@ NIH, Gates Foundation Pledge $200 Million to Bring Gene Therapies to Patients Who Need Them Most @ European Animal Research Association – European animal research statistics & Animal testing in the EU – comparative figures @ Animal research law in the EU: Directive 2010/63 – EARA -> Contacts @ The Future of Human Longevity
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https://time.com/5709297/nih-gates-foundation-gene-therapy/?fbclid=IwAR38WKbfZm9kd3NMtW-uMitHiw8ZABsWwz8Y0FX6j6WzUqx_wsUFhs3e2Mo http://eara.eu/en/animal-research/eu-animal-research-law-directive-2010-63/ http://eara.eu/en/contact-us/
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Jackson Laboratory Top Questions… Isn’t there a high rate of clinical failure for drugs tested in mice? Why do we still need to test on mice when we can just use computers? Why do we still need mouse models if human patients already provide large amounts of medical data? What’s more effective: human or animal studies? Why are mice excellent models for humans? What is the future of mouse-based research? Why mouse genetics? What is being done to improve the medical yield from mouse-based research? How did the lab mouse come to be? What is a mouse model? How can research in mice lead to new ways to prevent and treat disease? What does the mouse teach us that we can’t learn from yeast, worms, insects and fish? What regulatory bodies govern what we can do with mice? Why do we need mice for medical research? How can the public be assured that researchers are using mice in a responsible way? Why do we need mice when we can test drugs on human cells and tissues?
Why mouse genetics?
The ability to model human disease in the mouse makes it such a valuable experimental system. Genetically and genomically, the human and the mouse are very similar, with many of the disease-related genes are nearly identical.
Genetics of the mouse
Because of the early development of inbred lines, the mouse provides a robust tool to identify the genetic basis of both normal and disease traits. In 1915, the first genetic linkage identified in the mouse (and first autosomal linkage in mammals) established that genes for pink-eyed dilution and albino are inherited together.
Early genetic maps of the mouse genome, based on recombinational estimates from linkage crosses, were created using histocompatibility genes and spontaneous mutations that produced visible phenotypes. The major mapping centers during the 1930s-1970s were the Harwell MRC Genetics Unit in the U.K., the Biology Unit at the Atomic Energy Commission’s facility in Oak Ridge, Tennessee, and The Jackson Laboratory in Bar Harbor, Maine.
The discovery of polymorphic genes enabled rapid genetic mapping, because a newly discovered gene could be tested for linkage with many other genes. In the 1960s and 1970s, biochemical (isoenzyme) genetic marker systems were developed. In the 1980s and 1990s, DNA markers revolutionized genetic mapping: restriction fragment polymorphisms (RFLPs), simple sequence length polymorphisms (SSLPs) detected by polymerase chain reaction (PCR) amplification (e.g. MIT markers), and single nucleotide polymorphisms (SNPs). All, especially SNPs, are widespread throughout the genome. With DNA markers, newly discovered genes or mutations can be tested for linkage with many DNA markers on all chromosomes in a single cross. Also, stored DNAs from linkage crosses, mapping panels, or recombinant inbred strains can be typed repeatedly for new markers. These advances enable the rapid identification of potential human disease-causing genes through comparative mapping.
Genetic manipulation of the mouse genome
Historically, perhaps the most important advantage to using the mouse for biomedical research has been the ability to experimentally manipulate the mouse genome. Genes can be injected directly into the fertilized egg of a mouse, creating what is known as a transgenic animal. This approach allowed scientists to create a new set of models and experimental tools based on the manipulation of specific genes thought to be important in the pathology of certain diseases.
Subsequently, scientists developed techniques that allowed them to specifically target genes within the mouse genome – so-called “knockouts” – that further enhanced their biological toolkit. The foundation for this work was laid by the pioneering work of Leroy Stevens at The Jackson Laboratory, culminating in the discovery that pluripotent embryonic stem (ES) cells could be grown in culture and that mouse genes could be altered in such cells by homologous recombination or targeting. Thousands of mouse genes have been targeted in this fashion and the Knockout Mouse Project (KOMP), together with the International Knockout Mouse Consortium (IKMC), has made substantial progress toward the ambitious goal of knocking out all of the genes in the mouse genome. The next step, called KOMP2, turned these targeted ES cells into mice on a large scale, which are being phenotyped to provide a comprehensive resource of unparalleled value for biologists seeking to understand the genetic basis of mammalian biology and disease progression.
