Category Archives: Gene Medicine

The Department of Human Genetics is the youngest basic science department in the Geffen School of Medicine at UCLA. When the Department was launched just prior to the sequencing of the human genome, it was clear that the practice of genetics research would be forever changed by the infusion of massive amounts of new data. Organizing and making sense of this genomic data is one of the greatest scientific challenges ever faced by mankind. The knowledge generated will ultimately transform medicine through patient-specific treatments and prevention strategies.

The Department is dedicated to turning the mountains of raw genetic data into a detailed understanding of the molecular pathogenesis of human disease. The key to such understanding is the realization that genes not only code for specific proteins, but they also control the temporal development and maturation of every living organism through a complex web of interactions.

Housed in the new Gonda Research Center, the Department serves as a focal point for genetics research on the UCLA campus, with state of the art facilities for gene expression, sequencing, genotyping, and bioinformatics. In addition to its research mission, the Department offers many exciting training opportunities for graduate students, postdoctoral fellows, and medical residents. Our faculty and staff welcome inquiries from prospective students. We also hope that a quick look at our web pages will give you a better idea of the Department's research and educational activities.

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UCLA Human Genetics

1. The gene editing tool CRISPR-Cas9 was used to correct a mutant paternal MYBPC3 allele in human preimplantation embryos.

2. No off-target effects were detected.

Evidence Rating Level: 1 (Excellent)

Study Rundown: A dominant mutation in the gene MYBPC3 causes hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in otherwise healthy young athletes. While most current therapies focus on relieving symptoms of HCM, researchers in this study aimed to prevent transmission of the causative gene mutation by correcting it in preimplantation embryos.

Healthy donor eggs were injected with sperm that were heterozygous for the MYBPC3 mutation. After fertilization, recombinant Cas9 protein and single guide RNA that targeted MYBPC3 were microinjected into the zygotes. A majority of treated embryos survived and lost the mutation in this gene, without other genes being impaired. CRISPR-Cas9 targeting of MYBPC3 was found to be highly specific in the treated embryos.

This study was the first to use CRISPR-Cas9 to correct a harmful mutation without causing significant off-target effects. Although this genome editing technique is still far from clinical use and requires full discussion from a bioethics perspective, this research suggests the potential clinical efficacy of this therapy for in vitro fertilization and the correction of fatal mutations.

Click to read the study in Nature

Relevant Reading: Genome engineering through CRISPR/Cas9 technology in the human germline and pluripotent stem cells

In-Depth [in vitro study]: Human zygotes were produced by fertilizing 70 oocytes without MYBPC3 mutations with sperm from an HCM patient with a heterozygous mutation in MYBPC3. Eighteen days after fertilization, recombinant Cas9 protein, short guide RNA, and single-stranded oligodeoxynucleotideswere microinjected into the cytoplasm of the zygotes. A majority of zygotes survived this procedure, with a survival rate of 97.1%. Three days after injection of the Cas9 protein, 54 injected embryos were sequenced and 66.7% were found to be homozygous for the wild-type (WT) allele of MYBPC3. Almost half of the blastomeres from mosaic embryos were also found to be homozygous for the WT allele of this gene, demonstrating that the heterozygous mutation was repaired through homology-directed repair. These analyses demonstrated the efficient targeting by CRISPR-Cas9 in human embryos.

To improve the efficacy of gene correction, CRISPR-Cas9 was mixed with sperm and injected into 75 oocytes in metaphase II. This method resulted in an increase in WT embryos, with 72.4% successfully removing the mutation. Additionally, a majority of these oocytes developed into the eight-cell stage and then blastocysts, demonstrating no significant effect on embryonic development due to this therapy.

Finally, off-target effects were assessed through whole genome sequencing, digested genome sequencing, and whole exome sequencing. No insertions or deletions were detected in the WT blastomeres at 23 off-target loci, demonstrating the high targeting efficacy and potential safety of this treatment.

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CRISPR-Cas9 corrects hypertrophic cardiomyopathy gene mutation ... - 2 Minute Medicine

Ministers will have their work cut out as the UK has too often failed to translate medical breakthroughs into blockbusters made in Britain. An example is monoclonal antibodies, a common component of biological drugs discovered at Cambridge University in the Seventies.

It led to a Nobel Prize for the scientists involved and has since exploded into a field worth around 70bn globally today. Yet just 3,000 of the 100,000 people working in this area are in Britain. Over the past eight years the UKs historic status as a major net exporter of medicines has been gradually dwindling.

Since 2009, every year bar one has seen a lowering of net exports of pharmaceutical products and medical devices, with the UK even becoming a net importer for the first time on record in 2014, according to UN trade data. So what barriers will industry and the Government have to overcome to make the UK a medicines manufacturing powerhouse once again?

