Remote-controlled gene therapy uses ultrasound to kill cancer
By Michael Irving
December 09, 2024
A new kind of cancer gene therapy can be remotely activated at a specific part of the body. The team developed a version of CRISPR that responds to ultrasound, and demonstrated how it can be used to clear cancer in mice.
CRISPR is a powerful genetic editing tool that uses an enzyme called Cas9 to make precise edits to targeted genes. The problem is, it doesn’t always stay in the right part of the body, and can continue editing genes long after it’s needed, potentially triggering an immune response.
Now, scientists at the University of Southern California (USC) have demonstrated a new way to control when and where CRISPR does its work. In tests in mice, they used it to clear out cancer.
In practice, CRISPR could be incorporated into virus delivery vehicles and delivered intravenously to a patient. Then, focused ultrasound pulses can be directed at the desired part of the body, which activates the gene editing tool there and there alone. The trick is that the cells are designed to produce the Cas9 enzyme in response to heat, and that heat is induced by the ultrasound.
Researchers are shining a light on cancer cells' energy centers—literally—to damage these power sources and trigger widespread cancer cell death. In a new study, scientists combined strategies to deliver energy-disrupting gene therapy using nanoparticles manufactured to zero in only on cancer cells. Experiments showed the targeted therapy is effective at shrinking glioblastoma brain tumors and aggressive breast cancer tumors in mice.
The research team overcame a significant challenge to break up structures inside these cellular energy centers, called mitochondria, with a technique that induces light-activated electrical currents inside the cell. They named the technology mLumiOpto.
"We disrupt the membrane, so mitochondria cannot work functionally to produce energy or work as a signaling hub. This causes programmed cell death followed by DNA damage—our investigations showed these two mechanisms are involved and kill the cancer cells," said co-lead author Lufang Zhou, professor of biomedical engineering and surgery at The Ohio State University. "This is how the technology works by design."
A multinational study led by the LHON Study Group has revealed sustained visual improvements and a favorable safety profile five years following lenadogene nolparvovec gene therapy in patients with Leber hereditary optic neuropathy (LHON) caused by the MT-ND4 gene mutation.
LHON is most prevalently caused by the MT-ND4 gene mutation in mitochondrial DNA, characterized by acute and severe bilateral vision loss, primarily affecting retinal ganglion cells. Retinal ganglion cells are neurons tasked with relaying visual information from the retina to the brain
Lenadogene nolparvovec, an adeno-associated virus (AAV)-based gene therapy, was developed to address LHON and has been evaluated in four prior clinical studies, demonstrating early improvements.
The study, "Single-Eye Gene Therapy for Leber Hereditary Optic Neuropathy," published in JAMA Ophthalmology, details the findings of RESTORE, a long-term follow-up of two earlier Phase III trials, RESCUE and REVERSE, assessing lenadogene nolparvovec's efficacy for treating vision loss in LHON.
Researchers are making strides in improving gene therapies for genetic diseases, particularly chronic kidney disease, using adeno-associated virus, or AAV, vectors. While AAV-based treatments have shown promise, delivering these therapies effectively to the kidneys has remained a challenge—until now.
There are many different types of AAV capsids—the protein shells of virus particles—that have been used to deliver genes to cells, each with unique effects. Most commonly, AAV capsids are delivered into the body via intravenous injection, but this method has limited success in targeting kidney cells and can sometimes cause harmful side effects, especially to the liver.
New research by Oregon Health & Science University scientists, however, has uncovered multiple factors to improve gene delivery to the kidney, including AAV capsids, delivery routes such as IV injection or direct injection into the renal vein or renal pelvis—areas closer to the kidneys—and kidney disease conditions.
Researchers at the Experimental and Clinical Research Center (ECRC), a joint institution of the Max Delbrück Center and Charité—Universitätsmedizin Berlin, have developed a promising gene-editing approach intended to restore the function of a protein that is essential to repair and regrow muscle in patients with muscular dystrophy diseases. The findings are published in the journal Nature Communications.
The dysferlin protein is primarily responsible for repairing cell membranes. People with certain mutations in the gene coding for dysferlin develop muscular dystrophy—a group of muscle wasting diseases that affect thousands around the world.
