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Considerations and Advances in Huntington’s Disease Clinical Trial Design

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Biomarkers for Huntington's Disease

Part of the book series: Contemporary Clinical Neuroscience ((CCNE))

Abstract

The characterization of the Huntingtin gene in 1993, 10 years after it was the first disease-associated gene to be mapped to a chromosome in humans, brought with it much anticipation that treatment or a cure would soon follow. In 2023, clinical trials for HD are still ongoing, with many structured around therapies that aim to lower Huntingtin mRNA or protein levels. Clinical trial design, including the appropriate selection of a target population, outcome measures, and safety markers, is paramount to the success of such trials. The analysis of biomarkers, including volumetric neuroimaging and cerebrospinal fluid or blood protein levels, is also now an essential requirement for clinical trial design.

This chapter will cover the types and methodologies of current trials investigating Huntingtin-lowering therapies, as well as touch on past and present studies targeting other mechanisms downstream of the Huntingtin mutation. Advances in clinical trial design also include recent efforts to recruit participants who are earlier in their disease progression – prior to the onset of motoric symptom manifestation and a clinical motor diagnosis. In this chapter, we will thus present past and present means of quantifying disease stage and estimated disease progression and discuss the potential for neuroimaging and fluid biomarkers to be incorporated into these measures.

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Abbreviations

AAV:

Adeno-associated virus

ASO:

Antisense Oligonucleotide

BDNF:

Brain-Derived Neurotrophic Factor

CAP score:

CAG-Age Product score

CNS:

Central Nervous System

CSF:

Cerebrospinal fluid

DCL:

Diagnostic Confidence Level

HTT:

Huntingtin

HD:

Huntington’s disease

HD-ISS:

Huntington’s Disease Integrated Staging System

miRNA:

microRNA

MMSE:

Mini-Mental State Examination

MoCA:

Montreal Cognitive Assessment

NfL:

Neurofilament light

OLE:

Open-Label Extension

PIN score:

Prognostic Index Normed score

RNAi:

RNA interference

shRNA:

short hairpin RNA

siRNA:

short interfering RNA

SDMT:

Symbol Digit Modalities Test

SNP:

Single Nucleotide Polymorphism

TFC:

Total Functional Capacity

TMS:

Total Motor Score

UHDRS:

Unified Huntington’s Disease Rating Scale

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Authors and Affiliations

  1. Department of Neurosciences, University of California, San Diego, CA, USA

    Georgia M. Parkin & Jody Corey-Bloom

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  1. Georgia M. Parkin
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Correspondence to Georgia M. Parkin .

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Editors and Affiliations

  1. Department of Neurobiology and Behavior, University of California, Irvine, CA, USA

    Elizabeth A. Thomas

  2. Department of Neurosciences, University of California, San Diego, CA, USA

    Georgia M. Parkin

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Parkin, G.M., Corey-Bloom, J. (2023). Considerations and Advances in Huntington’s Disease Clinical Trial Design. In: Thomas, E.A., Parkin, G.M. (eds) Biomarkers for Huntington's Disease. Contemporary Clinical Neuroscience. Springer, Cham. https://doi.org/10.1007/978-3-031-32815-2_17

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