Imperial College London

DrAshaPatel

Faculty of MedicineNational Heart & Lung Institute

Lecturer in Cell & Gene Therapy
 
 
 
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Contact

 

asha.patel

 
 
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Location

 

Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

19 results found

, 2020, Bioengineering Innovative Solutions for Cancer, Publisher: Elsevier, ISBN: 9780128138861

Book

Delcassian D, Patel A, 2019, Nanotechnology and Drug Delivery, Bioengineering Innovative Solutions for Cancer, Editors: Ladame, Chang, Publisher: Academic Press, ISBN: 9780128138861

By covering the many different ways engineers can deliver innovative solutions to tackle cancer, this book is a valuable read for researchers who have an ambition to make an impact on people’s life in either an academic or industrial ...

Book chapter

Patel AK, Kaczmarek JC, Bose S, Kauffman KJ, Mir F, Heartlein MW, DeRosa F, Langer R, Anderson DGet al., 2019, Inhaled nanoformulated mRNA polyplexes for protein production in lung epithelium, Advanced Materials, Vol: 31, ISSN: 0935-9648

Noninvasive aerosol inhalation is an established method of drug delivery to the lung, and remains a desirable route for nucleic‐acid‐based therapeutics. In vitro transcribed (IVT) mRNA has broad therapeutic applicability as it permits temporal and dose‐dependent control of encoded protein expression. Inhaled delivery of IVT‐mRNA has not yet been demonstrated and requires development of safe and effective materials. To meet this need, hyperbranched poly(beta amino esters) (hPBAEs) are synthesized to enable nanoformulation of stable and concentrated polyplexes suitable for inhalation. This strategy achieves uniform distribution of luciferase mRNA throughout all five lobes of the lung and produces 101.2 ng g−1 of luciferase protein 24 h after inhalation of hPBAE polyplexes. Importantly, delivery is localized to the lung, and no luminescence is observed in other tissues. Furthermore, using an Ai14 reporter mouse model it is identified that 24.6% of the total lung epithelial cell population is transfected after a single dose. Repeat dosing of inhaled hPBAE‐mRNA generates consistent protein production in the lung, without local or systemic toxicity. The results indicate that nebulized delivery of IVT‐mRNA facilitated by hPBAE vectors may provide a clinically relevant delivery system to lung epithelium.

Journal article

Patel A, Anderson D, Kaczmarek J, Kauffman Ket al., 2019, Poly (beta-amino esters) and uses thereof, WO2019084229A1

Patent

Smith JGW, Owen T, Bhagwan JR, Mosqueira D, Scott E, Mannhardt I, Patel A, Barriales-Villa R, Monserrat L, Hansen A, Eschenhagen T, Harding SE, Marston S, Denning Cet al., 2018, Isogenic pairs of hiPSC-CMs with hypertrophic cardiomyopathy/LVNC-associated ACTC1 E99K mutation unveil differential functional deficits, Stem Cell Reports, Vol: 11, Pages: 1226-1243, ISSN: 2213-6711

Hypertrophic cardiomyopathy (HCM) is a primary disorder of contractility in heart muscle. To gain mechanistic insight and guide pharmacological rescue, this study models HCM using isogenic pairs of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the E99K-ACTC1 cardiac actin mutation. In both 3D engineered heart tissues and 2D monolayers, arrhythmogenesis was evident in all E99K-ACTC1 hiPSC-CMs. Aberrant phenotypes were most common in hiPSC-CMs produced from the heterozygote father. Unexpectedly, pathological phenotypes were less evident in E99K-expressing hiPSC-CMs from the two sons. Mechanistic insight from Ca2+ handling expression studies prompted pharmacological rescue experiments, wherein dual dantroline/ranolazine treatment was most effective. Our data are consistent with E99K mutant protein being a central cause of HCM but the three-way interaction between the primary genetic lesion, background (epi)genetics, and donor patient age may influence the pathogenic phenotype. This illustrates the value of isogenic hiPSC-CMs in genotype-phenotype correlations.

