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Archive - 2018 - Story

December 9th

A-T Children’s Project Announces Selection of First Child to Receive ASO Gene Therapy for Ataxia-Telangiectasia

On November 30, 2018, the Ataxia-Telangiectasia (A-T) Children’s Project and its President Brad Margus announced that the Project has selected a little, 18-month girl on the west coast of the U.S. to be the first A-T child in history to receive gene therapy. The Project had the pleasure of letting th girl's parents know the exciting news last week. How was the first child selected? The laboratory of Dr. Tim Yu at Boston Children’s Hospital/Harvard collected and grew skin, blood, and stem cells from three different young children who we believed had the right type of mutations in their A-T genes to be treated with an antisense oligonucleotide (ASO) gene therapy approach. The scientists then made many different oligonucleotides designed to silence each of the children’s mutations and tested them in each child’s cells. In the end, the group identified several oligonucleotide molecules that worked really well in this little girl’s cells, not only silencing her mutation and causing the A-T protein to be made correctly, but also causing downstream biological pathways to be activated as though her cells were from a healthy child (confirming this downstream function took us longer than planned to do, but now gives us more confidence to move forward). This means that we now have both our drug and our patient selected. Very soon, we’ll be signing a contract to begin the manufacture of enough quantity of the drug to run our “n of 1” clinical trial (we’ll keep the other oligonucleotides that worked as backups). We’ll also make sure that the drug produced will be clinical-grade to satisfy the FDA. As soon as we receive the first batch of this final version of the drug, we’ll test it for safety in rats before applying to the FDA for approval to start testing it in a human.

November 27th

Sugars & Microbiome in Mother's Milk Influence Neonatal Rotavirus Infection

Using a multidisciplinary approach, an international team of researchers from several institutions, including Baylor College of Medicine, reveals that complex interactions between sugars and the microbiome in human milk influence neonatal rotavirus infection. Reported online on November 27, 2018 in the journal Nature Communications, this study provides new understanding of rotavirus infections in newborns and identifies maternal components that could improve the performance of live, attenuated rotavirus vaccines. The open-access article is titled “Human Milk Oligosaccharides, Milk Microbiome and Infant Gut Microbiome Modulate Neonatal Rotavirus Infection.” "Rotavirus infection causes diarrhea and vomiting primarily in children younger than 5, with the exception of babies younger than 28 days of age, who usually have no symptoms. However, in some places, infections in newborns are associated with severe gastrointestinal problems. What factors mediate differences between newborns with and without symptoms are not clearly understood," said first and corresponding author Dr. Sasirekha Ramani (photo), Assistant Professor of Molecular Virology and Microbiology at Baylor College of Medicine. "We began our investigation years ago by determining that a particular strain of rotavirus was associated with both asymptomatic infections and clinical symptoms in newborns." Dr. Ramani and her colleagues first looked for answers from the perspective of the virus. They investigated whether factors such as the amount of virus in newborns or the genome of the virus could be linked to the presence of symptoms in newborns, but did not find any connection between those factors. The researchers then posed the question from the perspective of the newborn.

International Society for Extracellular Vesicles (ISEV) Releases 2018 Update of 2014 Guidelines for Studies of Extracellular Vesicles

On November 23, 2018, The International Society for Extracellular Vesicles (ISEV) published online an open-access position paper titled “Minimal Information for Studies of Extracellular Vesicles 2018 (MISEV2018); A Position Statement of the International Society for Extracellular Vesicles and Update of the MISEV2014 Guidelines.” The article is scheduled for hard-copy publication in Volume 8, Issue 1, of the 2019 Journal of Extracellular Vesicles. In the article abstract, the authors note the following: “The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The ISEV proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation.

Researching Rare Genetic Disease, Scientists Uncover Key Immune Regulator

Scientists at Scripps Research in California have found an important immune system-regulating protein that in principle could be targeted to treat cancers and chronic viral infections. In a study published online on November 12, 2018 in Nature Chemical Biology, the scientists set out to determine the function of a protein, ABHD12 (abhydrolase domain containing protein 12), whose absence causes a rare genetic disease featuring a host of brain and nerve problems. The article is titled “Selective Blockade of the Lyso-PS Lipase ABHD12 Stimulates Immune Responses in Vivo.” The researchers found that ABHD12 normally acts as a powerful "brake" on the immune system to keep it from becoming harmfully overactive. Mice engineered without the protein have signs of elevated inflammation, and their immune systems are more likely to overreact to a viral infection. The discovery suggests that the absence of ABHD12 in people with mutant versions of its gene may cause neurological disease at least in part via excessive immune activity. It also indicates that ABHD12 may be a useful target for drugs that boost the immune system--for example against cancers and viruses that normally persist by shutting down people's immune defenses. "This is a good example of how the study of a rare genetic disease can reveal a pathway that plays a key role in human biology," says study co-senior author Benjamin Cravatt, PhD, Professor and Chair of the Department of Chemical Physiology at Scripps Research. The rare disease in this case is a mix of progressive brain, peripheral nerve, and eye problems that scientists have given the acronym PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract). Since 2010, researchers have known that PHARC is caused by gene mutations that prevent ABHD12 from being made.

