Category Archives: Gene Medicine

Graupera M, Guillermet-Guibert J, Foukas LC, Phng LK, Cain RJ, Salpekar A, Pearce W, Meek S, Millan J, Cutillas PR, Smith AJ, Ridley AJ, Ruhrberg C, Gerhardt H, Vanhaesebroeck B. Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature. 2008 May 29;453(7195):662-6. doi: 10.1038/nature06892. Epub 2008 Apr 30.

Hafner C, Lpez-Knowles E, Luis NM, Toll A, Baselga E, Fernndez-Casado A, Hernndez S, Rib A, Mentzel T, Stoehr R, Hofstaedter F, Landthaler M, Vogt T, Pujol RM, Hartmann A, Real FX. Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern. Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13450-4. Epub 2007 Aug 2.

Kurek KC, Luks VL, Ayturk UM, Alomari AI, Fishman SJ, Spencer SA, Mulliken JB, Bowen ME, Yamamoto GL, Kozakewich HP, Warman ML. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet. 2012 Jun 8;90(6):1108-15. doi: 10.1016/j.ajhg.2012.05.006. Epub 2012 May 31.

Lee JH, Huynh M, Silhavy JL, Kim S, Dixon-Salazar T, Heiberg A, Scott E, Bafna V, Hill KJ, Collazo A, Funari V, Russ C, Gabriel SB, Mathern GW, Gleeson JG. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet. 2012 Jun 24;44(8):941-5. doi: 10.1038/ng.2329.

Lindhurst MJ, Parker VE, Payne F, Sapp JC, Rudge S, Harris J, Witkowski AM, Zhang Q, Groeneveld MP, Scott CE, Daly A, Huson SM, Tosi LL, Cunningham ML, Darling TN, Geer J, Gucev Z, Sutton VR, Tziotzios C, Dixon AK, Helliwell T, O'Rahilly S, Savage DB, Wakelam MJ, Barroso I, Biesecker LG, Semple RK. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet. 2012 Jun 24;44(8):928-33. doi: 10.1038/ng.2332.

Luks VL, Kamitaki N, Vivero MP, Uller W, Rab R, Bove JV, Rialon KL, Guevara CJ, Alomari AI, Greene AK, Fishman SJ, Kozakewich HP, Maclellan RA, Mulliken JB, Rahbar R, Spencer SA, Trenor CC 3rd, Upton J, Zurakowski D, Perkins JA, Kirsh A, Bennett JT, Dobyns WB, Kurek KC, Warman ML, McCarroll SA, Murillo R. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr. 2015 Apr;166(4):1048-54.e1-5. doi: 10.1016/j.jpeds.2014.12.069. Epub 2015 Feb 11.

Mirzaa G, Conway R, Graham JM Jr, Dobyns WB. PIK3CA-Related Segmental Overgrowth. 2013 Aug 15. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from http://www.ncbi.nlm.nih.gov/books/NBK153722/

Rivire JB, Mirzaa GM, O'Roak BJ, Beddaoui M, Alcantara D, Conway RL, St-Onge J, Schwartzentruber JA, Gripp KW, Nikkel SM, Worthylake T, Sullivan CT, Ward TR, Butler HE, Kramer NA, Albrecht B, Armour CM, Armstrong L, Caluseriu O, Cytrynbaum C, Drolet BA, Innes AM, Lauzon JL, Lin AE, Mancini GM, Meschino WS, Reggin JD, Saggar AK, Lerman-Sagie T, Uyanik G, Weksberg R, Zirn B, Beaulieu CL; Finding of Rare Disease Genes (FORGE) Canada Consortium, Majewski J, Bulman DE, O'Driscoll M, Shendure J, Graham JM Jr, Boycott KM, Dobyns WB. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet. 2012 Jun 24;44(8):934-40. doi: 10.1038/ng.2331.

Vahidnezhad H, Youssefian L, Uitto J. Klippel-Trenaunay syndrome belongs to the PIK3CA-related overgrowth spectrum (PROS). Exp Dermatol. 2016 Jan;25(1):17-9. doi: 10.1111/exd.12826. Epub 2015 Oct 13.

Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene. 2008 Sep 18;27(41):5486-96. doi: 10.1038/onc.2008.244. Review.

Zhao L, Vogt PK. Hot-spot mutations in p110alpha of phosphatidylinositol 3-kinase (pI3K): differential interactions with the regulatory subunit p85 and with RAS. Cell Cycle. 2010 Feb 1;9(3):596-600.

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PIK3CA gene - Genetics Home Reference - NIH

Carneiro F, Oliveira C, Suriano G, Seruca R. Molecular pathology of familial gastric cancer, with an emphasis on hereditary diffuse gastric cancer. J Clin Pathol. 2008 Jan;61(1):25-30. Epub 2007 May 18. Review.

Carneiro P, Fernandes MS, Figueiredo J, Caldeira J, Carvalho J, Pinheiro H, Leite M, Melo S, Oliveira P, Simes-Correia J, Oliveira MJ, Carneiro F, Figueiredo C, Paredes J, Oliveira C, Seruca R. E-cadherin dysfunction in gastric cancer--cellular consequences, clinical applications and open questions. FEBS Lett. 2012 Aug 31;586(18):2981-9. doi: 10.1016/j.febslet.2012.07.045. Epub 2012 Jul 25. Review.

Corso G, Figueiredo J, Biffi R, Trentin C, Bonanni B, Feroce I, Serrano D, Cassano E, Annibale B, Melo S, Seruca R, De Lorenzi F, Ferrara F, Piagnerelli R, Roviello F, Galimberti V. E-cadherin germline mutation carriers: clinical management and genetic implications. Cancer Metastasis Rev. 2014 Dec;33(4):1081-94. doi: 10.1007/s10555-014-9528-y. Review.

Figueiredo J, Sderberg O, Simes-Correia J, Grannas K, Suriano G, Seruca R. The importance of E-cadherin binding partners to evaluate the pathogenicity of E-cadherin missense mutations associated to HDGC. Eur J Hum Genet. 2013 Mar;21(3):301-9. doi: 10.1038/ejhg.2012.159. Epub 2012 Aug 1.

Fitzgerald RC, Hardwick R, Huntsman D, Carneiro F, Guilford P, Blair V, Chung DC, Norton J, Ragunath K, Van Krieken JH, Dwerryhouse S, Caldas C; International Gastric Cancer Linkage Consortium. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet. 2010 Jul;47(7):436-44. doi: 10.1136/jmg.2009.074237. Erratum in: J Med Genet. 2011 Mar;48(3):216. Van Krieken, Nicola [corrected to Van Grieken, Nicola C].

Ghoumid J, Stichelbout M, Jourdain AS, Frenois F, Lejeune-Dumoulin S, Alex-Cordier MP, Lebrun M, Guerreschi P, Duquennoy-Martinot V, Vinchon M, Ferri J, Jung M, Vicaire S, Vanlerberghe C, Escande F, Petit F, Manouvrier-Hanu S. Blepharocheilodontic syndrome is a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1. Genet Med. 2017 Mar 16. doi: 10.1038/gim.2017.11. [Epub ahead of print]

Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, Schrader KA, Schaeffer DF, Shumansky K, Zogopoulos G, Santos TA, Claro I, Carvalho J, Nielsen C, Padilla S, Lum A, Talhouk A, Baker-Lange K, Richardson S, Lewis I, Lindor NM, Pennell E, MacMillan A, Fernandez B, Keller G, Lynch H, Shah SP, Guilford P, Gallinger S, Corso G, Roviello F, Caldas C, Oliveira C, Pharoah PD, Huntsman DG. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol. 2015 Apr;1(1):23-32. doi: 10.1001/jamaoncol.2014.168. Erratum in: JAMA Oncol. 2015 Apr;1(1):110.

Kaurah P, Huntsman DG. Hereditary Diffuse Gastric Cancer. 2002 Nov 4 [updated 2014 Jul 31]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from http://www.ncbi.nlm.nih.gov/books/NBK1139/

Kobayashi H, Ohno S, Sasaki Y, Matsuura M. Hereditary breast and ovarian cancer susceptibility genes (review). Oncol Rep. 2013 Sep;30(3):1019-29. doi: 10.3892/or.2013.2541. Epub 2013 Jun 19. Review.