Journal article

Kaczmarek J, Kauffman K, Fenton O, Sadtler K, Patel AK, Heartlein MW, DeRosa F, Anderson Det al., 2018, Optimization of a degradable polymer−lipid nanoparticle forpotent systemic delivery of mRNA to the lung endothelium andimmune cells, Nano Letters, Vol: 18, Pages: 6449-6454, ISSN: 1530-6984

mRNA therapeutics hold great potential for treating a variety of diseases through protein-replacement, immunomodulation, and gene editing. However, much like siRNA therapy the majority of progress in mRNA delivery has been confined to the liver. Previously, we demonstrated that poly(β-amino esters), a class of degradable polymers, are capable of systemic mRNA delivery to the lungs in mice when formulated into nanoparticles with poly(ethylene glycol)–lipid conjugates. Using experimental design, a statistical approach to optimization that reduces experimental burden, we demonstrate herein that these degradable polymer–lipid nanoparticles can be optimized in terms of polymer synthesis and nanoparticle formulation to achieve a multiple order-of-magnitude increase in potency. Furthermore, using genetically engineered Cre reporter mice, we demonstrate that mRNA is functionally delivered to both the lung endothelium and pulmonary immune cells, expanding the potential utility of these nanoparticles.

Journal article

Delcassian D, Patel AK, Cortinas AB, Langer Ret al., 2018, Drug delivery across length scales., J Drug Target, Pages: 1-15

Over the last century, there has been a dramatic change in the nature of therapeutic, biologically active molecules available to treat disease. Therapies have evolved from extracted natural products towards rationally designed biomolecules, including small molecules, engineered proteins and nucleic acids. The use of potent drugs which target specific organs, cells or biochemical pathways, necessitates new tools which can enable controlled delivery and dosing of these therapeutics to their biological targets. Here, we review the miniaturisation of drug delivery systems from the macro to nano-scale, focussing on controlled dosing and controlled targeting as two key parameters in drug delivery device design. We describe how the miniaturisation of these devices enables the move from repeated, systemic dosing, to on-demand, targeted delivery of therapeutic drugs and highlight areas of focus for the future.

Journal article

Alexander M, Denning C, Celiz A, Smith J, Patel Aet al., 2017, Cell culture substrate, US20170191026A1

Patent

Kaczmarek JC, Patel AK, Kauffman KJ, Fenton OS, Webber MJ, Heartlein MW, DeRosa F, Anderson DGet al., 2016, Polymer-lipid nanoparticles for systemic delivery of mRNA to the lungs, Angewandte Chemie International Edition, Vol: 55, Pages: 13808-13812, ISSN: 1521-3757

Therapeutic nucleic acids hold great promise for the treatment of disease but require vectors for safe and effective delivery. Synthetic nanoparticle vectors composed of poly(β‐amino esters) (PBAEs) and nucleic acids have previously demonstrated potential utility for local delivery applications. To expand this potential utility to include systemic delivery of mRNA, hybrid polymer–lipid nanoformulations for systemic delivery to the lungs were developed. Through coformulation of PBAEs with lipid–polyethylene glycol (PEG), mRNA formulations were developed with increased serum stability and increased in vitro potency. The formulations were capable of functional delivery of mRNA to the lungs after intravenous administration in mice. To our knowledge, this is the first report of the systemic administration of mRNA for delivery to the lungs using degradable polymer–lipid nanoparticles.

Journal article

Denning C, Borgdorff V, Crutchley J, Firth KSA, George V, Kalra S, Kondrashov A, Hoang MD, Mosqueira D, Patel A, Prodanov L, Rajamohan D, Skarnes WC, Smith JGW, Young LEet al., 2016, Cardiomyocytes from human pluripotent stem cells: From laboratory curiosity to industrial biomedical platform, BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, Vol: 1863, Pages: 1728-1748, ISSN: 0167-4889

Journal article

Patel AK, Tibbitt MW, Celiz AD, Davies MC, Langer R, Denning C, Alexander MR, Anderson DGet al., 2016, High throughput screening for discovery of materials that control stem cell fate, CURRENT OPINION IN SOLID STATE & MATERIALS SCIENCE, Vol: 20, Pages: 202-211, ISSN: 1359-0286

nsights into the complex stem cell niche have identified the cell–material interface to be a potent reg-ulator of stem cell fate via material properties such as chemistry, topography and stiffness. In light of this,materials scientists have the opportunity to develop bioactive materials for stem cell culture that elicitspecific cellular responses. To accelerate materials discovery, high throughput screening platforms havebeen designed which can rapidly evaluate combinatorial material libraries in two and three-dimensionalenvironments. In this review, we present screening platforms for the discovery of material properties thatinfluence stem cell behavior.

