skunk at the picnic: an emerging concern that some enthusiastic CRISPR-ers are ignoring growing evidence that CRISPR might inadvertently alter regions of the genome other than the intended ones.

“In the early days of this field, algorithms were generated to predict off-target effects and [made] available on the web,” Joung said. Further research has shown, however, that such algorithms, including one from MIT and one calledE-CRISP, “miss a fair number” of off-target effects. “These tools are used in a lot of papers, but they really aren’t very good at predicting where there will be off-target effects,” he said. “We think we can get off-target effects to less than 1 percent, but we need to do better,” especially if genome-editing is to be safely used to treat patients.

Off-target effects occur because of how CRISPR works. It has two parts. RNA makes a beeline for the site in a genome specified by the RNA’s string of nucleotides, and an enzyme cuts the genome there. Trouble is, more than one site in a genome can have the same string of nucleotides. Scientists might address CRISPR to the genome version of 123 Main Street, aiming for 123 Main on chromosome 9, only to find CRISPR has instead gone to 123 Main on chromosome 14.

In one example Joung showed, CRISPR is supposed to edit a gene called VEGFA (which stimulates production of blood vessels, including those used by cancerous tumors) on chromosome 6. But, studies show, this CRISPR can also hit genes on virtually every one of the other 22 human chromosomes. The same is true for CRISPRs aimed at other genes. Although each CRISPR has zero to a dozen or so “known” off-target sites (where “known” means predicted by those web-based algorithms), Joung said, there can be as many as 150 “novel” off-target sites, meaning scientists had no idea those errors were possible.

One reason for concern about off-target effects is that genome-editing might disable a tumor-suppressor gene or activate a cancer-causing one. It might also allow pieces of two different chromosomes to get together, a phenomenon called translocation, which is the cause of chronic myeloid leukemia, among other problems.

Many researchers, including those planning clinical trials, are using web-based algorithms to predict which regions of the genome might get accidentally CRISPR’d. They include the scientists whose proposal to use CRISPR in patients was the first to be approved by an NIH committee. When scientists assure regulators that they looked for off-target effects in CRISPR’d cells growing in lab dishes, what they usually mean is that they looked for CRISPR’ing of genes that the algorithms flagged.

As a result, off-target effects might be occurring but, because scientists are doing the equivalent of the drunk searching for their lost keys only under the lamppost, they’re not being found.

Other articles on CRISPR and Gene Editing on this Open Access Journal Include:

FDA Cellular & Gene Therapy Guidances: Implications for CRSPR/Cas9 Trials

CRISPR/Cas9 Finds Its Way As an Important Tool For Drug Discovery & Development

CRISPR, the Genome Editing Technology is Nearing Human Trials: Human T cells will soon be modified using the CRISPR technique in a clinical trial to attack cancer cells

Use of CRISPR & RNAi for Drug Discovery, CHI’s World PreClinical Congress – Europe, November 14-15, 2016, Lisbon, Portugal

CRISPR: A Podcast from Nature.com on Gene Editing

AND Please See Our Following ebooks available on Amazon containing interviews with Dr. Jennifer Duodna

Volume One: Genomics Orientations for Personalized Medicine

Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS & BioInformatics, Simulations and the Genome Ontology

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A Conversation with Jennifer Doudna, Interviewer: Jan Witkowski, Executive Director, Banbury Center at Cold Spring Harbor Laboratory

Reporter: Aviva Lev-Ari, PhD, RN

A Conversation with Jennifer Doudna

INTERVIEWER: JAN WITKOWSKI Executive Director, Banbury Center at Cold Spring Harbor Laboratory

Jennifer Doudna is a Professor in the Department of Chemistry and the Department of Molecular and Cell Biology at the University of California –Berkeley.

Jan Witkowski: People know of you primarily through your work on the CRISPR –Cas9 system for genetic engineering. Can you go over the biology of the system and how you got involved in working on it?

Dr. Doudna: We started working on CRISPR (clustered regularly interspaced short palindromic repeats) biology about 10 years ago. A colleague of mine at Berkeley, Jillian Banfield, was doing research on bacterial comJmunities and the viruses that infect them. She had noticed a lot of repetitive sequences in their genomic data and wondered if these were being used in the form of RNA molecules to protect the bacteria from viral infection. This led to our work with Emmanuelle Charpentier to understand the function of a particular protein called Cas9 (CRISPRassociated protein 9), which turns out to be an RNAguided DNA cutting enzyme. This is a great way for bacteria to fight viruses. It’s an adaptive immune system. The bacteria acquire genetic material from viruses and insert them into these CRISPR sequences. They can transcribe the stored sequence into RNA, and then those RNA molecules can base-pair the matching viral DNAs sequences. They use RNA molecules to target the viral sequences and Cas9 cuts the viral DNA. About half of the sequenced bacterial genomes have one or more CRISPR loci in the genome. Jan

Witkowski: Why is it not more widespread?

Dr. Doudna: Bacteria have a lot of ways to avoid viruses. CRISPR systems operate in certain kinds of bacteria, perhaps in certain environments where they’re particularly advantageous. Other bacteria simply might not need them because they have other ways of fighting the viruses they encounter.

Jan Witkowski: Bacteria have different enzymes depending on the type of CRISPR system, but Cas9 is the one that caught people’s attention for genome engineering. Why is that particularly useful?

Dr. Doudna: It’s programmable. It can be targeting using a short sequence of RNA that provides the base-pairing information to recognize DNA molecules with a matching or complementary sequence. Cas9 is also useful because the enzyme cuts both strands of double-stranded DNA. 

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SOURCE

http://www.cshlpress.com/pdf/sample/2016/symp80/Symp80_Doudna.pdf?utm_source=Email&utm_medium=email&utm_content=DoudnaConversation&utm_campaign=July2016Email2

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