Britains drug makers outlined a blueprint this week for doing just that, in a report entitled Manufacturing Vision for UK Pharma. In it they called on government to invest up to 140m to build a further threedrugmanufacturing centres of excellence, like the one in Stevenage. They also urged pharmaceutical firms to learn from their counterparts in the automotive and aerospace industries on how to partner with government and pool research and development efforts.

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How do you turn world-leading British science into medicines? - Telegraph.co.uk

Binding of steroid estrogen hormones to estrogen receptor (ER) in the cell nucleus triggers the sequential recruitment different coactivators to regulate gene transcription.

Estrogen hormones regulate gene expression. They achieve this by first binding to estrogen receptor in the cell nucleus, which triggers the recruitment of different molecules called coactivators in specific order. In a study published in Molecular Cell, a team of researchers at Baylor College of Medicine, the University of Texas MD Anderson Cancer Center and the University of Texas Health Science Center at Houston shows that the sequential recruitment of coactivators is not simply adding molecules to the complex, it results in dynamic specific structural and functional changes that are necessary for effective regulation of gene expression.

Estrogens are a group of hormones that are essential for normal female sexual development and for the healthy functioning of the reproductive system. They also are involved in certain conditions, such as breast cancer. Estrogen also plays a role in male sexual function. Estrogens carry out their functions by turning genes on and off via a multi-step process. After estrogen binds to its receptor, different coactivators bind to the complex in a sequential manner.

Experimental evidence suggests that different estrogen-receptor coactivators communicate and cooperate with each other to regulate gene expression, said corresponding author Dr. Bert OMalley, chair and professor of molecular and cellular biology and Thomas C. Thompson Chair in Cell Biology at Baylor College of Medicine. However, how this communication takes place and how it guides the sequence of events that regulate gene expression was not clear.

In this study, OMalley, Dr. Wah Chiu, Distinguished Service Professor and Alvin Romansky Professor of Biochemistry and Molecular Biology at Baylor during the development of this project, and their colleagues combined cryo-electron microscopy structure analysis and biochemical techniques and showed how the recruitment of a specific coactivator CARM1 into the complex guides the subsequent steps leading to gene activation.

For the estrogen receptor complex to be able to regulate gene expression, the coactivator CARM1 needs to be added after other coactivators have been incorporated into the complex, said first author Dr. Ping Yi, assistant professor of molecular and cellular biology at Baylor. We discovered that when CARM1 is added, it changes the complex both chemically and structurally, and these changes guide subsequent steps that lead to gene activation.

We now have a better understanding of how this molecular machine works and of what role each one of the components plays. We are better prepared to understand what might have gone wrong when the machine fails, OMalley said.

Other contributors to this work include Zhao Wang, Qin Feng, Chao-Kai Chou, Grigore D. Pintilie, Hong Shen, Charles E. Foulds, Guizhen Fan, Irina Serysheva, Steven J. Ludtke, Michael F. Schmid, Mien-Chie Hung and Wah Chiu.

Support for this study was provided by the Komen Foundation (5PG12221410), the Department of Defense (R038318-I and W81XWH-15-1-0536); National institutes of Health grants (HD8818, NIDDK59820, P41GM103832 and R01GM079429); CNIHR, R21AI122418 and R01GMGM072804; CPRIT grants (RP150648 and DP150052); and a National Cancer Institute Cancer Center Support grant (P30CA125123) to the BCM Monoclonal Antibody/recombinant Protein Expression Core Facility.

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Research reveals how estrogen regulates gene expression - Baylor College of Medicine News (press release)

The new Stanford Center for Definitive and Curative Medicine will fosterthe development ofstem cell and gene therapies for genetic diseases, including sickle cell anemia.

More than280 million people around the world have diseases with genetic causes, experts estimate. While research has identified the underlying causes of several, scientists have developed few therapies that can address the causes or cure the diseases.

Treatments have been developed thatsignificantly improve patients health, however. They include public health initiatives, targeted therapies and surgery.

Scientists believe stem cell and gene therapy can cure some genetic diseases. They would likely do this either by rewiring cells to fight a disease more efficiently or by correcting a genetic errorin a patients DNA.

Stanford not only does excellent research in disease mechanisms, cell and stem cell biology, but also promotes collaboration between its medical schools and hospitals.

The initiative is a joint venture of theStanford University School of Medicine,Stanford Health CareandStanford Childrens Health.

Dean Predicts Center Will Be Major Force in the Precision-health Revolution

The Center for Definitive and Curative Medicine is going to be a major force in theprecision-health revolution, Dr. Lloyd Minor, dean of the School of Medicine, said in a press release. Our hope is that stem cell and gene-based therapeutics will enable Stanford Medicine to not just manage illness but cure it decisively and keep people healthy over a lifetime.