November 26th

FDA Approves ACTpen for Genentech’s ACTEMRA, a Single-Dose, Prefilled Autoinjector for Treatment of Rheumatoid Arthritis, Giant Cell Arteritis, & Two Forms of Juvenile Arthritis

On November 26,2018, Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced that the U.S. Food and Drug Administration (FDA) has approved ACTPen™ 162 mg/0.9 mL, a single-dose prefilled autoinjector for Actemra® (tocilizumab) as an additional formulation for adult patients with moderate to severe active rheumatoid arthritis (RA) who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs), and for adult patients with giant cell arteritis (GCA). Further, the ACTPen can be administered by caregivers to patients two years of age and older with active polyarticular juvenile idiopathic arthritis (PJIA) or active systemic juvenile idiopathic arthritis (SJIA). The ability of pediatric patients to self-inject with the ACTPen has not been tested. The ACTPen is expected to be available in January 2019. “When it comes to the administration of medicines, we believe patients should have choices, when possible,” said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development for Roche/Genentech. “With ACTPen for Actemra, we are pleased to offer an additional option to patients who may prefer using the new autoinjector over other formulations.”The FDA first approved Actemra intravenous infusion formulation (IV) for adults with RA in January 2010 and Actemra pre-filled syringe (PFS) formulations for subcutaneous injection (SC) for adults with RA in October 2013. In May 2017, Actemra SC became the first therapy approved by the FDA for the treatment of adult patients with GCA, a chronic and severe form of vasculitis characterized by inflammation of certain large blood vessels.

Perivascular Dendritic Cells Elicit Anaphylaxis by Relaying Allergens to Mast Cells Via Microvesicles

In work published online on November 9, 2018, in Science, Duke University Medical Center researchers, and colleagues, demonstrate that IgE-sensitized mast cells (MCs) (image) are indirectly activated by blood-borne allergens. In addition, the study revealshow perivascular dendritic cells (DCs) continuously sample blood and initiated and markedly enhance inflammatory and immune responses by rapidly discharging antigen-bearing microvesicles (MVs) to surrounding immune cells. the Science article is titled “Perivascular Dendritic Cells Elicit Anaphylaxis by Relaying Allergens to Mast Cells Via Microvesicles.” The results may resolve the conundrum of how mast cells, which are extravascular, are able to perceive and react to blood-borne allergens. The scientists describe the existence of a CD301b+ perivascular DC subset that continuously samples blood and relays antigens to neighboring MCs, which vigorously degranulate and trigger anaphylaxis. DC antigen transfer involved the active discharge of surface-associated antigens on 0.5- to 1.0-micrometer MVs generated by vacuolar protein sorting 4 (VPS4). Antigen sharing by DCs is not limited to MCs, as neighboring DCs also acquire antigen-bearing MVs. This capacity of antigen-bearing MVs to various immune cells in the perivascular space potentiates inflammatory and immune responses to blood-borne antigens. Anaphylaxis is a life-threatening allergic reaction triggered after antigen-specific immunoglobulin E (IgE) antibodies bind to target allergens. These antibodies than cross-link IgE-specific Fc receptors on the surface of MCs. The MCs rapidly release inflammatory mediators, including histamine, resulting in smooth muscle contraction, vasodilation, and blood vessel leakage.

Exosome-Like Nanoparticles (ELNs) Derived from Plants Are Taken Up by Mouse Gut Microbiota and Can Ameliorate Disease

In work published in the November 14, 2018 issue of Cell Host & Microbe, researchers from the James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville in Kentucky, together with colleagues, demonstrate that plant-derived exosome-like nanoparticles (ELNs) are taken up by the gut microbiota and contain RNA that alter the mouse microbiome composition and host physiology. The article is titled “Plant-Derived Exosomal MicroRNAs Shape the Gut Microbiota.” Specifically, the authors show that ginger ELNs (GELNs) are preferentially taken up by Lactobacillaceae in a GELN lipid-dependent manner and contain microRNAs (miRNAs) that target various genes in Lactobacillus rhamnosus (LGG). In particular, the authors noted that the GELN mdo-miR7267-3p-mediated targeting of the LGG monooxygenase ycnE yields increased indole-3-carboxaldehyde (I3A). GELN-RNAs or I3A, a ligand for aryl hydrocarbon receptor, are sufficient to induce production of IL-22, which is linked to barrier function improvement. According to the authors, these functions of GELN-RNAs can ameliorate mouse colitis via IL-22-dependent mechanisms. The authors conclude that their findings indicate how plant products and their effects on the microbiome can be used to target specific host processes to alleviate disease. Note that the image here was taken from the article abstract and can be much better viewed at the abstract itself (at the link below).

