Synthesis and Evaluation of Dendrimers for Autophagy Augmentation and Alleviation of Obstructive Lung Diseases
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Preservation of cellular homeostasis requires constant synthesis of fresh proteins and cellular organelles and efficient degradation or removal of damaged proteins and cellular components. This involves two cellular degradation processes or molecular mechanisms: the ubiquitin–proteasome and autophagy-lysosomal systems. Impairment of these catabolic processes has been linked to pathogenesis of a variety of chronic obstructive lung diseases such as COPD (chronic obstructive pulmonary disease) and CF (cystic fibrosis). Proteosomal and autophagic functions (proteostasis) are known to decline with advancing age leading to accumulation of cellular debris and proteins, initiating cellular senescence or death and accelerating lung aging. Obstructive lung diseases associated with airway hyperinflammation and mucus obstruction provide major challenges to the delivery and therapeutic efficacy of nanotherapeutics systems as they need to bypass the airway defense. Targeted autophagy augmentation has emerged, as a promising therapeutic utility for alleviating obstructive lung diseases, and promoting healthy aging. A targeted dendrimer-based approach has been designed to penetrate the airway obstruction and allow the selective correction of proteostasis/autophagy in the diseased cells while circumventing the side effects. This report describes methods for synthesis and therapeutic evaluation of autophagy augmenting dendrimers in the treatment of obstructive lung disease(s). The formulations and methods of autophagy augmentation described here are currently under clinical development in our laboratory for alleviating pathogenesis and progression of chronic obstructive lung diseases, and promoting healthy aging.
Key wordsCystic fibrosis COPD Asthma Emphysema Cystamine Cysteamine CFTR Autophagy Dendrimers Aging Lung Theranostics
The author was supported by the NIH (CTSA RRO25005 and RHL096931), Flight Attendant Medical Research Institute’s (FAMRI), Young Clinical Scientist Award (YCSA_082131), and CFF (CFF, R025-CR07 and VIJ07IO) grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Declaration of Interests: The author is the lead inventor on a patent targeting proteostasis mechanisms for rescuing CFTR protein-processing defect and CF lung disease. The author is also the lead inventor of nano-based selective drug delivery and therapeutic targeting for obstructive lung diseases. The author is a founder of VIJ BIOTECH & PRECISION THERANOSTICS INC that focuses on bench-side translation of novel CF and COPD therapeutics and declares that he has no other competing interests.
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