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IGIB researchers partially reverse a rare disorder The Hindu R. Prasad 10 FEBRUARY 2018 18:13 IST UPDATED: 10 FEBRUARY 2018 18:14 IST The syndrome also affects about one in one lakh people, causing a range of defect Researchers at Delhi’s Institute of Genomics & Integrative Biology (CSIR-IGIB) have for the first time used zebra fish to model the rare genetic disorder — Rubinstein Taybi Syndrome (RSTS) — seen in humans. They have also used two small molecules to partially reverse some of the defects caused by the disorder in zebrafish, thus showing them to be an ideal animal model for screening drug candidates. There is currently no cure or treatment for the disorder. The Rubinstein Taybi Syndrome has a frequency of about one in one lakh people, and causes intellectual disability, growth retardation (short stature), craniofacial deformities, heart defects and broad thumbs and toes. The results were published in the journal Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. Close to human genome Since zebrafish genome has very close similarity to human genome and the embryonic developmental is very similar in the two, the team led by Dr. Chetana Sachidanandan at IGIB went about checking if EP300, one of the two genes that cause the disorder is present in the fish and if mutations in this gene result in a RSTS-like disease in fish. Using chemicals, the researchers inhibited the activity of the protein Ep300 to see if this resulted in the manifestation of the disorder in the brain, heart, face and pectoral fins (equivalent to forearm in humans). “Like in the case of humans, the same organs were affected in the fish when the functioning of the protein was stopped. This helped in confirming that the protein in question does the same functions in fish and humans, ” she says. Since zebrafish commonly has two copies of many human genes, the researchers first checked if one or both the genes were functional and equivalent to the human gene that causes the disorder. “We found Ep300a gene was active and functional while Ep300b was not, ” says Prof. Tapas K. Kundu from the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bengaluru, the other corresponding author. The Ep300a gene is responsible for producing a protein (Ep300) that opens up the DNA. “The protein Ep300 is evolutionarily conserved from fish to humans. Though the Ep300 gene has been earlier identified in fish, its function was not known, ” says Prof. Kundu. Reversal of effects Like in the case of fish treated with chemicals manifesting the disorder, fish mutants that lacked the Ep300a gene too exhibited defects very similar to those seen in humans. “When we introduced excess amount of a tiny portion of the Ep300a protein in the mutants, the craniofacial deformities became less severe [mutants had severed craniofacial deformities] and pectoral fins in the fish became normal, ” she says. But neuronal defects were not reversed, even partially. “It might be because only a portion of the protein was put into the fish. Probably, that potion isn’t sufficient to compensate for the loss of the whole protein, ” she explains. “It’s proof-of-concept that just a piece of the protein is sufficient to reverse some defects, even if only partially, in zebrafish, ” Dr. Sachidanandan says. Alternatively, the researchers used two small molecules to reverse the defects. If the protein Ep300 is responsible for opening the DNA, there are other proteins that are responsible for closing the DNA. The two molecules were found from a screen of compounds well known for their ability to inhibit proteins responsible for closing the DNA. Like in the case when excess amount of Ep300 protein was introduced, both the molecules could partially restore facial defects but not the neuronal defects. “Introducing excess amount of a portion of the ep300 protein showed greater rescue of deformities than the small molecules, ” says Aswini Babu from IGIB and first author of the paper. “But rescuing the deformities using small molecules is a relatively easier and better option.”
  • 2018-02-14T06:18:11

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Gene editing can help treat congenital disease before birth Updated Oct 09, 2018 | 20:02 IST | IANSPrenatal treatment could open a door to disease prevention, for HT1 and potentially for other congenital disorders. Representational image Photo Credit: ThinkstockRepresentational Image New York: In a first, a team of scientists have performed prenatal gene editing to prevent a lethal metabolic disorder in laboratory mice, offering the potential to treat human congenital diseases before birth. The study led by research from Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania used both CRISPR-Cas9 and base editor 3 (BE3) gene-editing tools and reduced cholesterol levels in healthy mice treated in utero by targeting a gene that regulates those levels. They also used prenatal gene editing to improve liver function and prevent neonatal death in a subgroup of mice that had been engineered with a mutation causing the lethal liver disease hereditary tyrosinemia type 1 (HT1). Advertising Advertising HT1 in humans usually appears during infancy, and it is often treatable with a medicine called nitisinone and a strict diet. However, when treatments fail, patients are at risk of liver failure or liver cancer. Prenatal treatment could open a door to disease prevention, for HT1 and potentially for other congenital disorders. "Our ultimate goal is to translate the approach used in these proof-of-concept studies to treat severe diseases diagnosed early in pregnancy, " said William H. Peranteau, a paediatric and foetal surgeon at CHOP. "We hope to broaden this strategy to intervene prenatally in congenital diseases that currently have no effective treatment for most patients, and result in death or severe complications in infants, " he added. In the study, published in the journal Nature Medicine, the team used BE3, joined it with a modified CRISPR-associated protein 9. After birth, the mice carried stable amounts of edited liver cells for up to three months after the prenatal treatment, with no evidence of unwanted, off-target editing at other DNA sites. In the subgroup of the mice bio-engineered to model HT1, BE3 improved liver function and preserved survival. However, "a significant amount of work needs to be done before prenatal gene editing can be translated to the clinic, including investigations into more clinically relevant delivery mechanisms and ensuring the safety of this approach", said Peranteau. He added: "Nonetheless, we are excited about the potential of this approach to treat genetic diseases of the liver and other organs for which few therapeutic options exist."
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