[Cell Host & Microbe abstract]

November 23rd

Precision Medicine World Conference (PMWC) 2019 Conference in January in Silicon Valley; Q&A Session with Luminary Award Winner Genetic Alliance CEO Sharon Terry Available Now

The Precision Medicine World Conference (PMWC), celebrating ten years of operation, will take place at the Santa Clara Convention Center (Silicon Valley, California) January 20-23, 2019. This is expected to be the largest Precision Medicine World Conference ever, with 2,500 attendees. This amazing gathering of prestigious experts in multiple inter-related fields and those interested in learning more is co-hosted by UCSF, Stanford Health Care/Stanford Medicine, Duke University, Duke Health, and Johns Hopkins University. The program will cover innovative technologies, thriving initiatives, and clinical case studies that enable the translation of precision medicine into direct improvements in health care. Conference attendees (https://www.pmwcintl.com/about/#audience) will have an opportunity to learn first-hand about the latest developments and advancements in precision medicine and cutting-edge new strategies and solutions that are changing how patients are treated. The conference’s five-track program will include sessions on the following major topics, among many others: AI & Data Science; Clinical & Research Tools; Clinical Diagnostics; Creating Clinical Value with Liquid Biopsy ctDNA, etc.; Digital Health/Health and Wellness; Pharmacogenomics; Emerging Technologies in Precision Medicine; Immunotherapy; Large-Scale Bio-Data Resources to Support Drug Development; Rare Disease Diagnosis; and Wellness & Aging. Conference organizers have assembled a hugely impressive lineup of 450+ highly regarded speakers, featuring pioneering researchers and authorities across the healthcare and biotechnology sectors (https://www.pmwcintl.com/2019sv/speakers/).

November 23rd

Thousands of Recombination Events Identified in APP Gene in Alzheimer’s Brains; Changes Depend on Reverse Transcriptase; “Findings Provide Scientific Rationale for Immediate Clinical Evaluation of HIV Antiretroviral Therapies in People with Alzheimer's"

Scientists from Sanford Burnham Prebys Medical Discovery Institute (SBP) in San Diego, California, have identified gene recombination in neurons that produces thousands of new gene variants within Alzheimer's disease brains. The study, published online on November 21, 2018 in Nature, reveals for the first time how the Alzheimer's-linked gene, APP (the gene coding for amyloid precursor protein--see image), is recombined by using the same type of enzyme found in HIV. The article is titled “Somatic APP Gene Recombination in Alzheimer’s Disease and Normal Neurons.” Using new analytical methods focused on single and multiple-cell samples, the researchers found that the APP gene, which produces the toxic beta amyloid proteins defining Alzheimer's disease, gives rise to novel gene variants in neurons--creating a genomic mosaic. The process required reverse transcription and reinsertion of the variants back into the original genome, producing permanent DNA sequence changes within the cell's DNA blueprint. "We used new approaches to study the APP gene, which gives rise to amyloid plaques, a pathological hallmark of the disease," says Jerold Chun, MD, PhD, , senior author of the paper and Professor and Senior Vice President of Neuroscience Drug Discovery at SBP. "Gene recombination was discovered as both a normal process for the brain and one that goes wrong in Alzheimer's disease." One hundred percent of the Alzheimer's disease brain samples contained an over-abundance of distinct APP gene variants, compared to samples from normal brains. Among these Alzheimer's-enriched variations, the scientists identified 11 single-nucleotide changes identical to known mutations in familial Alzheimer's disease--a very rare inherited form of the disorder.

November 20th

Enzyme on Surface of Some Lung Cancers Enhances Cancer Growth & May Be Target for Treatment

University of Texas (UT) Southwestern researchers have found that an enzyme on the surface of some lung cancer cells helps feed the cancer, making it a tempting treatment target. The enzyme, transmembrane serine protease 11B (TMPRSS11B), is described in a report published in the November 20, 2018 issue of Cell Reports. The open-access article is titled “Transmembrane Protease TMPRSS11B Promotes Lung Cancer Growth by Enhancing Lactate Export and Glycolytic Metabolism.” In addition to being found in squamous cell lung cancer and prostate cancer, the enzyme also has been identified in squamous cell head, neck, and cervical cancers, said Dr. Kathryn O’Donnell (photo), Assistant Professor of Molecular Biology. Her team identified TMPRSS11B while searching for genes that can convert precancerous lung cells into malignant cells that can form tumors. “In this study, we found that the enzyme strongly promoted the growth of certain types of lung cancer cells. We uncovered a new mechanism that expands our understanding of how cancer cells reprogram their metabolism to provide energy for rapid growth as they form tumors,” Dr. O’Donnell said. The researchers noticed that the enzyme was expressed at increased levels in human squamous cell lung cancers – a common type of non-small cell lung cancer – and that suppressing the levels of TMPRSS11B through gene editing or RNA interference reduced tumor growth in mouse models, she said. The research focused on TMPRSS11B’s ability to encourage the movement of lactate, a byproduct of cell metabolism long thought to be a waste product. Ground-breaking research last year from UT Southwestern Professor Dr. Ralph DeBerardinis’ laboratory found that, in fact, lactate provides fuel for growing tumors. Dr.