Periodic Reporting for period 1 - SynMech (A synaptic mechanogenetic technology to repair brain connectivity)
Periodo di rendicontazione: 2023-02-01 al 2024-01-31
SynMech aims to develop a mechanogenetic technology to regulate functional connectivity of neural circuits. The goal is to demonstrate its potential for therapeutic purposes in high-prevalence treatment-resistant brain disorders, such as epilepsy and stroke.
Epilepsy affects 50 million individuals worldwide, over 20% of them experiencing seizures despite receiving optimal medical treatment. Focal neocortical epilepsy is frequently drug-resistant; the most successful intervention for this type of epilepsy remains surgical resection. However, this approach is only viable in cases where the epileptogenic zone is located at a sufficient distance from eloquent cortex areas - regions whose removal would result in the loss of sensory processing, linguistic ability, or paralysis.
Globally, thirteen million strokes occur annually, leading to enduring deficits for the majority of survivors. Present treatments involve intravenous tissue plasminogen activator for clot breakdown and intra-arterial thrombectomy, but their effectiveness is limited to less than 10% of patients due to the strict time frame for administration following ischemic stroke onset. Despite the application of neuro-rehabilitative practices, a significant portion of stroke survivors faces persistent functional loss, with incomplete recovery over time.
Current clinical methods involving electrical and magnetic stimulation to mitigate seizures or facilitate recovery post-stroke broadly impact both excitatory and inhibitory neurons in the targeted region, resulting in generally limited effectiveness. Recent developments in preclinical optogenetic and gene therapy approaches, aimed at specific neuron types, hold potential for modulating network excitability in conditions like epilepsy and stroke. However, there are challenges hindering the translation of these strategies into human therapies, such as the requirement for invasive implants in optogenetics and the inability to fine-tune current gene therapy methods based on individual patient responses.
Mechanogenetics is an emerging field in health science seeking to modulate neural networks by integrating the benefits of optogenetics and magneto-mechanical stimulations. Like optogenetics, it employs targeted actuators to achieve circuit specificity but leverages magnetic fields to remotely stimulate the brain, eliminating the necessity for invasive brain implants.
While possessing robust theoretical foundations and showing encouraging experimental outcomes, the application of mechanogenetics to rectify a malfunctioning brain remains elusive as of now. Technological challenges related to spatial resolution and in vivo implementation hinder our current ability to achieve this goal.
SynMech presents a novel approach involving functionalized biocompatible magnetic nanoparticles and bioengineered synaptic mechanosensors. These elements synergistically integrate at targeted synaptic connections to bidirectionally regulate brain circuit connectivity in response to focused magnetic fields delivered through high-permeability transcranial magnetic stimulators. By hijacking the signaling pathways associated with synaptic mechanosensors, SynMech endeavors to induce a sustained normalization of neural circuit activity beyond the duration of the therapeutic intervention.
Synaptic mechanogenetics presents an appealing avenue for addressing brain disorders marked by localized connectivity issues necessitating intense and time-sensitive therapeutic interventions following a significant brain injury. This is particularly relevant for drug-resistant focal epilepsy cases where surgery is not advisable and for stroke patients whose long-term functional recovery is notably influenced within the initial 1-3 months after the stroke event. Importantly, SynMech strategy for focal epilepsy does not rule out the possibility of surgical resection of the epileptogenic zone. Instead, it provides a less invasive treatment option that, if unsuccessful, could be followed by definitive resection.
As a novel approach, the SynMech strategy inherently carries a high level of risk. However, its potential for significant gains and future medical applications is equally high, as it strives to evolve current transcranial magnetic stimulation into a technology capable of achieving precise and adjustable wireless control over brain connectivity. Specifically, SynMech technology holds the promise to bring about a paradigm shift in healthcare, transitioning from mere treatment to healing by means of a transformative solution that aims to facilitate the rewiring of dysfunctional neural circuits, potentially leading to an improvement in both the life expectancy and quality of life for patients. Ultimately, this could contribute to a reduction in overall healthcare costs, thereby impacting society on a broader scale.
