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Modulating gene regulation to treat genetic disorders

Nature Reviews Drug Discovery volume 19, pages 757–775 (2020)Cite this article

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Abstract

Over a thousand diseases are caused by mutations that alter gene expression levels. The potential of nuclease-deficient zinc fingers, TALEs or CRISPR fusion systems to treat these diseases by modulating gene expression has recently emerged. These systems can be applied to modify the activity of gene-regulatory elements — promoters, enhancers, silencers and insulators, subsequently changing their target gene expression levels to achieve therapeutic benefits — an approach termed cis-regulation therapy (CRT). Here, we review emerging CRT technologies and assess their therapeutic potential for treating a wide range of diseases caused by abnormal gene dosage. The challenges facing the translation of CRT into the clinic are discussed.

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Fig. 1: DNA targeting modules and effector domains used in CRT.
Fig. 2: Using CRT to upregulate gene transcription.
Fig. 3: Using CRT to downregulate gene transcription.
Fig. 4: Using CRT to modulate DNA methylation or DNA looping.

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Acknowledgements

This article was supported in part by grants 1R01DK090382 and 1R01DK124769 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Simons Foundation Autism Research Initiative grants 629287 and 564256, the University of California, San Francisco (UCSF) School of Pharmacy 2017 Mary Anne Koda-Kimble Seed Award for Innovation and the Innovative Genomics Institute RIDER award 2019. The authors regret they could not include and highlight the comprehensive list of citations of their fellow scientists due to space limitations.

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Authors and Affiliations

  1. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA

    Navneet Matharu & Nadav Ahituv

  2. Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA

    Navneet Matharu & Nadav Ahituv

  3. Innovative Genomics Institute, University of California San Francisco, San Francisco, CA, USA

    Navneet Matharu

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  1. Navneet Matharu
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N.M. and N.A. conceptualized, reviewed the literature and wrote the manuscript.

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Correspondence to Navneet Matharu or Nadav Ahituv.

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Competing interests

N.A. is an equity holder of, and a scientific advisor for Encoded Therapeutics, a gene regulation therapeutics company. N.A. and N.M. are cofounders of Enhancer Therapeutics Inc. and co-inventors on a related patent (Publication number WO/2018/148256). N.M. and N.A. are co-inventors on a patent (US Patent US2018017186) submitted by the University of California, San Francisco, that covers gene therapy for haploinsufficiency.

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Glossary

Cis-Regulatory elements

(CREs). DNA sequences that regulate the transcription of a neighbouring gene.

Packaging

Assembly of the nucleic acids and capsid during virus generation.

DNA scars

Irreversible and unintended DNA changes caused mainly due to off-targeting by DNA targeting modules with functional nucleases.

DNA looping

Physical DNA–DNA interaction in the genome within 3D nuclear space.

Nanoparticles

Particles that are between 1 and 100 nm in diameter.

Intracerebroventricular

A route of delivery via injection into the cerebrospinal fluid in cerebral ventricles.

Trinucleotide repeat expansion

A specific 3-bp DNA sequence that has more copies than normal in the genome.

Bioavailability

The proportion of the therapeutic agent upon administration that has an active effect.

Off-targeting

The effects arising due to non-specific and unintended targeting of DNA targeting modules such as zinc fingers, transcription activator-like effector (TALE) and CRISPR in the genome.

Delivery routes

The methods of administration of a therapeutic agent based on the site of action.

Capsid

(Also known as a viral envelope). The proteinaceous shell that packages the genetic material of the virus. Its structure is important in determining viral stability, delivery and host interactions.

Pre-existing immunity

The adaptive immune response of the body due to pre-exposure to an antigen.

AAV serotypes

(Adeno-associated virus serotypes). The variations in the capsid surface proteins of an adeno-associated virus that can define its transduction efficiency in different tissue or cell types.

Blood–brain barrier

The blood–brain barrier is the membrane made from endothelial cells surrounding the blood vessels that selectively allows solutes to transfer from the blood to the central nervous system.

Intrathecal

A route of delivery via injection into the spinal canal in order to avoid the blood–brain barrier selective permeability.

Intravitreal

A route of delivery into the vitreous humour of the eye.

Episomes

Circular DNA that is not integrated in the genome.

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Matharu, N., Ahituv, N. Modulating gene regulation to treat genetic disorders. Nat Rev Drug Discov 19, 757–775 (2020). https://doi.org/10.1038/s41573-020-0083-7

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