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Gene Transfer into Human Hematopoietic Stem Cells
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Serguei Kisselev, Tatiana Seregina, Richard K. Burt, Charles J. Link
Another form of autosomal recessive SCID is a result of multiple point mutations in adenosine deaminase (ADA) gene. The defect leads to disruption of purine nucleosides metabolism followed by impaired lymphocyte development.50,111 In 1993 Kohn and colleagues initiated the first clinical trial employing retroviral transfer of normal ADA complementary DNA into cord blood (CB) derived CD34+ HSC followed by autologous transplantation in neonates.112 It has been demostrated that ADA-containing peripheral blood mononuclear cells have persisted in patients from this trial up to 8 years, with T lymphocytes showing the highest prevalence of gene marking.113 Unfortunately, the levels of transgene expression in these studies were variable and clinial effect was limited.51 Aiuti and colleagues initiated a similar trial using modified retroviral vector transduction of bone marrow derived CD34+ HSC.114 In this trial, the sustained engraftment of transduced HSC resulting in significant improvement of immune functions was demonstrated.
Cytochromes P450, Cardiovascular Homeostasis and Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Chin Eng Ong, Amelia Dong, Boon Hooi Tan, Yan Pan
Due to biological opposite nature of TxA2 and PGI2, the balance and regulation of these two mediators is important in both healthy and diseased vasculature. PGI2 modulates in vivo platelet-vascular interactions in an opposite manner to that of TxA2 (Praticò and Dogné, 2009). Factors that alter their biological activities would therefore cause changes in vascular function. A clear example is the Ghosal hemato-diaphyseal syndrome, a rare autosomal recessive trait, where the CYP5A1 gene is mutated (Geneviève et al., 2008). The dysfunction of the gene impacts negatively on platelet aggregation and atherothrombosis progression. In addition to altered platelet aggregation, patients with this syndrome also demonstrate altered bone density, progressive sclerosing dysplasia in the midsection of long bones, defective hematopoiesis and refractory anemia, all of which are associated with hematologic and vascular dysfunction. Mutations in CYP8A1gene, on the other hand, are associated with essential hypertension and cerebral infarction (Nakayama et al., 2000; Nakayama et al., 2002). Japanese families with CYP8A1 polymorphism were found to display a history of hypertension and cerebral infarction, suggesting that abnormal CYP8A1 activity may lead to defective vasculature and platelet function. Another study demonstrated that C1117A polymorphism in CYP8A1 was linked to development of left main coronary artery disease, a rare but hazardous form of coronary artery disease (Bousoula et al., 2012).
Applications for Drug Development
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
Jessica Kalra, Donald T. Yapp, Murray Webb, Marcel B. Bally
Huntington’s disease is an autosomal dominant disorder in which a CAG trinucleotide repeat is observed in the Huntingtin gene. Late onset symptoms include involuntary choreform movements and cognitive impairment. Histologically, patients have some neuronal loss in the striatum. Animal models of Huntington’s disease (HD) are induced by neurotoxins such as quinolinic acid, ibotenic acid, or 3-nitropropionic acid, which destroy or impair the corticostriatal projection. A rat transgenic HD model has been established using a cDNA carrying 51 CAG trinucleotide repeats under the control of the Huntingtin gene promoter. The transgenic rat exhibits adult-onset neurological phenotypes with reduced anxiety, cognitive impairments, and progressive motor dysfunction, as well as typical histopathological alterations in the form of neuronal nuclear inclusions in the brain. Von Horsten et al. have been able to use MRI to image striatal shrinkage and ventricular enlargement in transgenic animals. This group has also used 18F-FDG PET to image brain glucose metabolism and shown a reduction similar to that seen in patients with HD (von Horsten et al. 2003). In 2000, Araujo et al. used micro-PET and [3-(29–18F]fluoroethyl)spiperone to image dopamine receptor binding as well as 18F-FDG to image glucose metabolism in a quinolinic-induced rat model of HD (Araujo et al. 2000).
How the quest to improve sheep reproduction provided insight into oocyte control of follicular development
Published in Journal of the Royal Society of New Zealand, 2018
The original ewe, A281, carrying the Inverdale mutation was incorporated into a newly established high fecundity flock in 1979 (Davis et al. 1991, 1995). While this ewe did not fit the original specification for the flock, as she was a commercial flock ewe of mixed breeding with unknown parentage, her subsequent lifetime lambing record was exceptional. During her lifetime she had 33 lambs over 11 lambings including two sets of twins, seven sets of triplets and two sets of quadruplets. Breeding trials established the location of the gene on the X-chromosome, as males carrying the mutation did not produce carrier sons (Davis et al. 1991). In addition, the variation in the ovulation rate of daughters of a carrier ram was less than would be expected if the gene was autosomal where half the daughters would be heterozygous for the gene.
Developing gene drive technologies to eradicate invasive rodents from islands
Published in Journal of Responsible Innovation, 2018
Caroline M. Leitschuh, Dona Kanavy, Gregory A. Backus, Rene X. Valdez, Megan Serr, Elizabeth A. Pitts, David Threadgill, John Godwin
A way of reversing the production of male-only offspring if either the t-haplotype or CRISPR were used would be to introduce wild type males and females resistant to the drive system back into the population. Because success of the t-haplotype system is dependent on being above a certain frequency in the population, releasing wild type mice back into the system and not releasing any more GE mice should be enough to re-establish an invasive mouse colony. Though this has not been tested directly, there is ample evidence that female mice prefer mice without the t-haplotype (Carroll et al. 2004; Lindholm et al. 2013; Manser, König, and Lindholm 2015), and if there are enough male mice without the t-haplotype reintroduced, the wild females are likely to preferentially mate with those males. If using CRISPR as a gene drive system, the most effective way to reverse the system would be targeting an innocuous sequence found only in the engineered mice to override the current system, instead of targeting the Sry gene directly. Targeting the Sry gene would target both the autosomal Sry as well the Sry gene present on the Y-chromosome, which would also disrupt normal male-female ratios. While the resulting mice would still have autosomal Sry genes, their function would be disrupted and they would have normal male to female ratios in their offspring.
Gene Editing: A View Through the Prism of Inherited Metabolic Disorders
Published in The New Bioethics, 2018
The inherited metabolic disorders arise when a mutation in a given gene results in a deficiency of the related enzyme. The majority of these conditions are inherited in an autosomal recessive manner, whereby both the maternally inherited and paternally inherited copy of the given gene must harbour a mutation for the disease to manifest. In the usual situation this means that both parents are heterozygous carriers of the condition, i.e. they each carry one mutated copy of the gene and one ‘healthy’ copy. Thus a deficiency of the enzyme phenylalanine hydroxylase caused by mutations in the PAH gene gives rise to the condition phenylketonuria (PKU), associated with pathologically high phenylalanine levels as this amino acid cannot be converted to tyrosine. Untreated, PKU results in significant progressive damage to the central nervous system, manifesting with microcephaly, developmental delay and significant cognitive impairment. PKU is eminently treatable with dietary phenylalanine restriction, and detection via newborn screening permits treatment to be commenced before damage occurs. Many of the metabolic disorders, however, carry a devastating prognosis, for example mucopolysaccharidosis type III (Sanfilippo syndrome) which is caused by deficiency of one of the several lysosomal enzymes that degrade complex macro-molecules (the glycosaminoglycans), with the result that these macro-molecules accumulate in different tissues of the body including the brain and cause a relentlessly progressive neurodegenerative disorder, with childhood onset dementia and significantly curtailed life-expectancy.