More H, Humar B, Weber W, Ward R, Christian A, Lintott C, Graziano F, Ruzzo AM, Acosta E, Boman B, Harlan M, Ferreira P, Seruca R, Suriano G, Guilford P. Identification of seven novel germline mutations in the human E-cadherin (CDH1) gene. Hum Mutat. 2007 Feb;28(2):203.

Oliveira C, Pinheiro H, Figueiredo J, Seruca R, Carneiro F. E-cadherin alterations in hereditary disorders with emphasis on hereditary diffuse gastric cancer. Prog Mol Biol Transl Sci. 2013;116:337-59. doi: 10.1016/B978-0-12-394311-8.00015-7. Review.

Park D, Kresen R, Axcrona U, Noren T, Sauer T. Expression pattern of adhesion molecules (E-cadherin, alpha-, beta-, gamma-catenin and claudin-7), their influence on survival in primary breast carcinoma, and their corresponding axillary lymph node metastasis. APMIS. 2007 Jan;115(1):52-65.

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CDH1 gene - Genetics Home Reference - NIH

At least 200 mutations in the SOD1 gene have been found to cause amyotrophic lateral sclerosis (ALS), a condition characterized by progressive muscle weakness, a loss of muscle mass, and an inability to control movement. Most of these mutations change one of the protein building blocks (amino acids) in the superoxide dismutase enzyme. About half of all Americans with ALS caused by SOD1 gene mutations have a particular mutation that replaces the amino acid alanine with the amino acid valine at position 5 in the enzyme, written as Ala5Val or A5V. (Because of variations in the ways amino acids are counted in proteins, this mutation is sometimes called Ala4Val or A4V.) ALS caused by the A5V mutation is generally associated with a shorter life expectancy compared with ALS caused by other genetic mutations.

ALS is caused by the death of nerve cells that control muscle movement (motor neurons). It is unclear why these cells are particularly sensitive to SOD1 gene mutations. Researchers have suggested several ways in which the altered enzyme may cause the death of motor neurons. These possibilities include an increase in harmful superoxide radicals, increased production of other types of toxic radicals, increased cell death, or accumulation of clumps (aggregates) of misfolded superoxide dismutase that may be toxic to cells.

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SOD1 gene - Genetics Home Reference - NIH

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METIS Precision Medicine The one gene company

Date: Dec. 3, 2015

FOR IMMEDIATE RELEASE

Fundamental research into the ways by which bacteria defend themselves against viruses has recently led to the development of powerful new techniques that make it possible to perform gene editing that is, precisely altering genetic sequences in living cells, including those of humans, at much higher accuracy and efficiency than ever before possible. These techniques are already in broad use in biomedical research. They may also enable wide-ranging clinical applications in medicine. At the same time, the prospect of human genome editing raises many important scientific, ethical, and societal questions.

After three days of thoughtful discussion of these issues, the members of the Organizing Committee for the International Summit on Human Gene Editing have reached the following conclusions:

1. Basic and Preclinical Research. Intensive basic and preclinical research is clearly needed and should proceed, subject to appropriate legal and ethical rules and oversight, on (i) technologies for editing genetic sequences in human cells, (ii) the potential benefits and risks of proposed clinical uses, and (iii) understanding the biology of human embryos and germline cells. If, in the process of research, early human embryos or germline cells undergo gene editing, the modified cells should not be used to establish a pregnancy.

2. Clinical Use: Somatic. Many promising and valuable clinical applications of gene editing are directed at altering genetic sequences only in somatic cells that is, cells whose genomes are not transmitted to the next generation. Examples that have been proposed include editing genes for sickle-cell anemia in blood cells or for improving the ability of immune cells to target cancer. There is a need to understand the risks, such as inaccurate editing, and the potential benefits of each proposed genetic modification. Because proposed clinical uses are intended to affect only the individual who receives them, they can be appropriately and rigorously evaluated within existing and evolving regulatory frameworks for gene therapy, and regulators can weigh risks and potential benefits in approving clinical trials and therapies.

