Animal models of Huntington’s disease and their applicability to novel drug discovery and development

ABSTRACT

Introduction

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by an expansion in the CAG trinucleotide repeat in huntingtin (Htt) gene. The discovery of the HD-causing gene prompted the creation of new HD animal models, proving that mutations in the HD gene are linked to either loss of function of the wild-type (un-mutated) gene or toxic gain in the function of a mutated gene.

Areas Covered

Animal models of HD have led to an increased understanding of its pathogenesis and resulted in the discovery of new therapeutic targets/drugs. The focus of this review is on the selection and validation of animal models for HD drug discovery. Furthermore, several drugs tested using various models in the preclinical phase have been compiled to demonstrate the applicability of these HD animal models.

Expert opinion

The applicability of animal models for HD drug discovery has been well demonstrated. Nevertheless, despite the enormous progression made to date, the development of drug therapy to completely alleviate disease progression has not been achieved. Most of the pre-clinically tested drugs have shown promising results in alleviating HD-associated neurodegeneration and motor and non-motor symptoms, but only a few of them thrived to produce satisfactory results in the clinical phase. This failure has raised concerns about the selection of HD animal models and species, and new strategies for selection are mandated.

KEYWORDS:

• Huntington’s disease
• animal models
• neurodegeneration
• drug discovery
• drug development

Article highlights

• Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by an expansion in the CAG trinucleotide repeat in huntingtin (Htt) gene.

• The key pathogenic processes involved in neuronal degeneration in HD include oxidative stress, mitochondrial dysfunction, apoptosis, neuroinflammation, transcriptional regulation, altered neurotransmitter signaling, and mitochondrial biogenesis

• Only two FDA-approved drugs (tetrabenazine and deutetrabenazine) are available in the market, which provide symptomatic relief with untoward side effects.

• The selection of animal model is regarded as the most critical factor in the drug discovery process. The rationale for selecting or discarding any specific animal model includes standard protocols within a specialized field, disease, or circumstance that may confound results.

• Various invertebrate models have been used for the drug development process in HD, but Caenorhabditis elegans (C. elegans), and Drosophila melanogaster models are most widely used.

• Vertebrate models, such as zebrafish and rodent models, and higher mammal models including sheep, pigs, and non-human primate models are also used in HD drug discovery and development.

• Despite the enormous progression made to date, the development of drug therapy to completely alleviate disease progression has not been achieved. The selection process consequently needs to be refined.

Declaration of interest

The authors thank the Central University of Punjab (CUPB), Bathinda, India, and the Indian Council of Medical Research, New Delhi, India, for providing a Senior Research Fellowship to S Upadhayay to pursue his research at the department of Pharmacology, CUPB. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Abbreviations

3-NP	=	3-Nitropropionic acid
AAV9	=	Adeno-associated virus-9
ASOs	=	Antisense oligonucleotides
BDNF	=	Brain Derived Neurotrophic Factor
HD	=	Huntington’s disease
HTT	=	Huntingtin protein
Htt	=	Huntingtin gene
KA	=	Kainic acid
KMO	=	Kynurenine 3-monooxygenase
MA	=	Malonic acid
MSNs	=	Medium Spiny Neurons
NMDA	=	N-methyl-D-aspartate
QA	=	Quinolinic acid
SOD	=	Superoxide dismutase
TEs	=	Transposable elements
MSNs	=	Medium spiny neurons

Additional information

Funding

This Paper was not funded.