Curative Cell and Gene Therapy for Osteogenesis Imperfecta

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ABSTRACT

Osteogenesis imperfecta (OI) describes a series of genetic bone fragility disorders that can have a substantive impact on patient quality of life. The multidisciplinary approach to management of children and adults with OI primarily involves the administration of antiresorptive medication, allied health (physiotherapy and occupational therapy), and orthopedic surgery. However, advances in gene editing technology and gene therapy vectors bring with them the promise of gene‐targeted interventions to provide an enduring or perhaps permanent cure for OI. This review describes emergent technologies for cell‐ and gene‐targeted therapies, major hurdles to their implementation, and the prospects of their future success with a focus on bone disorders. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Sue Richards, Nazneen Aziz, Sherri Bale … (2015)

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.

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Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage

Alexis Komor, Yongjoo Kim, Michael Packer … (2016)

Current genome-editing technologies introduce double-stranded (ds) DNA breaks at a target locus as the first step to gene correction. 1,2 Although most genetic diseases arise from point mutations, current approaches to point mutation correction are inefficient and typically induce an abundance of random insertions and deletions (indels) at the target locus from the cellular response to dsDNA breaks. 1,2 Here we report the development of base editing, a new approach to genome editing that enables the direct, irreversible conversion of one target DNA base into another in a programmable manner, without requiring dsDNA backbone cleavage or a donor template. We engineered fusions of CRISPR/Cas9 and a cytidine deaminase enzyme that retain the ability to be programmed with a guide RNA, do not induce dsDNA breaks, and mediate the direct conversion of cytidine to uridine, thereby effecting a C→T (or G→A) substitution. The resulting “base editors” convert cytidines within a window of approximately five nucleotides (nt), and can efficiently correct a variety of point mutations relevant to human disease. In four transformed human and murine cell lines, second- and third-generation base editors that fuse uracil glycosylase inhibitor (UGI), and that use a Cas9 nickase targeting the non-edited strand, manipulate the cellular DNA repair response to favor desired base-editing outcomes, resulting in permanent correction of ∼15-75% of total cellular DNA with minimal (typically ≤ 1%) indel formation. Base editing expands the scope and efficiency of genome editing of point mutations.

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Search-and-replace genome editing without double-strand breaks or donor DNA

Andrew Anzalone, Peyton B. Randolph, Jessie Davis … (2019)

Summary Most genetic variants that contribute to disease 1 are challenging to correct efficiently and without excess byproducts 2–5 . Here we describe prime editing, a versatile and precise genome editing method that directly writes new genetic information into a specified DNA site using a catalytically impaired Cas9 fused to an engineered reverse transcriptase, programmed with a prime editing guide RNA (pegRNA) that both specifies the target site and encodes the desired edit. We performed >175 edits in human cells including targeted insertions, deletions, and all 12 types of point mutations without requiring double-strand breaks or donor DNA templates. We applied prime editing in human cells to correct efficiently and with few byproducts the primary genetic causes of sickle cell disease (requiring a transversion in HBB) and Tay-Sachs disease (requiring a deletion in HEXA), to install a protective transversion in PRNP, and to precisely insert various tags and epitopes into target loci. Four human cell lines and primary post-mitotic mouse cortical neurons support prime editing with varying efficiencies. Prime editing shows higher or similar efficiency and fewer byproducts than homology-directed repair, complementary strengths and weaknesses compared to base editing, and much lower off-target editing than Cas9 nuclease at known Cas9 off-target sites. Prime editing substantially expands the scope and capabilities of genome editing, and in principle can correct up to 89% of known genetic variants associated with human diseases.

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Author and article information

Contributors

Aaron Schindeler:

ORCID: https://orcid.org/0000-0002-7757-6281

aaron.schindeler@sydney.edu.au

Journal

Journal ID (nlm-ta): J Bone Miner Res

Journal ID (iso-abbrev): J Bone Miner Res

Journal ID (doi): 10.1002/(ISSN)1523-4681

Journal ID (publisher-id): JBMR

Title: Journal of Bone and Mineral Research

Publisher: John Wiley & Sons, Inc. (Hoboken, USA )

ISSN (Print): 0884-0431

ISSN (Electronic): 1523-4681

Publication date (Electronic): 17 April 2022

Publication date (Print): May 2022

Volume: 37

Issue: 5 ( doiID: 10.1002/jbmr.v37.5 )

Pages: 826-836

Affiliations

[ ¹ ] Bioengineering and Molecular Medicine Laboratory the Children's Hospital at Westmead and the Westmead Institute for Medical Research Westmead Australia

[ ² ] Children's Hospital Westmead Clinical School University of Sydney Camperdown Australia

[ ³ ] Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health The University of Sydney and Sydney Children's Hospitals Network Westmead Australia

[ ⁴ ] Faculty of Medicine The University of Queensland Brisbane QLD Australia

[ ⁵ ] Department of Endocrinology and Diabetes Queensland Children's Hospital Brisbane QLD Australia

[ ⁶ ] Child Health Research Centre and Faculty of Medicine The University of Queensland Brisbane Queensland Australia

Author notes

[*] [* ] Address correspondence to: Aaron Schindeler, PhD., Bioengineering and Molecular Medicine Laboratory, the Children's Hospital at Westmead and the Westmead Institute for Medical Research, WIMR Street Address: 176 Hawkesbury Rd, Westmead, NSW 2145, Australia. E‐mail: aaron.schindeler@ 123456sydney.edu.au

Author information

Aaron Schindeler https://orcid.org/0000-0002-7757-6281

Lucinda R Lee https://orcid.org/0000-0002-9094-7171

Alexandra K O'Donohue https://orcid.org/0000-0003-2267-3671

Samantha L Ginn https://orcid.org/0000-0002-0876-6292

Craig F Munns https://orcid.org/0000-0001-5898-5808

Article

Publisher ID: JBMR4549

DOI: 10.1002/jbmr.4549

PMC ID: 9324990

PubMed ID: 35306687

SO-VID: 5847c6b4-fee4-4773-a405-69ef2395e78c

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date revision received : 03 February 2022

Date received : 04 November 2021

Date accepted : 27 February 2022

Page count

Figures: 1, Tables: 3, Pages: 11, Words: 11610

Funding

Funded by: Hope Foundation , doi 10.13039/100013748;

Custom metadata

source-schema-version-number 2.0

cover-date May 2022

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:26.07.2022

ScienceOpen disciplines: Human biology

Keywords: gene therapy,cell therapy,osteogenesis imperfecta,collagen

Data availability:

ScienceOpen disciplines: Human biology

Keywords: gene therapy, cell therapy, osteogenesis imperfecta, collagen

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Curative Cell and Gene Therapy for Osteogenesis Imperfecta

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Most cited references 146

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage

Search-and-replace genome editing without double-strand breaks or donor DNA

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