Professor Simone Spuler and her team led by Dr. Helena Escobar in the Myology Lab at ECRC have successfully removed muscle stem cells from two patients with limb-girdle muscular dystrophy, corrected the genetic error and restored functioning dysferlin proteins in cell culture. In new mouse models of the disease, they used the same process to collect cells, edit them and transplant the corrected cells back into mice, where protein function was restored and muscles began to regrow.
Influential inventions often combine existing tools in new ways. The iPhone, for instance, amalgamated the telephone, web browser and camera, among many other devices.
The same is now possible in gene editing. Rather than employ separate tools for editing genes and regulating their expression, these distinct goals can now be combined into a single tool that can simultaneously and independently address different genetic diseases in the same cell.
In a new paper in Nature Communications, researchers in the Center for Precision Engineering for Health (CPE4H) at the University of Pennsylvania School of Engineering and Applied Science (Penn Engineering) describe minimal versatile genetic perturbation technology (mvGPT).
Capable of precisely editing genes, activating gene expression and repressing genes all at the same time, the technology opens new doors to treating genetic diseases and investigating the fundamental mechanisms of how our DNA functions.
"Not all genetic diseases are solely caused by errors in the genetic code itself," says Sherry Gao, Presidential Penn Compact Associate Professor in Chemical and Biomolecular Engineering (CBE) and in Bioengineering (BE) and the paper's senior author. "In some cases, diseases with genetic components—like type I diabetes—are due to how much or little certain genes are expressed."
Dravet syndrome and other developmental epileptic encephalopathies are rare but devastating conditions that cause a host of symptoms in children, including seizures, intellectual disability, and even sudden death.
Most cases are caused by a genetic mutation; Dravet syndrome in particular is most often caused by variants in the sodium channel gene SCN1A.
Recent research from Michigan Medicine takes aim at another variant in SCN1B, which causes an even more severe form of DEE.
Mice without the SCN1B gene experience seizures and 100% mortality just three weeks after birth.
Using mouse models, the investigative team, led by Chunling Chen, M.D., and Yukun Yuan, M.D., Ph.D., in the lab of Lori Isom, Ph.D., of the Department of Pharmacology at the Medical School, tested a gene therapy to replace SCN1B to increase the expression of beta-1 protein, which is necessary for the regulation of sodium channels in the brain.
Administering the therapy to newborn mice increased their survival, reduced the severity of their seizures and restored brain neuron excitability.
Researchers from the NIHR Moorfields Biomedical Research Centre and University College London have found that gene therapy improved visual acuity and preserved retinal structure in young children with AIPL1-associated severe retinal dystrophy. This is the first human trial of gene supplementation therapy targeting this condition.
Retinal dystrophy caused by biallelic variants in the AIPL1 gene leads to severe visual impairment from birth, with progressive degeneration and limited treatment options. Previous studies of early-onset rod-cone dystrophies, including AIPL1-related forms, highlighted a critical window for intervention during early childhood, when some photoreceptor structure remains intact. Prior research using Aipl1-deficient mouse models and human retinal organoids demonstrated partial restoration of photoreceptor function through gene therapy.
In the study, "Gene therapy in children with AIPL1-associated severe retinal dystrophy: an open-label, first-in-human interventional study," published in The Lancet, researchers administered a single subretinal injection of a recombinant adeno-associated viral vector (rAAV8.hRKp.AIPL1) carrying the AIPL1 gene to one eye of each child to assess the safety and efficacy of gene supplementation therapy in improving visual function and preserving retinal structure.
Four children aged 1.0 to 2.8 years with confirmed AIPL1 mutations received a subretinal injection of rAAV8.hRKp.AIPL1 in one eye. The gene therapy vector, produced under UK regulatory approval, delivered the AIPL1 coding sequence using a human rhodopsin kinase promoter. Oral prednisolone was administered perioperatively to mitigate inflammation. Visual acuity, functional vision, retinal structure, and cortical responses were evaluated over a mean follow-up of 3.5 years.
Scientists in the UK have successfully used gene therapy to restore some vision to legally blind children with an inherited retinal condition. All 11 children in the clinical trial saw improvements within weeks of a single surgical treatment.
