FDA Approves First Gene Therapy for GSDIa
The FDA has granted accelerated approval to GENGLYCOS, making it the first treatment designed to address the underlying cause of glycogen storage disease type Ia.
Ultragenyx’s AAV8-based gene therapy is approved for patients aged eight years and older. It delivers a functional copy of G6PC, the gene responsible for producing an enzyme that allows the liver to release glucose during fasting.
Without that enzyme, patients face potentially life-threatening hypoglycaemia and must consume raw cornstarch throughout the day and night. In a placebo-controlled Phase III trial involving 46 participants, GENGLYCOS significantly reduced the amount of cornstarch required after 48 weeks.
The approval is conditional on further evidence of clinical benefit. Ultragenyx will collect two years of commercial-treatment data and follow treated patients for up to 10 years. Source
Sugar-Based Freezing Method Could Broaden Access to CAR T Therapy
Freezing CAR T cells with naturally occurring sugars could allow more hospitals to administer the therapies without specialist processing immediately before treatment.
Most CAR T cells are manufactured centrally and shipped frozen to treatment centers. The dimethyl sulfoxide used to protect them must generally be removed before infusion – a step that requires specialist capabilities and can reduce cell viability.
MIT’s alternative uses electroporation to load the cells with trehalose and sucrose. Although a small amount of dimethyl sulfoxide is still required, its concentration is low enough that the cells could potentially be used directly after thawing.
More cells survived freezing and thawing with the sugar-based formulation than with the conventional method. The resulting CAR T cells also improved survival in mouse models of lymphoma and glioblastoma. Tests on mesenchymal stem cells produced similar preservation benefits, suggesting the approach could have applications beyond CAR T therapy.
The researchers now want to assess the process in hospital workflows before considering a small clinical study. Source
Ultrasound Helps CAR T Cells Recognize Solid Tumors
USC researchers have used focused ultrasound to make solid tumors visible to CAR T cells, producing substantial tumor shrinkage in preclinical models of brain and liver cancer.
Their SHIFTERS system addresses one of the principal obstacles to using CAR T-cell therapy against solid cancers: the lack of a safe and consistent target. Instead of relying on a naturally occurring tumor marker, it makes cancer cells temporarily display CD19, which existing CAR T cells are already designed to recognize.
Two conditions are required to activate the system. Low oxygen within the tumor switches on one component, while focused ultrasound supplies a second, physician-controlled signal intended to confine CD19 expression to the treated tissue.
Only 10–25 percent of tumor cells needed to display the marker to provoke wider killing, including of neighbouring cells without CD19. Source
Flexible Nanoparticle Strengthens RNA Delivery
A lipid nanoparticle developed by Nagoya University and Fujifilm has delivered both conventional mRNA and longer-lasting circular RNA, increasing mRNA activity approximately tenfold over existing carriers.
Called FL0445-LNP, the biodegradable particle contains branched lipid chains that give it the flexibility to accommodate nucleic acids with different sizes and structures. It also generated little inflammatory activity during laboratory testing.
To demonstrate its therapeutic potential, the team used the carrier to deliver genetic instructions for producing GLP-1 in mice. Both linear mRNA and capped circular RNA produced the peptide, but the circular construct showed greater functional activity.
Circular RNA resists degradation because it has no exposed ends, potentially allowing it to direct protein production for longer. Pairing it with a carrier capable of handling varied payloads could support cancer vaccines, genome editing, treatments for genetic disorders, and longer-lasting metabolic medicines, although considerable development work remains. Source
Red Blood Cells Inspire Versatile Gene-Therapy Carriers
Expired red blood cells may provide the building blocks for therapeutic carriers capable of transporting everything from proteins to whole gene-therapy viruses.
Scientists at The Ohio State University extracted lipids from the cells and used microfluidics to assemble them into extracellular vesicle-like particles. Loading the cargo as each particle formed allowed greater control over its contents and surface properties.
The carriers could conceal adeno-associated viruses from neutralizing antibodies without preventing the viruses from delivering their genetic payloads. Adding a CD47 peptide also helped the particles avoid being engulfed by macrophages.
For targeted cancer delivery, the team equipped the particles with molecules that recognize PD-L1. The modified carriers were preferentially taken up by PD-L1-positive breast cancer cells. In mice, they circulated through several organs and accumulated notably in the lungs. Source
Mitochondria Could Hold Clues to CAR T Neurotoxicity
Serious neurological reactions to CAR T-cell therapy may be intensified by malfunctioning mitochondria, according to a study, raising the possibility of treating them with repurposed medicines rather than relying solely on steroids.
UC Irvine researchers have identified mitochondrial dysfunction as a potential driver of immune effector cell-associated neurotoxicity syndrome, or ICANS. The complication can cause confusion, brain inflammation, seizures, and other potentially life-threatening symptoms.
Corticosteroids are commonly used to control the inflammation, but they can produce substantial side effects and may not address the underlying biological processes. Drugs that act on mitochondria could offer a more targeted, steroid-sparing approach.
Because several such medicines already have established safety profiles, suitable candidates might reach clinical evaluation faster than newly developed compounds. Source
Gene Therapy Reverses Inherited Heart Disease in Preclinical Models
A single injection of a healthy ALPK3 gene restored heart function in adult mice with established cardiomyopathy and corrected defective beating in heart tissue grown from patient cells.
Variants in ALPK3 disrupt the structural machinery that enables heart muscle to contract. In children, the resulting cardiomyopathy can cause abnormal rhythms, progressive heart failure, and the eventual need for transplantation.
Delivering a functional copy of the gene prevented disease in newborn mice and reversed it after symptoms had developed in adults. Normal strength and rhythm also returned in laboratory-grown “mini hearts” carrying the same genetic defect.
Unexpectedly, increasing ALPK3 also improved contraction in tissue carrying truncated TTN variants, the most common genetic cause of dilated cardiomyopathy. This raises the possibility of treating conditions caused by genes such as TTN that are too large for conventional replacement therapy. Source
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