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Category: genetics – Page 7

MicroRNA-based gene therapy to treat ALS

A single IV injection of a microRNA-based biologic suppressed production of the mutant SOD1 protein that causes amyotrophic lateral sclerosis (ALS); delayed disease onset by 60 days; and extended lifespan by 100 days, more than triple the average survival time, in mice models of the disease.

The gene therapy, delivered via adeno-associated virus (AAV) vector, preserved motor neurons and maintained neuromuscular connections in treated animals, which translated into improved muscle and respiratory function, motor performance, and lifespan in pre-clinical studies. These findings, published in Nature Communications, have the potential for clinical application in patients with SOD1-caused ALS, as well as other neurodegenerative diseases caused by toxic, gain-of-function gene mutations.

“These therapeutic benefits, from a single IV injection, are unprecedented among gene therapy approaches in this mouse model,” said the senior author. “No other studies have been able to achieve this kind of survival extension. This makes us very optimistic that our approach could have a meaningful impact for patients suffering from this horrible disease and warrants further clinical evaluation.”

Overcoming Cancer Resistance: Strategies and Modalities for Effective Treatment

Resistance to cancer drugs is a complex phenomenon that poses a significant challenge in the treatment of various malignancies. This review comprehensively explores cancer resistance mechanisms and discusses emerging strategies and modalities to overcome this obstacle. Many factors contribute to cancer resistance, including genetic mutations, activation of alternative signaling pathways, and alterations in the tumor microenvironment. Innovative approaches, such as targeted protein degradation, immunotherapy combinations, precision medicine, and novel drug delivery systems, hold promise for improving treatment outcomes. Understanding the intricacies of cancer resistance and leveraging innovative modalities are essential for advancing cancer therapy.

Gene Therapy Improves Stem Cell Transplant Success

Stem cell transplantation (or bone marrow transplantation) and gene therapy have revolutionized the way oncologists treat patients. Both approaches have the potential to cure patients with sickle cell disease, b-thalassemia, immune disorders, and even several blood cancers. There are specific transplants that can occur: autologous and allogenic. Both forms of transplantation are dependent on the source of the donor cells. Autologous transplants use the patient’s healthy stem cells taken from the patient before systemic treatment, like chemotherapy. Allogenic transplants use stem cells collected from healthy donors. Typically stems cells for an allogenic transplant is from a family member or umbilical cord blood to genetically match the recipient. If stem cells are not genetically matched, then the donor will recognize the stem cells as foreign and reject the transplant. This rejection is known as Graft-versus-Host Disease (GvHD). Infusion of stem cells only takes about 15 minutes, but the engraftment or the ability for cells to proliferate and establish themselves in the bone marrow takes up to 18 days. For full immune system recovery, most physicians see patients recover within a year. However, stem cell transplants are not perfect. There is a high rate of GvHD, infection, and disease relapse. Patients also usually receive chemotherapy before a transplant, which increases toxicity and reduces success of the procedure. Scientists are currently working on how to improve the success rate of transplantation.

A recent article in Nature, by Dr. Pietro Genovese and others, demonstrated that stem cell transplantations are safer when chemotherapy is replaced with a targeted treatment. Researchers used antibodies that recognize and target markers on blood-forming stem cells. This approach helps clear harmful preexisting stem cells from the patient before transplantation, instead of using toxic chemotherapeutic agents that damage DNA throughout the body. The antibody approach is more specific and reduces toxicity in patients. Genovese is an Assistant Professor at Dana Farber and Boston Children’s Cancer and Blood Disorders Center. His work focuses on gene-editing and bioengineering technologies that improve stem and immune cells. Specifically, Genovese investigates ways to improve gene therapy and develop approaches to enhance treatment for patients with hematological malignancies.

Previously, an antibody could not discern between current recipient and infused autologous stem cells. Antibodies could also attack transplanted cells from a separate donor (allogenic). To avoid these issues, Genovese and his team have used gene-editing tools to select for a specific biomarker on the surface of donor stem cells. The small edit prevented the antibody from binding to the donor stem cells. These antibodies were able to avoid the healthy stem cells and still eliminate the infected stem cells. This approach allows the donor stem cells to properly graft in the host and improve success of transplantation.

How molecular tethers and asynchronous replication drive parasite proliferation

Malaria parasites proliferate in an unusual way. Rather than dividing into two daughter cells like human cells, they first amplify their genetic material tenfold, hundredfold or even thousandfold before simultaneously producing a corresponding number of daughter parasites. Until now, the mechanisms controlling these processes were only partly understood.

