THE JOSHI LAB
Exploring opportunities behind barriers - Brain Drug Delivery
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The pervasiveness of neurological diseases/disorders around the world can seldom be understated. Among the biggest challenges in delivering therapeutic compounds to the brain is the blood-brain barrier – the guardian of cerebral homeostasis. Our lab is interested in delivering payloads, including RNA therapeutics past this barrier by harnessing from, and innovating in, biomaterial development and their biochemical underpinnings and physiological manifestations. By careful and constructive modulation of nanoparticle surface chemistry and coating density, we were able to deliver siRNA therapeutics for the treatment of traumatic brain injury (TBI), and demonstrated 50% knockdown of Tau - a pathological protein. We continue to build on such delivery strategies, whilst continuing to improve delivery efficiency to maximize efficacy against a range of targets that are implicated in pathologies such as TBI and Alzheimer’s Disease. Ultimately, we hope to chart a strategical course that ensures maximal clinical translatability and feasibility of brain delivery platforms, thereby pushing the boundaries of the present and the future.
Marching against joint degeneration - Our work on Osteoarthritis
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Current treatments for osteoarthritis (OA) only provide symptomatic relief without modifying the disease progression. Disease-modifying osteoarthritis drugs (DMOADs) have shown promise for inhibiting or reversing OA progression in pre-clinical studies. However, their clinical translation has been limited due to short half-life in the joints. We are developing simple and scalable delivery platforms for intra-articular delivery of disease modifying small molecule drugs and gene therapies in a sustained manner. We are also interested in understanding: i) how release kinetics of disease modifying therapeutics and mechanical loading in joints affect the therapeutic efficacy, and ii) how different materials interact with different cell types within the joint. Using cues from these studies, we aim to build innovative delivery strategies that can prevent joint degeneration and can pave the way for clinical translation of promising disease modifying therapeutics.
Breathing life into innovation - Tapping into under-utilized routes
Inhalation is an attractive route to deliver therapeutics for lung diseases such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease (COPD). This pathway offers direct local delivery of drugs to the disease site, thereby speeding up action time and reducing dosage, while minimizing systemic side effects. Over the past few decades, biologics, including antibodies and RNA therapeutics have revolutionized the treatment of lung diseases. However, such biologic therapies are administered systemically, which suffers from poor penetration into the lungs and can potentially result in systemic side effects. Our uniquely engineered inhalable platforms therefore have the potential to ‘be a fresh breath’, allowing for precise delivery of biologics to specific cell populations within the lung, leading to maximized efficacy and a parallel decrease in toxicity.
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Nasal drug delivery is non-invasive and bypasses the harsh gastrointestinal environment and hepatic first-pass metabolism. Nasal vaccines have harnessed the uniqueness offered by this pathway, since it can potently elicit both mucosal and systemic immune responses. However, physiological barriers in the nasal cavity, including rapid mucociliary clearance, and mucosal and epithelial layers pose limitations to achieve efficient intra- or trans-nasal delivery. Our work is focused around overcoming these barriers to enhance the efficiency of nasal drug delivery while maximizing safety.
Prolonged solutions for short-term problems
Long-acting drug delivery systems, including both injectables and implants have revolutionized prevention and treatment strategies for different conditions. Multiple long-acting systems are currently in clinical use for psychotic disorders, infectious diseases such as HIV, substance abuse disorder, hormonal therapy, and localized delivery in different tissues, including the eye. We are working towards creating next-generation long-acting delivery approaches that can overcome the limitations of current systems, including high initial burst release and sub-optimal duration of drug release, especially for hydrophilic drugs. We recognize the magnitude of these problems and are deeply interested in viewing them as short-term obstacles that can be hurdled past, once integrative solutions are put in place. Using our next-generation platforms, we intend to achieve ultra-long-acting delivery of therapeutics for different applications, including HIV, substance abuse disorder and organ transplant.
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