We are entering a new era in medicine, one in which we will put healthy genes into stem cells and transplant them into patients,said Christopher Dawes, the president and CEO of Stanford Childrens Health. And with the Stanford Center for Definitive and Curative Medicine, we will be able to bring these therapies to patients more quickly than ever before.

The work of the center is not being done anywhere else in the country only at Stanford, said David Entwistle, president and CEO of Stanford Health Care. We have a pipeline of clinical translational therapies that the center is now driving forward, enabling us to translate basic science discoveries into state-of-the-art therapies for diseases which up until now have been considered incurable.

Dr. Maria Grazia Roncarolo will direct the center,which will be in the Department of Pediatrics.The renowned medical doctor and scientist is the George D. Smith Professor of Stem Cell and Regenerative Medicine.

It is a privilege to lead the center and to leverage my previous experience to build Stanfords preeminence in stem cell and gene therapies, said Roncarolo, who is also chief of pediatric stem cell transplantation and regenerative medicine, co-director of theBass Center for Childhood Cancer and Blood Diseases,and co-director of theStanford Institute for Stem Cell Biology and Regenerative Medicine.

Main Mission Will Be to Turn Scientific Discoveries Into Treatments

Stanford Medicines unique environment brings together scientific discovery, translational medicine and clinical treatment, Roncarolo added. We will accelerate Stanfords fundamental discoveries toward novel stem cell and gene therapies to transform the field and to bring cures to hundreds of diseases affecting millions of children worldwide.

The centers main mission will be to turn scientific discoveries into treatments. A world-classinterdisciplinary team of scientists should help it deliver on that promise.

Leaders of the team will include Dr. Matthew Porteus, an associate professor of pediatrics, and Dr. Anthony Oro, the Eugene and Gloria Bauer Professor of dermatology. Dr. Sandeep Soni will direct the centers stem cell clinical trial office.

The center will provide novel therapies that can prevent irreversible damage in children, and allow them to live normal, healthy lives, said Dr. Mary Leonard, chair of pediatrics at Stanford Childrens Health. The stem cell and gene therapy efforts within the center are aligned with the strategic vision of the Department of Pediatrics and Stanfordsprecision-healthvision, where we go beyond simply providing treatment for children to instead cure them definitively for their entire lives.

A unique feature of the center will be a close association with the Stanford Laboratory for Cell and Gene Medicine, which is working on new cell and gene therapies.

The lab has already developed genetically corrected bone marrow cells as a treatment for sickle cell anemia. Other genetically modified cells it has created include skin grafts for children with the genetic disease epidermolysis bullosa and lymphocytes for children with leukemia.

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Stanford Center Hopes to Take Stem Cell and Gene Therapies to a New Level - Sickle Cell Anemia News

Raleigh, N.C. Many people spend years searching for a diagnosis of a debilitating medical problem, paying for treatments or surgery that don't help. Now, researchers at UNC say that, for some, recent advances in genetic testing could fix their problems once and for all.

Elizabeth Davis, a local genes study participant, does not take walking for granted. For 30 years, she could barely walk at all. "When I was 6, I started walking on my toes," she said. "I started going to different doctors, trying to find out what it was."

The muscles in Davis' foot had tightened up, causing her pain. She needed crutches and, sometimes, a wheelchair. For years, the cause of her condition remained a mystery.

According to Dr. James Evans, a researcher at UNC's Center for Genetic Medicine, about 30 percent of patients find an answer to their problems when they participate in a genes study. Participants' blood samples are analyzed with the latest advances in DNA sequencing.

"The patients themselves typically seek us out because they've been looking for answers for a long time," said Evans. "There might not be a known treatment, so sometimes that answer doesn't really change their life significantly."

Davis saw positive results after participating in the study, and Dr. Jonathan Berg, an Assistant Professor of Genetics at UNC, was happy with the results. "Her case is an unusual one in that it just happened to be a condition that is exquisitely treatable -- with just a pill," said Berg.

The genes study discovered that Davis had a muscle rigidity problem similar to that of many people with Parkinson's Disease. Doctors learned that it was Dopa, a drug used by millions of Americans with the disease, could help Davis walk again.

"The relief was fast and just by taking a quarter of a pill," said Davis. "I overheard my oldest son telling his friend that 'his mom is not on crutches anymore.' I'll never forget him saying that."

The study, funded by the National Institutes of Health, has even bigger plans for the future. UNC researchers say they're planning a randomized controlled trial to see if these types of genetic tests can benefit patients in the long run and prove to be a cost-effective diagnostic test.

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In pain? For some, gene studies could provide a quick cure - WRAL.com