About

Michael Castle is an Assistant Professor In Residence in the Neurosciences School at UC San Diego, located at 9500 Gilman Drive, La Jolla, CA 92093. His research focuses on neural stem cell transplantation to restore forelimb function in primates with spinal cord injury, as evidenced by his publications in high-impact journals such as Nature Biotechnology. His work involves the development and application of gene transfer techniques, particularly using adeno-associated virus (AAV) vectors, to study and promote neural regeneration and repair. Castle's contributions include extensive research on the mechanisms of axonal transport of AAV serotypes, the development of targeted gene delivery methods in the nervous system, and the investigation of gene therapy approaches for neurological conditions such as Alzheimer's disease. His research integrates molecular biology, gene therapy, and neural circuit targeting, with a focus on translating these findings into therapeutic strategies for neural injuries and neurodegenerative diseases.

Research topics

• Biology
• Neuroscience
• Genetics
• Computer Science
• Artificial Intelligence
• Engineering
• Medicine
• Statistical physics
• Quantum mechanics
• Acoustics
• Internal medicine
• Cell biology
• Electrical engineering
• Physics

Selected publications

• AAV2retro Enters Axons of Passage and Extensively Transduces Corticospinal Neurons After Injection into Spinal White Matter

  Brain Sciences · 2025-09-28

  articleOpen accessSenior authorCorresponding

  BACKGROUND: Adult neurons in the central nervous system often fail to regenerate after spinal cord injury (SCI). Regenerative gene therapies could potentially promote corticospinal axon regeneration, restoration of motor circuitry, and functional improvement after SCI, but translational methods for targeted gene delivery to corticospinal neurons are needed. AAV2retro is an engineered variant of the adeno-associated virus 2 (AAV2) capsid that demonstrates greatly enhanced retrograde transduction of projection neurons. When injected into spinal gray matter, AAV2retro retrogradely transduces neurons in the sensorimotor cortex that project to the injected spinal level. METHODS: We initially hypothesized that injection of AAV2retro into the dorsal column white matter immediately rostral of a mouse cervical spinal injury would target transected axons and broadly transduce both forelimb and hindlimb corticospinal neurons. We tested this hypothesis by comparing four groups of mice treated with AAV2retro carrying the tdTomato reporter gene by (1) injection into intact C4 gray matter, (2) injection into intact C4 dorsal column white matter, (3) injection into C4 gray matter bordering a C5 dorsal column lesion, and (4) injection into C4 dorsal column white matter bordering a C5 dorsal column lesion. RESULTS: After injection of AAV2retro into intact C4 dorsal column white matter, we observed extensive transduction of corticospinal neurons throughout both the forelimb and hindlimb sensorimotor cortical regions, and large numbers of transduced hindlimb corticospinal axons in the lumbar spinal cord. Dorsal column injections did not detectably damage the white matter beyond a narrow injection track. In contrast, after injection of intact C4 gray matter, we observed minimal labeling of neurons in the hindlimb sensorimotor cortex or corticospinal axons in the lumbar spinal cord. CONCLUSIONS: We conclude that AAV2retro can enter axons of passage in the dorsal column white matter of the spinal cord, and that injecting the cervical dorsal columns can efficiently target both forelimb and hindlimb corticospinal neurons in mice. This new approach for targeted gene delivery to corticospinal neurons could improve the safety and specificity of regenerative gene therapies for spinal cord injury.

  PublisherOA PDFDOI

• Thiorphan reprograms neurons to promote functional recovery after spinal cord injury

  Nature · 2025-10-29 · 6 citations

  articleOpen access

  Abstract We previously identified an embryonic shift in the corticospinal motor neuronal transcriptome after spinal cord injury associated with successful axonal regeneration 1 . Exploiting this transcriptional regenerative ‘signature’, here we used in silico screens to identify small molecules that generate similar shifts in the transcriptome, and identified thiorphan—a neutral endopeptidase inhibitor—as a lead candidate. In a new adult motor cortex neuronal in vitro screen 2 , thiorphan increased neurite outgrowth 1.8-fold ( P < 0.001). We then infused thiorphan into the central nervous system beginning 2 weeks after severe C5 spinal cord contusions and, when combined with a neural stem cell graft, thiorphan elicited significant improvements in forelimb function ( P < 0.005) and corticospinal regeneration ( P < 0.05). Extending clinical relevance, thiorphan significantly increased neurite outgrowth in primary cortical neuronal cultures from a 56-year-old human. These findings represent a new path for drug discovery, starting from in silico screens to proof-of-concept in adult human brain cultures.