Journal article

Celiz AD, Smith JGW, Patel AK, Hook AL, Rajamohan D, George VT, Flatt L, Patel MJ, Epa VC, Singh T, Langer R, Anderson DG, Allen ND, Hay DC, Winkler DA, Barrett DA, Davies MC, Young LE, Denning C, Alexander MRet al., 2015, Discovery of a Novel Polymer for Human Pluripotent Stem Cell Expansion and Multilineage Differentiation, Advanced Materials, Vol: 27, Pages: 4006-4012, ISSN: 0935-9648

A scalable and cost-effective synthetic polymer substrate that supports robust expansion and subsequent multilineage differentiation of human pluripotent stem cells (hPSCs) with defined commercial media is presented. This substrate can be applied to common cultureware and used off-the-shelf after long-term storage. Expansion and differentiation of hPSCs are performed entirely on the polymeric surface, enabling the clinical potential of hPSC-derived cells to be realized.

Journal article

Patel AK, Celiz AD, Rajamohan D, Anderson DG, Langer R, Davies MC, Alexander MR, Denning Cet al., 2015, A defined synthetic substrate for serum-free culture of human stem cell derived cardiomyocytes with improved functional maturity identified using combinatorial materials microarrays, Biomaterials, Vol: 61, Pages: 257-265, ISSN: 0142-9612

Cardiomyocytes from human stem cells have applications in regenerative medicine and can provide models for heart disease and toxicity screening. Soluble components of the culture system such as growth factors within serum and insoluble components such as the substrate on which cells adhere to are important variables controlling the biological activity of cells. Using a combinatorial materials approach we develop a synthetic, chemically defined cellular niche for the support of functional cardiomyocytes derived from human embryonic stem cells (hESC-CMs) in a serum-free fully defined culture system. Almost 700 polymers were synthesized and evaluated for their utility as growth substrates. From this group, 20 polymers were identified that supported cardiomyocyte adhesion and spreading. The most promising 3 polymers were scaled up for extended culture of hESC-CMs for 15 days and were characterized using patch clamp electrophysiology and myofibril analysis to find that functional and structural phenotype was maintained on these synthetic substrates without the need for coating with extracellular matrix protein. In addition, we found that hESC-CMs cultured on a co-polymer of isobornyl methacrylate and tert-butylamino-ethyl methacrylate exhibited significantly longer sarcomeres relative to gelatin control. The potential utility of increased structural integrity was demonstrated in an in vitro toxicity assay that found an increase in detection sensitivity of myofibril disruption by the anti-cancer drug doxorubicin at a concentration of 0.05 μM in cardiomyocytes cultured on the co-polymer compared to 0.5 μM on gelatin. The chemical moieties identified in this large-scale screen provide chemically defined conditions for the culture and manipulation of hESC-CMs, as well as a framework for the rational design of superior biomaterials.

Journal article

Patel AK, Celiz A, Rajamohan D, Alexander M, Denning Cet al., 2015, Identification of a defined synthetic substrate for cultureof human cardiomyocytes, In Vitro Toxicology Society Annual Meeting

Conference paper

Smith JGW, Celiz AD, Patel AK, Short RD, Alexander MR, Denning Cet al., 2015, Scaling human pluripotent stem cell expansion and differentiation: are cell factories becoming a reality?, REGENERATIVE MEDICINE, Vol: 10, Pages: 925-930, ISSN: 1746-0751

Journal article

Rafiq QA, Ortega I, Jenkins SI, Wilson SL, Patel AK, Barnes AL, Adams CF, Delcassian D, Smith Det al., 2015, The early career researcher's toolkit: translating tissue engineering, regenerative medicine and cell therapy products, REGENERATIVE MEDICINE, Vol: 10, Pages: 989-1003, ISSN: 1746-0751

Journal article

Celiz AD, Smith JGW, Patel AK, Langer R, Anderson DG, Barrett DA, Young LE, Davies MC, Denning C, Alexander MRet al., 2014, Chemically diverse polymer microarrays and high throughput surface characterisation: a method for discovery of materials for stem cell culture, BIOMATERIALS SCIENCE, Vol: 2, Pages: 1604-1611, ISSN: 2047-4830

Journal article

Rajamohan D, Matsa E, Kalra S, Crutchley J, Patel A, George V, Denning Cet al., 2013, Current status of drug screening and disease modelling in human pluripotent stem cells, BIOESSAYS, Vol: 35, Pages: 281-298, ISSN: 0265-9247

Journal article

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