And the toolkit continues to expand. Mouse genes can be replaced with human genes to study gene function or to produce more human-like model systems in the mouse. For example, the so-called “NOD scid gamma” mouse developed by Leonard Shultz at The Jackson Laboratory lacks mature T or B cells and functional NK cells, is deficient in cytokine signaling, and can accept transplantation of virtually any human tissue. And just within the past few years, low-cost high throughput sequencing (HTS) and genomic engineering using CRISPR-Cas9 has launched a revolution in mouse model development, allowing researchers to engineer mouse models for human disease with unprecedented speed, precision and efficiency. The ability to directly relate human patient data with mouse model development at the nucleotide level is opening an exciting new chapter in biomedical research, with enormous potential benefit.
Identifying causative mutations in the mouse genome
Despite the increasing sophistication of genetically manipulating the mouse genome, naturally occurring spontaneous and chemically induced mutations continue to provide valuable human disease models in mice. Naturally occurring mutations resemble human disease-causing mutations and often mimic the resulting disease well. Analysis of spontaneous mutations at The Jackson Laboratory has provided models for such human diseases as muscular dystrophies, craniofacial and skeletal abnormalities, Lou Gehrig’s disease, and blindness from cataracts, retinal degeneration and glaucoma.
Until recently, determining the causative mutated gene was a long and costly process. In 2002, the genome sequence of the C57BL/6J mouse strain was completed and now, the Mouse Genomes Project, an international collaborative effort, has sequenced and made publicly available genome-level characterization of 17 additional inbred mouse strains.
Most recently, HTS has made possible the once unimaginable goal of identifying spontaneous mutations rapidly, efficiently and economically. Current technologies enable HTS of large intervals, whole exomes and the entire genome using interval-specific array capture, exome capture and whole genome sequencing in both mice and humans. In collaboration with technology companies, Jackson Laboratory scientists have been instrumental in developing mouse exome capture technologies and have established a high throughput DNA sequence collection and data analysis pipeline to identify spontaneous mutations. Scientists at The Jackson Laboratory continue to collaborate with external scientists to enhance the bioinformatic analysis of HTS data and assess other methods, such as array comparative genome hybridization and RNASeq, for identifying large duplications and deletions not currently identified by HTS analysis. Thus, the complete sequencing data of diverse inbred mouse strains, the capability to sequence de novo new mutant strains or human patient mutations and the availability of bioinformatics resources will offer rapid and precise exploration of the genetic variation underlying spontaneous mutations in mouse and human.
Genetic background effects
In both humans and mice, genetic background can strongly influence the clinical symptoms or phenotype caused by disease genes. Genetic differences among human beings are one reason that genetically complex diseases like cancer or diabetes vary in severity from one individual to another. Analysis of such variability in the mouse can reveal the underlying genetic basis in human beings.
For example, multiple genes that lead to atherosclerosis have been discovered in the mouse; many of the same genes were subsequently identified in human beings. Scientists must be aware of the possible effect of modifying genes when transferring genes to new strain backgrounds, but their discovery also can reveal metabolic pathways and identify genes that contribute to variability in human diseases. For example, homozygotes for the spontaneous dactylaplasia mutation die prenatally or around the time of birth on some backgrounds and are viable on others; the lethality is controlled by a second major modifying gene. Similarly, homozygotes for the curly bare mutation have two different phenotypes depending on the alleles present at a modifier gene. Determining what genes modify a phenotype can identify genes that contribute to variability in a trait or disease in human beings and often reveal digenic or multigenic systems of interacting genes and molecular pathways.
Some modifier genes can totally suppress the phenotypic effect of a mutant gene. For example, the thrombocytopenia and cardiomyopathy (cmp) mutation causes a severe cardiomyopathy on the A/J background, where the mutation was discovered, but the disease disappears when the mutation is placed on the C57BL/6J background. Identification of such suppressive modifier alleles can provide insight into therapeutic approaches for protecting individuals against disease. In the case of cmp, the modifier effect is diet-dependent, suggesting manipulating the diet could ameliorate a similar condition in humans. Finally, when genetically engineered mutations are inbred or transferred to an inbred background, the phenotype on the new background can vary dramatically from the original phenotype reported in the literature.
Value of inbred strains and strain panels
Inbred strains are well-characterized, genetically uniform mouse models that can be used for a wide variety of human biological and disease research. Genetic variability among humans can be mimicked by the large number of inbred mouse strains. Each strain is genetically different from the others but genetically homogeneous, enabling reproducible studies of human diseases with variability in clinical symptoms.