  PublisherOA PDFDOI

• Extensive restoration of forelimb function in primates with spinal cord injury by neural stem cell transplantation

  Nature Biotechnology · 2025-11-17 · 2 citations

  articleOpen access
  PublisherOA PDFDOI

• Synthetic Mechanical Lattices with Synthetic Interactions

  arXiv (Cornell University) · 2021

  • Computer Science
  • Computer Science
  • Physics

  Metamaterials based on mechanical elements have been developed over the past decade as a powerful platform for exploring analogs of electron transport in exotic regimes that are hard to produce in real materials. In addition to enabling new physics explorations, such developments promise to advance the control over acoustic and mechanical metamaterials, and consequently to enable new capabilities for controlling the transport of sound and energy. Here, we demonstrate the building blocks of highly tunable mechanical metamaterials based on real-time measurement and feedback of modular mechanical elements. We experimentally engineer synthetic lattice Hamiltonians describing the transport of mechanical energy (phonons) in our mechanical system, with control over local site energies and loss and gain as well as control over the complex hopping between oscillators, including a natural extension to non-reciprocal hopping. Beyond linear terms, we experimentally demonstrate how this measurement-based feedback approach opens the window to independently introducing nonlinear interaction terms. Looking forward, synthetic mechanical lattices open the door to exploring phenomena related to topology, non-Hermiticity, and nonlinear dynamics in non-standard geometries, higher dimensions, and with novel multi-body interactions.

  PublisherDOI

• Intersectional targeting of defined neural circuits by adeno‐associated virus vectors

  Journal of Neuroscience Research · 2020 · 19 citations

  Senior authorCorresponding
  • Neuroscience
  • Biology
  • Cell biology

  The mammalian nervous system is a complex network of interconnected cells. We review emerging techniques that use the axonal transport of adeno-associated virus (AAV) vectors to dissect neural circuits. These intersectional approaches specifically target AAV-mediated gene expression to discrete neuron populations based on their axonal connectivity, including: (a) neurons with one defined output, (b) neurons with one defined input, (c) neurons with one defined input and one defined output, and (d) neurons with two defined inputs or outputs. The number of labeled neurons can be directly controlled to trace axonal projections and examine cellular morphology. These approaches can precisely target the expression of fluorescent reporters, optogenetic ion channels, chemogenetic receptors, disease-associated proteins, and other factors to defined neural circuits in mammals ranging from mice to macaques, and thereby provide a powerful new means to understand the structure and function of the nervous system.

  PublisherOA PDFDOI

• Postmortem Analysis in a Clinical Trial of AAV2-NGF Gene Therapy for Alzheimer's Disease Identifies a Need for Improved Vector Delivery

  Human Gene Therapy · 2020 · 116 citations

  1st authorCorresponding
  • Neuroscience
  • Medicine
  • Biology

  vector genomes of AAV2-NGF by stereotactic injection of the nucleus basalis of Meynert. After a mean survival of 4.0 years, AAV2-NGF targeting, spread, and expression were assessed by immunolabeling of NGF and the low-affinity NGF receptor p75 at 15 delivery sites in 3 autopsied patients. NGF gene expression persisted for at least 7 years at sites of AAV2-NGF injection. However, the mean distance of AAV2-NGF spread was only 0.96 ± 0.34 mm. NGF did not directly reach cholinergic neurons at any of the 15 injection sites due to limited spread and inaccurate stereotactic targeting. Because AAV2-NGF did not directly engage the target cholinergic neurons, we cannot conclude that growth factor gene therapy is ineffective for AD. Upcoming clinical trials for AD will utilize real-time magnetic resonance imaging guidance and convection-enhanced delivery to improve the targeting and spread of growth factor gene delivery.

