ASNTR 2023 Abstracts

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TL;DR

This collection of ASNTR 2023 abstracts presents a broad survey of preclinical research in neural repair and regeneration, spanning cell transplantation, gene therapy, and pharmacological approaches for conditions including spinal cord injury, stroke, Parkinson's disease, Alzheimer's disease, and traumatic brain injury. Key themes include the use of induced pluripotent stem cells (iPSCs) for cell replacement and drug delivery, targeting glial cells (astrocytes and microglia) to modulate neuroinflammation, and employing chemogenetic and optogenetic tools to control neural circuit activity. The findings collectively advance the translational pipeline for regenerative neurology, with several studies reporting functional recovery in animal models and early-stage clinical trial data.

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**Background:** The American Society for Neural Therapy and Repair (ASNTR) 2023 abstracts represent the current state of preclinical and early clinical research in neural repair and regeneration. The field is characterized by a convergence of advanced technologies—including induced pluripotent stem cells (iPSCs), CRISPR/Cas9 gene editing, chemogenetics, bioluminescent optogenetics, and advanced biomaterials—to address the limited regenerative capacity of the central nervous system (CNS). Major therapeutic targets include spinal cord injury (SCI), stroke, traumatic brain injury (TBI), Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and other neurodegenerative conditions. A unifying theme is the recognition that glial cells (astrocytes, microglia, and oligodendrocytes) are not passive bystanders but active participants in both injury and repair, making them critical therapeutic targets.

**Methods:** The abstracts employ a wide array of experimental models and techniques. For spinal cord injury, multiple groups use cervical contusion or hemisection models in rats and mice, assessing respiratory function via diaphragm electromyography and motor recovery through locomotor scores. Cell transplantation strategies include iPSC-derived neural progenitors (iNPCs), glial-enriched progenitor cells (hiPSC-GEPs), and engineered spinal interneurons (SpINs), often combined with growth factor delivery (e.g., GDNF, BDNF, VEGF). Gene therapy approaches utilize AAV vectors for targeted delivery of neurotrophic factors, chemogenetic receptors (e.g., hM4Di), or proneural transcription factors (e.g., NeuroD1). Stroke models include photothrombotic and middle cerebral artery occlusion (MCAO) in rodents, with outcomes measured by behavioral tasks (grid-walking, cylinder task) and immunohistochemistry for neurogenesis, angiogenesis, and gliosis. TBI models employ controlled cortical impact (CCI) in mice, assessing sustained attention via the 3-choice serial reaction time task (3-CSRT) and motor function via rotarod and beam walk. Parkinson's disease models include 6-OHDA and MPTP lesioning, as well as AAV-mediated alpha-synuclein overexpression, with outcomes measured by tyrosine hydroxylase (TH) staining and behavioral tests. Alzheimer's disease research utilizes transgenic mouse models (e.g., 5xFAD, PS19) and human iPSC-derived cortical neurons, examining amyloid-beta aggregation, tau pathology, and electrophysiological function via patch clamp and microelectrode arrays (MEAs).

**Key Results:** Several studies report significant therapeutic benefits. In SCI, transplantation of iPSC-derived pre-motor spinal interneurons into the injured cervical cord resulted in anatomical and functional integration, with optogenetic activation demonstrating donor-host connectivity and improved diaphragm activity. AAV-mediated delivery of integrin alpha9 and kindlin-1 to dorsal root ganglia promoted robust sensory axon regeneration after dorsal column crush, with approximately 40% of axons regenerating at least 4 cm above the lesion, accompanied by significant improvement in mechanical and thermal sensation. In stroke, a thermoresponsive hydrogel (F6) delivering BDNF and VEGF improved motor function more rapidly than either factor alone, while also reducing reactive astrogliosis and microgliosis and promoting neurogenesis and angiogenesis. In TBI, chronic administration of the alpha7 nicotinic acetylcholine receptor positive allosteric modulator NS-1738, particularly when combined with environmental enrichment, improved sustained attention and reduced systemic inflammation, effects that were blocked by the antagonist methyllycaconitine (MLA). In PD, ablation of microglia using the CSF1R inhibitor PLX5622 in the subacute MPTP model was protective against loss of striatal DA fiber density and DA neurons in the substantia nigra, and this protection was associated with reduced CXCL10 levels. In AD, treatment with iPSC-derived mononuclear phagocytes (iMPs) significantly improved spatial working memory and hippocampus-dependent short-term memory in both aging and 5xFAD mice, while also restoring synaptic transporter VGLUT1 expression and modulating neuroinflammation. A clinical trial (DBS-Plus) involving 68 PD participants who received autologous peripheral nerve tissue grafts to the substantia nigra during deep brain stimulation surgery reported safety and feasibility, with a significant decrease in UPDRS III scores (−8.8 points, 95% CI: −11.8 to −5.9, P < .0001) compared with historical controls.

**Clinical Implications:** The findings across these abstracts have substantial translational potential. The successful integration of transplanted human iPSC-derived interneurons with injured spinal circuits provides a strong rationale for advancing cell therapies for SCI. The demonstration that AAV-mediated gene therapy can achieve long-distance sensory axon regeneration offers a new avenue for restoring sensation after spinal cord injury. The use of injectable hydrogels for sustained local delivery of neurotrophic factors represents a clinically feasible strategy for stroke recovery. The combination of pharmacotherapy with environmental enrichment in TBI models mirrors clinical rehabilitation paradigms and supports the development of multimodal treatment protocols. The neuroprotective effects of microglial modulation in PD models suggest that targeting neuroinflammation could be a disease-modifying strategy. The positive safety and efficacy signals from the DBS-Plus clinical trial in PD are particularly encouraging, as they demonstrate the feasibility of combining cell-based repair with standard-of-care neuromodulation. Overall, these studies highlight a shift toward more sophisticated, combinatorial, and clinically informed approaches to neural repair, moving the field closer to effective treatments for currently incurable neurological conditions.