3. Clinical Use: Germline. Gene editing might also be used, in principle, to make genetic alterations in gametes or embryos, which will be carried by all of the cells of a resulting child and will be passed on to subsequent generations as part of the human gene pool. Examples that have been proposed range from avoidance of severe inherited diseases to enhancement of human capabilities. Such modifications of human genomes might include the introduction of naturally occurring variants or totally novel genetic changes thought to be beneficial.

Germline editing poses many important issues, including: (i) the risks of inaccurate editing (such as off-target mutations) and incomplete editing of the cells of early-stage embryos (mosaicism); (ii) the difficulty of predicting harmful effects that genetic changes may have under the wide range of circumstances experienced by the human population, including interactions with other genetic variants and with the environment; (iii) the obligation to consider implications for both the individual and the future generations who will carry the genetic alterations; (iv) the fact that, once introduced into the human population, genetic alterations would be difficult to remove and would not remain within any single community or country; (v) the possibility that permanent genetic enhancements to subsets of the population could exacerbate social inequities or be used coercively; and (vi) the moral and ethical considerations in purposefully altering human evolution using this technology.

It would be irresponsible to proceed with any clinical use of germline editing unless and until (i) the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives, and (ii) there is broad societal consensus about the appropriateness of the proposed application. Moreover, any clinical use should proceed only under appropriate regulatory oversight. At present, these criteria have not been met for any proposed clinical use: the safety issues have not yet been adequately explored; the cases of most compelling benefit are limited; and many nations have legislative or regulatory bans on germline modification. However, as scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis.

4. Need for an Ongoing Forum. While each nation ultimately has the authority to regulate activities under its jurisdiction, the human genome is shared among all nations. The international community should strive to establish norms concerning acceptable uses of human germline editing and to harmonize regulations, in order to discourage unacceptable activities while advancing human health and welfare.

We therefore call upon the national academies that co-hosted the summit the U.S. National Academy of Sciences and U.S. National Academy of Medicine; the Royal Society; and the Chinese Academy of Sciences to take the lead in creating an ongoing international forum to discuss potential clinical uses of gene editing; help inform decisions by national policymakers and others; formulate recommendations and guidelines; and promote coordination among nations.

The forum should be inclusive among nations and engage a wide range of perspectives and expertise including from biomedical scientists, social scientists, ethicists, health care providers, patients and their families, people with disabilities, policymakers, regulators, research funders, faith leaders, public interest advocates, industry representatives, and members of the general public.* Clinical use includes both clinical research and therapy.

Organizing Committee for the International Summit on Human Gene Editing

David Baltimore(chair)President Emeritus and Robert Andrews Millikan Professor of BiologyCalifornia Institute of TechnologyPasadena

Franoise Baylis Professor and Canada Research Chair in Bioethics and Philosophy Dalhousie UniversityNova Scotia

Paul BergRobert W. and Vivian K. Cahill Professor Emeritus, and Director Emeritus, Beckman Center for Molecular and Genetic MedicineStanford University School of MedicineStanford, Calif.

George Q. DaleySamuel E. Lux IV Chair in Hematology/Oncology, andDirector, Stem Cell Transplantation ProgramBoston Children's Hospital and Dana-Farber Cancer InstituteBoston

Jennifer A. DoudnaInvestigator, Howard Hughes Medical Institute; andLi Ka Shing Chancellor's Chair in Biomedical and Health Sciences, Professor of Molecular and Cell Biology, and Professor of ChemistryUniversity of CaliforniaBerkeley

Eric S. LanderFounding DirectorBroad Institute of Harvard and MITCambridge, Mass.