Because each inbred strain possesses unique combinations of phenotypes and alleles, some strains are susceptible to specific diseases whereas others are resistant. For example, C57BL/6J mice rarely develop spontaneous cancer, but A/J mice have a high incidence of lung tumors and mammary cancer (in mated females). Designing an experiment using an inbred strain should include looking up strain characteristics or contacting Jackson Laboratory Technical Support scientists to determine the best strain for the experiment.
Strain differences are used to study the genetics of complex diseases like diabetes, heart disease or atherosclerosis. For example, C57BL/6J males are highly susceptible to diet-induced obesity and atherosclerosis whereas A/J mice are relatively resistant. By mating mice of these two strains together and analyzing their second-generation offspring, the susceptibility or resistance to atherosclerosis can be enhanced and analyzed. With continued inbreeding (sibling mating), these extreme phenotypes can become “fixed” in a new population of inbred mice or recombinant inbred lines to provide new tools to better understand the underlying genetics that lead to susceptibility or resistance to human diseases. Several panels of Recombinant Inbred (RI) strains are available from The Jackson Laboratory. Jackson Laboratory scientists (in collaboration with researchers worldwide) developed the Collaborative Cross RI set, derived from eight diverse inbred founder strains, including three wild-derived strains, that will have 100s of RI strains when completed.
In sharp contrast to inbred strains, outbred stocks are genetically heterogeneous, highly diverse resources that mimic the genetic variation found in the human population and eliminate the need to study multiple strains. Diversity Outbred mice, derived from Collaborative Cross strains, are the most genetically diverse resource available; each mouse uniquely represents a novel combination of alleles and gene expression. For example, in a cohort of 50 mice, phenotypic extremes are observed for metabolic measurements (e.g. plasma glucose, insulin, triglycerides and cholesterol), body weight and composition and more. These mice provide another valuable tool for mapping genes and quantitative trait loci (QTLs) at high (single gene) resolution, for behavioral toxicology and to study gene-gene and gene-environment interactions that lead to disease susceptibility, drug resistance and secondary complications associated with human diseases.
NIH, Gates Foundation Pledge $200 Million to Bring Gene Therapies to Patients Who Need Them Most
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- NIH, GATES FOUNDATION PLEDGE $200 MILLION TO BRING GENE THERAPIES TO PATIENTS WHO NEED THEM MOST
NIH, Gates Foundation Pledge $200 Million to Bring Gene Therapies to Patients Who Need Them Most
Some of the most cutting-edge — and effective — treatments in medicine are unaffordable to the majority of people who need them, with price tags sometimes exceeding $1 million. A new initiative from the National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation is meant to change that unfortunate reality.
Over the next four years, the NIH and the Gates Foundation will each invest $100 million toward developing gene-based cures for sickle cell disease and HIV, with a special focus on making these treatments available to the patients who need them most, the NIH announced Wednesday. Both HIV and sickle cell disease — a group of inherited disorders that lead to abnormal red blood cell shape and function, potentially contributing to a number of possible complications — disproportionately affect those living in lower-income areas, namely Africa, and people of color, who in the U.S. are more likely than white Americans to struggle with poverty.
“This unprecedented collaboration focuses from the get-go on access, scalability and affordability of advanced gene-based strategies for sickle cell disease and HIV to make sure everybody, everywhere has the opportunity to be cured, not just those in high-income countries,” NIH Director Dr. Francis Collins said in the NIH statement. “We aim to go big or go home.”
Gene therapies, which alter genes in order to treat or prevent disease, have already yielded breakthroughs for highly difficult-to-treat conditions including blindness and leukemia, but these treatments have been inaccessible to those in lower-resource countries, the statement says. The new initiative will first focus on developing gene-based treatments for sickle cell disease and HIV, then shift attention to accessibility.
The Brief Newsletter
In terms of development, researchers have already zeroed in on potential pathways for gene-based treatments. For sickle cell disease, the statement says, a therapy could either correct the gene mutations that cause the disorder in the first place, or help the body achieve normal red blood cell function. For HIV, it could mean targeting infected DNA that lives inside a person’s cells, even if they are taking antiretroviral treatment.
Researchers are already working on potential cures for both sickle cell disease and HIV, but the new initiative could mean any breakthroughs that are achieved reach a much broader swath of the population. That said, the challenges of both developing and disseminating gene therapies are vast.
“I’m not going to lie,” Collins told reporters on Wednesday. “This is a bold goal.”
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