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Nano-Mediated Molecular Targeting in Diagnosis and Mitigation of Wilson Disease

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Abstract

Wilson disease, a rare genetic disorder resulting from mutations in the ATP7B gene disrupts copper metabolism, leading to its harmful accumulation in hepatocytes, the brain, and other organs. It affects roughly 1 in 30,000 individuals, with 1 in 90 being gene carriers. Beyond gene mutations, the disease involves complex factors contributing to copper imbalance. Ongoing research seeks to unravel intricate molecular pathways, offering fresh insights into the disease’s mechanisms. Simultaneously, there is a dedicated effort to develop effective therapeutic strategies. Nanotechnology-driven formulations are showing promise for both treatment and early diagnosis of Wilson disease. This comprehensive review covers the entire spectrum of the condition, encompassing pathophysiology, potential biomarkers, established and emerging therapies, ongoing clinical trials, and innovative nanotechnology applications. This multifaceted approach holds the potential to improve our understanding, diagnosis, and management of Wilson’s disease, which remains a challenging and potentially life-threatening disorder.

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The review article-related raw data files/figures/tables are available from the corresponding author.

Abbreviations

2-OG:

2-Oxoglutarate

8-OHdG:

8-Hydroxy-2′-deoxyguanosine

AAV:

Adeno-associated virus

ATOX-1:

Human antioxidant protein 1

ATP:

Adenosine triphosphate

ATP7A:

Cu(I) transporting ATPase A

ATP7B :

Cu(I) transporting ATPase B

BBB:

Blood-brain barrier

CCS:

Copper chaperon for superoxide dismutase

CHE:

Pseudocholinesterase

COMMD1:

Copper metabolism domain-containing 1 protein

COX:

Cytochrome c oxidase assembly protein

Cp:

Ceruloplasmin

CTR-1:

Copper-transporting protein-1

CTR2:

Copper-transporting protein-2

Cu:

Copper

DMSA:

Dimercaptosuccinic acid

EASL:

European Association for the Study of the Liver

GDL:

GanDouLing

GFAP:

Glial fibrillary acidic protein

GSH:

Glutathione

LEA:

Long-Evans Agouti rat model

LEC:

Long-Evans Cinnamon rat model

MiADMSA:

Monoisoamyl 2,3-dimercaptosuccinic acid

MTs:

Copper-binding metallothioneins

NCC:

Non-caeruloplasmin-bound copper

NfL:

Neurofilament

SAM:

S-adenosyl-methionine

Sco 1/2:

Cytochrome c oxidase subunits 1 and 2

SDH:

Succinate dehydrogenase

SHED:

Stem cells from human-exfoliated deciduous teeth

SHED-Heps:

SHED-converted hepatocyte-like cells

SOD1:

Superoxide dismutase 1

SREBP-2:

Sterol regulatory-binding protein 2

TGN:

Trans-Golgi network

TTM:

Tetrathiomolybdate

Tx-j:

Jackson’s toxic milk mouse model

UCH-L1:

Ubiquitin carboxyl-terminal hydrolase L1

WD:

Wilson’s disease

WGBS:

Whole-genome bisulfite sequencing

XIAP:

X-linked inhibitor of apoptosis protein

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Acknowledgements

The authors acknowledge the Department of Pharmaceuticals under the Ministry of Chemicals and Fertilizers, Government of India. The NIPER communication number for the review article is NIPER-R/Communication number/509. Also, the authors would like to acknowledge DST-SERB (Project No. SRG/2022/001285) for their finacial support.

Funding

This work was supported by DST-SERB [SERB Project No. SRG/2022/001285].

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Authors and Affiliations

  1. Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research-Raebareli (NIPER-Raebareli), Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP, 226002, India

    Akanksha Chaturvedi & Rahul Shukla

  2. Department of Pharmacy, Banasthali University, Banasthali, Rajasthan, 304022, India

    Swapnil Sharma

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  1. Akanksha Chaturvedi
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Contributions

Dr. Rahul Shukla: conceptualization, review, and editing; Dr. Swapnil Sharma: formal analysis and editing; Akanksha Chaturvedi: writing, reviewing, validation, visualization.

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Correspondence to Rahul Shukla.

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Highlights

• Wilson disease is mediated by genetic disruption in Cu(I) transporting ATPase beta polypeptide, i.e., ATP7B.

• Early diagnosis and treatment of the disease could mitigate the ailment and suppress its chronic consequences in an individual.

• Several therapies including chelation are being adapted to treat copper overload; resist at a point due to reported side effects.

• Illustration of novel therapies purporting Wilson disease.

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Chaturvedi, A., Sharma, S. & Shukla, R. Nano-Mediated Molecular Targeting in Diagnosis and Mitigation of Wilson Disease. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03816-8

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