Epilepsy affects 50 million individuals worldwide, over 20% of them experiencing seizures despite receiving optimal medical treatment. Focal neocortical epilepsy is frequently drug-resistant; the most successful intervention for this type of epilepsy remains surgical resection. However, this approach is only viable in cases where the epileptogenic zone is located at a sufficient distance from eloquent cortex areas - regions whose removal would result in the loss of sensory processing, linguistic ability, or paralysis.
Globally, thirteen million strokes occur annually, leading to enduring deficits for the majority of survivors. Present treatments involve intravenous tissue plasminogen activator for clot breakdown and intra-arterial thrombectomy, but their effectiveness is limited to less than 10% of patients due to the strict time frame for administration following ischemic stroke onset. Despite the application of neuro-rehabilitative practices, a significant portion of stroke survivors faces persistent functional loss, with incomplete recovery over time.
Current clinical methods involving electrical and magnetic stimulation to mitigate seizures or facilitate recovery post-stroke broadly impact both excitatory and inhibitory neurons in the targeted region, resulting in generally limited effectiveness. Recent developments in preclinical optogenetic and gene therapy approaches, aimed at specific neuron types, hold potential for modulating network excitability in conditions like epilepsy and stroke. However, there are challenges hindering the translation of these strategies into human therapies, such as the requirement for invasive implants in optogenetics and the inability to fine-tune current gene therapy methods based on individual patient responses.
Mechanogenetics is an emerging field in health science seeking to modulate neural networks by integrating the benefits of optogenetics and magneto-mechanical stimulations. Like optogenetics, it employs targeted actuators to achieve circuit specificity but leverages magnetic fields to remotely stimulate the brain, eliminating the necessity for invasive brain implants.
While possessing robust theoretical foundations and showing encouraging experimental outcomes, the application of mechanogenetics to rectify a malfunctioning brain remains elusive as of now. Technological challenges related to spatial resolution and in vivo implementation hinder our current ability to achieve this goal.
SynMech presents a novel approach involving functionalized biocompatible magnetic nanoparticles and bioengineered synaptic mechanosensors. These elements synergistically integrate at targeted synaptic connections to bidirectionally regulate brain circuit connectivity in response to focused magnetic fields delivered through high-permeability transcranial magnetic stimulators. By hijacking the signaling pathways associated with synaptic mechanosensors, SynMech endeavors to induce a sustained normalization of neural circuit activity beyond the duration of the therapeutic intervention.
Synaptic mechanogenetics presents an appealing avenue for addressing brain disorders marked by localized connectivity issues necessitating intense and time-sensitive therapeutic interventions following a significant brain injury. This is particularly relevant for drug-resistant focal epilepsy cases where surgery is not advisable and for stroke patients whose long-term functional recovery is notably influenced within the initial 1-3 months after the stroke event. Importantly, SynMech strategy for focal epilepsy does not rule out the possibility of surgical resection of the epileptogenic zone. Instead, it provides a less invasive treatment option that, if unsuccessful, could be followed by definitive resection.
As a novel approach, the SynMech strategy inherently carries a high level of risk. However, its potential for significant gains and future medical applications is equally high, as it strives to evolve current transcranial magnetic stimulation into a technology capable of achieving precise and adjustable wireless control over brain connectivity. Specifically, SynMech technology holds the promise to bring about a paradigm shift in healthcare, transitioning from mere treatment to healing by means of a transformative solution that aims to facilitate the rewiring of dysfunctional neural circuits, potentially leading to an improvement in both the life expectancy and quality of life for patients. Ultimately, this could contribute to a reduction in overall healthcare costs, thereby impacting society on a broader scale.
In the initial project year, SynMech achieved the technological advancement of expressing neuron-type specific infection for synaptic mechano-sensors, initiated the production of nanoparticles designed to selectively bind to these mechano-sensors, and progressed in the development of magnetic stimulators.
The SynMech approach, utilizing magnetic fields that can penetrate brain tissue without hindrance, is anticipated to surpass existing therapeutic paradigms. This is due to its non-reliance on the implantation of invasive devices, while simultaneously holding the potential to achieve the subcellular resolution required for addressing connectivity defects that form the basis of most brain disorders.