Disease-directed engineering for physiology-driven treatment interventions in neurological disorders

Abstract

Neurological disease is killing us. While there have long been attempts to develop therapies for both acute and chronic neurological diseases, no current treatments are curative. Additionally, therapeutic development for neurological disease takes 15 years and often costs several billion dollars. More than 96% of these therapies will fail in late stage clinical trials. Engineering novel treatment interventions for neurological disease can improve outcomes and quality of life for millions; however, therapeutics should be designed with the underlying physiology and pathology in mind. In this perspective, we aim to unpack the importance of, and need to understand, the physiology of neurological disease. We first dive into the normal physiological considerations that should guide experimental design, and then assess the pathophysiological factors of acute and chronic neurological disease that should direct treatment design. We provide an analysis of a nanobased therapeutic intervention that proved successful in translation due to incorporation of physiology at all stages of the research process. We also provide an opinion on the importance of keeping a high-level view to designing and administering treatment interventions. Finally, we close with an implementation strategy for applying a disease-directed engineering approach. Our assessment encourages embracing the complexity of neurological disease, as well as increasing efforts to provide system-level thinking in our development of therapeutics for neurological disease.

Variability and sex-dependence of hypothermic neuroprotection in a rat model of neonatal hypoxic–ischaemic brain injury: a single laboratory meta-analysis

“…To increase the likelihood of successful translation, any promising therapy would then be repeated using larger groups sizes and long-term pathological and behavioural assessments 27,55 , ideally in multiple laboratories. This would then inform work in larger animals such at the piglet or fetal sheep 73 . As the pipeline applied to promising therapies for term neonatal HIE is fairly robust, one of the most important areas for development is the implementation of significantly robust studies in rodents such that later work in larger models is focused on the most promising therapies.…”

Nanoparticle‐microglial interaction in the ischemic brain is modulated by injury duration and treatment

“…78 function or exacerbate damage. [80][81][82] Given that ischemic injury manifests in regional patterns in multiple phases, 83,84…”

“…Due to the intricate balance of pro‐ and anti‐inflammatory activity in the brain microenvironment after disease, region specific control can also reduce over‐scavenging of ROS or excessive inhibition of inflammatory processes that could interrupt healthy cellular function or exacerbate damage 80‐82 . Given that ischemic injury manifests in regional patterns in multiple phases, 83,84 the continued investigation of regional variations in the brain could inform therapeutic strategies that are highly advantageous in combating immediate and ongoing regionally‐dependent disease sequelae.…”

Nanotherapeutic modulation of excitotoxicity and oxidative stress in acute brain injury

“…As with the majority of putative therapies developed for treating neurological disorders, any lack of success in the clinical setting could potentially be determined earlier by developing an adequate preclinical pipeline. 178 This was the goal of the STAIR (Stroke Therapy Academic Industry Roundtable) criteria when they were developed more than two decades ago. To fully meet the criteria, a therapy had to be successfully tested: i) in two or more laboratories, ii) in two or more species, iii) in animals at a disease-appropriate life stage, iv) in both sexes, v) in both temporary and permanent models of ischemia, vi) at least 1 hour after reperfusion, vii) at two or more doses, viii) using a clinically relevant mode of delivery, ix) using both histological and behavioral outcomes, and x) with outcomes at least 4 weeks after injury.…”

“…Unfortunately, these criteria, as well as the ARRIVE (Animal Research: Reporting of In Vivo Experiments) criteria for design and reporting of preclinical studies, are still rarely applied today. 178 In addition to these criteria, any use of nanotechnology to transport therapeutic cargo must also include the necessary controls to account for the nanoparticle vehicle and any component of the nanoparticle that could result in toxicity, off-site effects, or added therapeutic benefit. For nanoparticles encapsulating a therapeutic, this typically involves adding treatment groups for the empty nanoparticle and the free drug.…”