Gene therapy for CNS disorders: modalities, delivery and translational challenges.

Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.

Non-TGFß profibrotic signaling in ulcerative colitis after in vivo experimental intestinal injury in humans.

Although impaired regeneration is important in many gastrointestinal diseases including ulcerative colitis (UC), the dynamics of mucosal regeneration in humans are poorly investigated. We have developed a model to study these processes in vivo in humans. Epithelial restitution (ER) and extracellular matrix (ECM) regulation after an experimental injury of the sigmoid colonic mucosa was assessed by repeated high-resolution endoscopic imaging, histological assessment, RNA sequencing, deconvolution analysis, and 16S rDNA sequencing of the injury niche microbiome of 19 patients with UC in remission and 20 control subjects. Human ER had a 48-h lag before induction of regenerative epithelial cells [wound-associated epithelial (WAE) and transit amplifying (TA) cells] along with the increase of fibroblast-derived stem cell growth factor gremlin 1 mRNA (GREM1). However, UC deconvolution data showed rapid induction of inflammatory fibroblasts and upregulation of major structural ECM collagen mRNAs along with tissue inhibitor of metalloproteinase 1 (TIMP1), suggesting increased profibrotic ECM deposition. No change was seen in transforming growth factor ß (TGFß) mRNA, whereas the profibrotic cytokines interleukin 13 (IL13) and IL11 were upregulated in UC, suggesting that human postinjury responses could be TGFß-independent. In conclusion, we found distinct regulatory layers of regeneration in the normal human colon and a potential targetable profibrotic dysregulation in UC that could lead to long-term end-organ failure, i.e., intestinal damage.NEW & NOTEWORTHY The study reveals the regulatory dynamics of epithelial regeneration and extracellular matrix remodeling after experimental injury of the human colon in vivo and shows that human intestinal regeneration is different from data obtained from animals. A lag phase in epithelial restitution is associated with induction of stromal cell-derived epithelial growth factors. Postinjury regeneration is transforming growth factor ß-independent, and we find a profibrotic response in patients with ulcerative colitis despite being in remission.

Precise modulation and use of reactive oxygen species for immunotherapy.

Reactive oxygen species (ROS) play an important role in regulating the immune system by affecting pathogens, cancer cells, and immune cells. Recent advances in biomaterials have leveraged this mechanism to precisely modulate ROS levels in target tissues for improving the effectiveness of immunotherapies in infectious diseases, cancer, and autoimmune diseases. Moreover, ROS-responsive biomaterials can trigger the release of immunotherapeutics and provide tunable release kinetics, which can further boost their efficacy. This review will discuss the latest biomaterial-based approaches for both precise modulation of ROS levels and using ROS as a stimulus to control the release kinetics of immunotherapeutics. Finally, we will discuss the existing challenges and potential solutions for clinical translation of ROS-modulating and ROS-responsive approaches for immunotherapy, and provide an outlook for future research.

A Virus-Inspired Inhalable Liponanogel Induces Potent Antitumor Immunity and Regression in Metastatic Lung Tumors.

Pulmonary delivery of immunostimulatory agents such as poly(I:C) to activate double-stranded RNA sensors MDA5 and RIG-I within lung-resident antigen-presenting cells is a potential strategy to enhance antitumor immunity by promoting type I interferon secretion. Nevertheless, following pulmonary delivery, poly(I:C) suffers from rapid degradation and poor endosomal escape, thus limiting its potency. Inspired by the structure of a virus that utilizes internal viral proteins to tune the loading and cytosolic delivery of viral nucleic acids, we developed a liponanogel (LNG)-based platform to overcome the delivery challenges of poly(I:C). The LNG comprised an anionic polymer hyaluronic acid-based nanogel core coated by a lipid shell, which served as a protective layer to stabilize the nanogel core in the lungs. The nanogel core was protonated within acidic endosomes to enhance the endosomal membrane permeability and cytosolic delivery of poly(I:C). After pulmonary delivery, LNG-poly(I:C) induced 13.7-fold more IFNß than poly(I:C) alone and two-fold more than poly(I:C) loaded in the state-of-art lipid nanoparticles [LNP-poly(I:C)]. Additionally, LNG-poly(I:C) induced more potent CD8+ T-cell immunity and stronger therapeutic effects than LNP-poly(I:C). The combination of LNG-poly(I:C) and PD-L1 targeting led to regression of established lung metastases. Due to the ease of manufacturing and the high biocompatibility of LNG, pulmonary delivery of LNG may be broadly applicable to the treatment of different lung tumors and may spur the development of innovative strategies for cancer immunotherapy. Significance: Pulmonary delivery of poly(I:C) with a virus-inspired inhalable liponanogel strongly activates cytosolic MDA5 and RIG-I and stimulates antitumor immunity, representing a promising strategy for safe and effective treatment of metastatic lung tumors.

A Pressure-Sensitive, Repositionable Bioadhesive for Instant, Atraumatic Surgical Application on Internal Organs.

Pressure-sensitive adhesives are widely utilized due to their instant and reversible adhesion to various dry substrates. Though offering intuitive and robust attachment of medical devices on skin, currently available clinical pressure-sensitive adhesives do not attach to internal organs, mainly due to the presence of interfacial water on the tissue surface that acts as a barrier to adhesion. In this work, a pressure-sensitive, repositionable bioadhesive (PSB) that adheres to internal organs by synergistically combining the characteristic viscoelastic properties of pressure-sensitive adhesives and the interfacial behavior of hydrogel bioadhesives, is introduced. Composed of a viscoelastic copolymer, the PSB absorbs interfacial water to enable instant adhesion on wet internal organs, such as the heart and lungs, and removal after use without causing any tissue damage. The PSB's capabilities in diverse on-demand surgical and analytical scenarios including tissue stabilization of soft organs and the integration of bioelectronic devices in rat and porcine models, are demonstrated.

A Mechanically Resilient Soft Hydrogel Improves Drug Delivery for Treating Post-Traumatic Osteoarthritis in Physically Active Joints.

Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in early post-traumatic osteoarthritis (PTOA) when symptoms are minimal and patients are physically active. DMOAD delivery systems therefore must withstand repeated mechanical loading without affecting the drug release kinetics. Although soft materials are preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt drug release. Here, we report a mechanically resilient soft hydrogel that rapidly self-heals under conditions resembling human running while maintaining sustained release of the cathepsin-K inhibitor L-006235 used as a proof-of-concept DMOAD. Notably, this hydrogel outperformed a previously reported hydrogel designed for intra-articular drug delivery, used as a control in our study, which neither recovered nor maintained drug release under mechanical loading. Upon injection into mouse knee joints, the hydrogel showed consistent release kinetics of the encapsulated agent in both treadmill-running and non-running mice. In a mouse model of aggressive PTOA exacerbated by treadmill running, L-006235 hydrogel markedly reduced cartilage degeneration. To our knowledge, this is the first hydrogel proven to withstand human running conditions and enable sustained DMOAD delivery in physically active joints, and the first study demonstrating reduced disease progression in a severe PTOA model under rigorous physical activity, highlighting the hydrogel's potential for PTOA treatment in active patients.