Robin Lovell-BadgeGroup Leader and HeadDivision of Stem Cell Biology and Developmental GeneticsThe Francis Crick InstituteLondon

Pilar OssorioProfessor of Law and BioethicsUniversity of Wisconsin; andEthics Scholar-in-ResidenceMorgridge Institute for Research Madison

Duanqing PeiProfessor of Stem Cell Biology, and Director General, Guangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhou

Adrian ThrasherProfessor of Paediatric Immunology and Wellcome Trust Principal FellowUniversity College London Institute of Child HealthLondon

Ernst-Ludwig WinnackerDirector Emeritus, Laboratory of Molecular Biology, Gene Center, andProfessor Emeritus Ludwig-Maximilians University of MunichMunich

Qi ZhouDeputy Director, Institute of ZoologyChinese Academy of SciencesBeijing

Originally posted here:
On Human Gene Editing: International Summit Statement

Genome editing (also called gene editing) is a group of technologies that give scientists the ability to change an organism's DNA. These technologies allow genetic material to be added, removed, or altered at particular locations in the genome. Several approaches to genome editing have been developed. A recent one is known as CRISPR-Cas9, which is short for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9. The CRISPR-Cas9 system has generated a lot of excitement in the scientific community because it is faster, cheaper, more accurate, and more efficient than other existing genome editing methods.

CRISPR-Cas9 was adapted from a naturally occurring genome editing system in bacteria. The bacteria capture snippets of DNA from invading viruses and use them to create DNA segments known as CRISPR arrays. The CRISPR arrays allow the bacteria to "remember" the viruses (or closely related ones). If the viruses attack again, the bacteria produce RNA segments from the CRISPR arrays to target the viruses' DNA. The bacteria then use Cas9 or a similar enzyme to cut the DNA apart, which disables the virus.

The CRISPR-Cas9 system works similarly in the lab. Researchers create a small piece of RNA with a short"guide" sequence that attaches (binds) to a specific target sequence of DNA in a genome. The RNA also binds to the Cas9 enzyme. As in bacteria, the modified RNA is used to recognize the DNA sequence, and the Cas9 enzyme cuts the DNA at the targeted location. Although Cas9 is the enzyme that is used most often, other enzymes (for example Cpf1) can also be used. Once the DNA is cut, researchers use the cell's own DNA repair machinery to add or delete pieces of genetic material, or to make changes to the DNA by replacing an existing segment with a customized DNA sequence.

Genome editing is of great interest in the prevention and treatment of human diseases. Currently, most research on genome editing is done to understand diseases using cells and animal models. Scientists are still working to determine whether this approach is safe and effective for use in people. It is being explored in research on a wide variety of diseases, including single-gene disorders such as cystic fibrosis, hemophilia, and sickle cell disease. It also holds promise for the treatment and prevention of more complex diseases, such as cancer, heart disease, mental illness, and human immunodeficiency virus (HIV) infection.

Ethical concerns arise when genome editing, using technologies such as CRISPR-Cas9, is used to alter human genomes. Most of the changes introduced with genome editing are limited to somatic cells, which are cells other than egg and sperm cells. These changes affect only certain tissues and are not passed from one generation to the next. However, changes made to genes in egg or sperm cells (germline cells) or in the genes of an embryo could be passed to future generations. Germline cell and embryo genome editing bring up a number of ethical challenges, including whether it would be permissible to use this technology to enhance normal human traits (such as height or intelligence). Based on concerns about ethics and safety, germline cell and embryo genome editing are currently illegal in many countries.

Gupta RM, Musunuru K. Expanding the genetic editing tool kit: ZFNs, TALENs, and CRISPR-Cas9. J Clin Invest. 2014 Oct;124(10):4154-61. doi: 10.1172/JCI72992. Epub 2014 Oct 1. Review. PubMed: 25271723. Free full-text available from PubMed Central: PMC4191047.

Hsu PD, Lander ES, Zhang F. Development and applications of CRISPR-Cas9 for genome engineering. Cell. 2014 Jun 5;157(6):1262-78. doi:10.1016/j.cell.2014.05.010. Review. PubMed: 24906146. Free full-text available from PubMed Central: PMC4343198.

Komor AC, Badran AH, Liu DR. CRISPR-Based Technologies for the Manipulation of Eukaryotic Genomes. Cell. 2017 Apr 20;169(3):559. doi:10.1016/j.cell.2017.04.005. PubMed: 28431253.

Lander ES. The Heroes of CRISPR. Cell. 2016 Jan 14;164(1-2):18-28. doi:10.1016/j.cell.2015.12.041. Review. PubMed: 26771483.

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What are genome editing and CRISPR-Cas9? - Genetics Home ...