  PublisherOA PDFDOI

• In Situ Hybridization for Detection of AAV-Mediated Gene Expression

  Methods in molecular biology · 2019-01-01 · 8 citations

  articleOpen access
  PublisherOA PDFDOI

• O5‐06‐05: IMPROVED INTRATHECAL VECTOR DELIVERY FOR GENE THERAPY IN ALZHEIMER'S DISEASE

  Alzheimer s & Dementia · 2019-07-01

  article1st authorCorresponding

  There are several promising gene therapies for Alzheimer's disease (AD), including growth factors, proteolytic enzymes, anti-inflammatory genes, and anti-tau or anti-amyloid antibodies. Effective treatment of the cerebral cortex is essential for therapeutic gene delivery in AD. The human cortex is extensively folded, with a total surface area of approximately five square feet, and methods to broadly transduce the cortex by direct intraparenchymal injection do not currently exist. Intrathecal administration of adeno-associated virus 9 (AAV9) to the cerebrospinal fluid (CSF) drives gene expression throughout the nervous system, but gene transfer to the cortex is inconsistent in rodents and monkeys. Following intrathecal AAV9 infusion in rats, we observed gene expression in brain regions where CSF appears to settle under gravity. We hypothesized that inverting rats with feet 30 degrees above the head, as well as rotating rats continuously between upright and inverted positions, for 2 hours after intrathecal AAV9 infusion would enhance cortical gene delivery. Both inversion and rotation significantly increased the number of transduced neurons by more than 15-fold compared to rats that recovered in an upright position. In addition to entorhinal, prefrontal, frontal, parietal, and limbic cortices, transduction of hippocampus and of basal forebrain were also enhanced by more than 15-fold. 95% of transduced cells were neurons. This simple and effective method for broad gene transfer to cerebral cortex and basal forebrain represents a potentially important advance in gene therapy for AD.

  PublisherDOI

• Adeno-Associated Virus Vectors: Design and Delivery

  2019-01-01 · 3 citations

  article1st authorCorresponding
  PublisherDOI

• P2‐027: TARGET ENGAGEMENT IN A PHASE II CLINICAL TRIAL OF AAV2‐NGF GENE THERAPY FOR ALZHEIMER'S DISEASE

  Alzheimer s & Dementia · 2018-07-01 · 1 citations

  article1st authorCorresponding

  Cholinergic neurons of the basal forebrain degenerate in Alzheimer's disease (AD), contributing to declines in cognitive function. Nerve Growth Factor (NGF) stimulates cholinergic neurons and prevents neuronal death, representing a candidate neuroprotective therapy in AD. We recently completed a Phase II, multi-center, placebo-controlled trial of NGF gene delivery (AAV2-NGF) into the brain in 49 AD patients. After two years, gene delivery was safe but did not detectably improve cognitive outcomes. Brains from three study patients have become available, allowing analysis of accuracy of gene delivery, persistence of gene expression, and target engagement. AAV2-NGF was injected into three sites per side of the brain, bilaterally targeting cholinergic neurons of the nucleus basalis of Meynert (nbM), which extend cholinergic axons to the cortex. Total vector dose was 2x1011 vector genomes. NGF expression and spread were measured by NGF and p75 receptor immunolabeling. 5 brain halves were examined. NGF was expressed in all patients. The mean diameter of NGF spread from each injection site was 0.92±0.38 mm; this was less than predicted from preclinical studies. The mean distance between the zone of NGF expression and neurons of the nbM was 1.89±1.00 mm. NGF failed to directly spread to the nbM at any site. Nonetheless, cholinergic axons were detectable in the injection sites, suggesting partial access of nbM neurons to NGF, despite a lack of direct NGF spread to the neurons. AAV2-NGF failed to spread directly into the nbM in this study, limiting the ability to draw conclusions regarding the efficacy of trophic support in reducing cognitive decline in AD. Both the distance of NGF spread and the proximity of the needle tip to nbM were less than expected. Based on these findings, we have developed new methods for gene delivery into the brain, using: 1) MR-guided injections to ensure precise needle placement, 2) convection enhanced delivery of AAV2 to increase vector spread, and 3) co-infusion of gadoteridol with AAV2 to confirm vector targeting and spread at the time of gene delivery. Upcoming BDNF trials in AD will employ this technology.

  PublisherDOI

Frequent coauthors

• John H. Wolfe

  University of Pennsylvania

  15 shared

• Mark H. Tuszynski

  University of California, San Diego

  7 shared

• Albert M. Maguire

  Children's Hospital of Philadelphia

  6 shared

• Jean Bennett

  University of Pennsylvania

  6 shared

• Cassia N. Cearley

  5 shared

• Luk H. Vandenberghe

  Smith-Kettlewell Eye Research Institute

  5 shared

• April R. Giles

  Regenxbio (United States)

  4 shared

• Eran Perlson

  4 shared

Labs

• Michael Castle | UCSD ProfilesPI

Education

• Ph.D., Neurosciences

  University of California, San Diego

  2015

• B.S., Neuroscience

  University of California, San Diego

  2010