The children were all born with a form of severe retinal dystrophy called LCA4, leaving them with only a limited ability to perceive light. This form of the disease is caused by mutations in the AIPL1 gene, which results in deficiencies of the protein of the same name. This protein plays a key role in converting light into electrical signals that the brain can interpret.
In the study, the children received a gene therapy targeting AIPL1 delivered directly into their retina. Four weeks after their treatment, their vision was evaluated using a range of tests, including following a pen light, moving crayons between cups, locating white objects on a dark background, and navigating a corridor. Retinal structure and brain activity in response to light was also measured.
And sure enough, all 11 children treated so far have seen “meaningful responses” to the therapy. They were all between one and four years old at time of treatment, and their progress has been followed for three to four years since.
Stem cell therapy trial reverses "irreversible" damage to cornea
By Michael Irving
March 08, 2025
Eye injuries that damage the cornea are usually irreversible and cause blindness. But a new clinical trial has repaired this damage in patients thanks to a transplant of stem cells from their healthy eyes.
The cornea is the outer layer of the eye, which focuses light towards the retina. Since it’s on the frontline of potential hazards from the outside world, the cornea features a population of limbal epithelial stem cells, which repair minor damage to keep the surface smooth and functional.
Unfortunately, injuries like thermal or chemical burns can damage the cornea beyond the capability of these resident stem cells. There’s not much else that can be done – even a cornea transplant won’t take hold if the damage is too severe.
CRISPR cuts gene from head and neck cancers through direct injection—50% of tumors eliminated in animal models
by Tel-Aviv University
https://medicalxpress.com/news/2025-03- ... umors.html
Researchers from Tel Aviv University utilized CRISPR to cut a single gene from cancer cells of head and neck tumors—and successfully eliminated 50% of the tumors in model animals. This study was led by Dr. Razan Masarwy, MD, Ph.D. from the lab of Prof. Dan Peer. The findings are published in the journal Advanced Science.
The research team says, "Until now, CRISPR wasn't used for cancer because it was assumed that knocking out a single gene wouldn't topple the whole structure. We demonstrate that some genes are absolutely essential for cancer cell survival, making them excellent targets for CRISPR therapy."
"Head and neck cancers are very common, ranking fifth in cancer mortality," says Prof. Peer. "These are localized cancers, typically starting in the tongue, throat, or neck, which can later metastasize. If detected early, localized treatment can effectively target the tumor. Our aim was to use genetic editing of a single gene expressed in this type of cancer to collapse the entire pyramid of the cancerous cell. This gene is the cancer-specific SOX2, also expressed in other types of cancer, and overexpressed in these particular tumors."
Swedish researchers have identified genetic variants that increase the risk of atherosclerosis. The aim is for these new findings to enable earlier detection of atherosclerosis and improved treatment of cardiovascular diseases such as heart attack and stroke.
The study, published in the journal Nature Communications, represents the largest gene mapping of atherosclerosis using advanced diagnostic imaging to date. The researchers behind the study are based at universities and university hospitals throughout Sweden.
Atherosclerosis is the disease process that causes plaque to form in the blood vessels supplying the body's organs with blood. These accumulations of plaque grow over time and can form clots that cause a sudden stop in the blood supply.
If this happens in the coronary arteries of the heart, the heart muscle suffers acute oxygen deprivation, causing a heart attack. If it occurs with plaque formed in the carotid arteries, the clot can be carried by the blood to the brain and cause a stroke.
A recent study led by the UAB demonstrates the potential of gene therapy to restore motor capacity in an ultra-rare disease, megalencephalic leukoencephalopathy with subcortical cysts (MLC), even when treatment begins after symptom onset.
MLC is a rare childhood neurological disorder that primarily affects the brain's white matter. It is characterized by macrocephaly, impaired motor coordination, and epilepsy, among other symptoms. More than 75% of diagnosed cases are caused by mutations in the MLC1 gene, which encodes a protein located in the membrane of a type of brain cell called astrocyte. This protein plays a key role in regulating water and ion balance in the brain, but its exact function is still not well understood.