Two recently published studies by researchers from Heidelberg University’s Faculty of Medicine, Harvard Medical School and the German Cancer Research Center (DKFZ) provide important insights into the molecular basis of this proliferation strategy and reveal how the parasite makes particularly efficient use of limited resources within infected blood cells. The findings open new perspectives for the development of future antimalarial drugs.

Decoding 3D chromatin architecture reveals distinct enhancer classes underlying hierarchical gene regulation in prostate cancer

The transcription process is controlled by non-coding regulatory elements, more than 70% of which are putative enhancers. These enhancers comprise over 600,000 regions and are marked by histone modifications. However, the mechanisms by which altered enhancers in cancer cooperate within the three-dimensional chromatin architecture to drive oncogenic programs remain poorly understood.

By integrating 201 H3K27ac ChIP-seq datasets from prostate, we identify 3,216 high-confidence prostate cancer-specific putative enhancers. Ultra-high-resolution chromatin interaction profiling by Region Capture Micro-C at a representative chr6q24.1 locus reveals that these enhancers form cancer-specific, highly nested interactions with promoters that coalesce into a multi-connected hub absent in normal prostate cells. CRISPR/Cas9 perturbations of these enhancers, examined one by one, distinguish enhancer classes within the hub. Deletion of a central enhancer collapses hub-wide enhancer activities and architecture, leading to the downregulation of target genes, impaired proliferation, and reduced clonogenic growth. In contrast, deletion of a redundant enhancer results in minimal transcriptional changes, as neighboring enhancers rescue cancer signaling through compensatory architectural rewiring that strengthens alternative enhancer-promoter interactions.

Newly discovered microprotein linked to type 2 diabetes, shows promise as a precision treatment

A previously unknown microprotein hidden within the human mitochondrial genome may help explain certain forms of type 2 diabetes and could point toward a new precision medicine approach to treating it, according to a new USC study.

Obesity and type 2 diabetes are among the fastest-growing threats to human health, yet their genetic underpinnings remain only partly understood. While most disease-gene research focuses on the larger set of DNA found in the nucleus within cells, the much smaller genome found in mitochondria—cells’ energy factories—is now known to encode a family of microproteins with wide-ranging biological effects.

The new study adds a striking example to that list, said Pinchas Cohen, the study’s senior author, USC Distinguished Professor and dean of the USC Leonard Davis School of Gerontology. The findings were published in the journal Theranostics.

Personalized gene therapy helps teen with rare form of severe epilepsy walk independently

SCN2A-related developmental epileptic encephalopathy (DEE) is a rare, severe form of childhood epilepsy and one of the most common causes of monogenic autism. The condition is caused by single mutations in the sodium voltage-gated channel alpha subunit (SCN2A) gene, which controls the flow of sodium ions into neurons. These mutations promote abnormal brain excitability, resulting in uncontrolled seizures along with developmental delays, autism, movement problems and gastrointestinal issues. Most of these mutations are de novo (not inherited from a parent) and arise spontaneously.

Traditional antiseizure medications are often ineffective and do not address the underlying genetic cause of SCN2A-related DEE.

Now, an international team of researchers led by the University of California San Diego and Rady Children’s Institute for Genomic Medicine has treated two children with the condition using gene therapy tailored to each child’s specific SCN2A mutation.

AI‑designed gene‑editing enzymes expand the CRISPR toolbox

Scientists have made many advances using traditional CRISPR technology, especially in medicine, but they are now seeking ways to create genuinely new gene-editing enzymes with properties that have not already evolved naturally. A new study, published in Science, describes a new AI-designed synthetic TnpB enzyme, called SynTnpBs, that has outperformed the natural reference enzyme.

Creating new gene editors CRISPR tools use a programmable guide RNA to direct an enzyme to a specific target in the genome to edit (cut, insert or correct) DNA. The TnpB enzyme is a compact ancestor of certain CRISPR enzymes, called CRISPR-Cas12 enzymes. Researchers think its small size could make it useful in situations where delivery space is limited, like some kinds of gene editing in plants. However, these enzymes can be difficult to redesign.

While AI has been useful for automating complex genome editing and predicting DNA repair outcomes, most AI methods used for generating gene-editing enzymes have produced versions that are still very similar to natural proteins. When researchers have attempted to create new editors with novel, useful properties, they have found it challenging to change the protein without breaking the molecular contacts needed for DNA editing.

Withinpatient gene transfer between transiently and chronically infecting bacteria causes extreme antibiotic resistance during lung infections Microbiology

Antibiotic resistance gene acquisition by Pseudomonas aeruginosa and Achromobacter from transiently infecting bacteria drives rapid and extreme resistance to tobramycin during chronic lung infection within patients.

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