Would Human Preimplantation Gene Therapy Based on CRISPR-Cas9 Genome Editing Increase Cancer Risk in the Offspring?

Given ubiquitous human exposure to ethylene oxide (EO), regardless of occupation or geography, the current risk-specific concentrations (RSCs: 0.0001–0.01 ppb) from the U.S. Environmental Protection Agency (EPA) cancer risk assessment for EO are not useful metrics for managing EO exposures to the general U.S. population. The magnitude of the RSCs for EO are so low, relative to typical endogenous equivalent metabolic concentrations (1.1–5.5 ppb) that contribute ~93% of total exposure, that the RSCs provide little utility in identifying excess environmental exposures that might increase cancer risk. EO monitoring data collected in the vicinity of eight EO-emitting facilities and corresponding background locations were used to characterize potential excess exogenous concentrations. Both 50th and 90th percentile exogenous exposure concentrations were combined with the 50th percentile endogenous exposure concentration for the nonsmoking population, and then compared to percentiles of total equivalent concentration for this population. No potential total exposure concentration for these local populations exceeded the normal total equivalent concentration 95th percentile, indicating that excess facility-related exposures are unlikely to require additional management to protect public health.

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Cancer risk prompts US to curb gene therapy

Nature ◽

10.1038/422007a ◽

2003 ◽

Vol 422 (6927) ◽

pp. 7-7 ◽

Cited By ~ 13

Author(s):

Erika Check

Keyword(s):

Gene Therapy ◽

Cancer Risk

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Progress in Gene Therapy to Prevent Retinal Ganglion Cell Loss in Glaucoma and Leber’s Hereditary Optic Neuropathy

Neural Plasticity ◽

10.1155/2018/7108948 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 12

Author(s):

Sara E. Ratican ◽

Andrew Osborne ◽

Keith R. Martin

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Optic Nerve ◽

Genome Editing ◽

Optic Neuropathy ◽

Single Gene ◽

Leber’S Hereditary Optic Neuropathy ◽

Leber's Hereditary Optic Neuropathy ◽

Potential Use ◽

Hereditary Optic Neuropathy

The eye is at the forefront of the application of gene therapy techniques to medicine. In the United States, a gene therapy treatment for Leber’s congenital amaurosis, a rare inherited retinal disease, recently became the first gene therapy to be approved by the FDA for the treatment of disease caused by mutations in a specific gene. Phase III clinical trials of gene therapy for other single-gene defect diseases of the retina and optic nerve are also currently underway. However, for optic nerve diseases not caused by single-gene defects, gene therapy strategies are likely to focus on slowing or preventing neuronal death through the expression of neuroprotective agents. In addition to these strategies, there has also been recent interest in the potential use of precise genome editing techniques to treat ocular disease. This review focuses on recent developments in gene therapy techniques for the treatment of glaucoma and Leber’s hereditary optic neuropathy (LHON). We discuss recent successes in clinical trials for the treatment of LHON using gene supplementation therapy, promising neuroprotective strategies that have been employed in animal models of glaucoma and the potential use of genome editing techniques in treating optic nerve disease.

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Cancer Susceptibility Genes and Common Gene Variants That Increase Cancer Risk

Cancer Risk Assessment ◽

10.1201/b14140-10 ◽

2005 ◽

pp. 181-204

Author(s):

Ragnhild A. Lothe ◽

Anne-Lise Børresen-Dale

Keyword(s):

Cancer Risk ◽

Cancer Susceptibility ◽

Susceptibility Genes ◽

Gene Variants ◽

Increase Cancer Risk ◽

Common Gene ◽

Cancer Susceptibility Genes

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Genome Editing Strategies to Treat Beta-Hemoglobinopathies

Blood ◽

10.1182/blood.v130.suppl_1.sci-16.sci-16 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. SCI-16-SCI-16

Author(s):

Mitchell J Weiss

Keyword(s):

Gene Therapy ◽

Genome Editing ◽

Conflicts Of Interest ◽

Gene Mutations ◽

Fetal Hemoglobin ◽

Beta Thalassemia ◽

Great Promise ◽

Globin Genes ◽

Hematopoietic Stem ◽

Medical Therapies

Genetic forms of anemia caused by HBB gene mutations that impair beta globin production are extremely common worldwide. The resultant disorders, mainly sickle cell disease (SCD) and beta-thalassemia, cause substantial morbidity and early mortality. Treatments for these diseases include medical therapies and bone marrow transplantation (BMT), which can be curative. However, medical therapies are suboptimal and BMT is associated with serious toxicities, particularly because HLA-matched allogeneic sibling donors are not available for most patients. Thus, new therapies are urgently needed for millions of affected individuals. Gene therapy offers great promise to cure SCD and beta thalassemia and emerging genome editing technologies represent a new form of gene therapy. Approaches to cure SCD and beta-thalassemia via genome editing include: 1) Correction of HBB mutations by homology directed repair (HDR); 2) use of non-homologous end joining (NHEJ) to activate gamma globin production and raise fetal hemoglobin (HbF) levels; 3) NHEJ to disrupt alpha-globin genes (HBA1 or HBA2) and thereby alleviate globin chain imbalance in intermediately severe forms of beta thalassemia. Challenges for these approaches include selection of the most effective genome editing tools, optimizing their delivery to hematopoietic stem cells (HSCs), improving specificity and better understanding potential off target effects, particularly those that are biologically relevant. Technologies for genome editing are advancing rapidly and being tested in preclinical models for HBB-mutated disorders. Ultimately, however, the best strategies can only be identified in clinical trials. This will require close collaborations between basic/translational researchers who study genome editing, clinical hematologists and collaboration between experts in academia and the bio-pharmaceutical industry. Disclosures No relevant conflicts of interest to declare.

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Recent progress in genome editing for gene therapy applications: the French perspective

Human Gene Therapy ◽

10.1089/hum.2021.191 ◽

2021 ◽

Author(s):

Mario Amendola ◽

Aurélie Bedel ◽

Ana Buj Bello ◽

Mathieu Carrara ◽

Jean-paul Concordet ◽

...

Keyword(s):

Gene Therapy ◽

Genome Editing ◽

Recent Progress

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Development of gene therapy using genome editing technology

Journal of Hematopoietic Cell Transplantation ◽

10.7889/hct-17-014 ◽

2018 ◽

Vol 7 (2) ◽

pp. 32-39

Author(s):

Masafumi Onodera

Keyword(s):

Gene Therapy ◽

Genome Editing

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Improving Precise CRISPR Genome Editing by Small Molecules: Is there a Magic Potion?

Cells ◽

10.3390/cells9051318 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1318 ◽

Cited By ~ 2

Author(s):

Nadja Bischoff ◽

Sandra Wimberger ◽

Marcello Maresca ◽

Cord Brakebusch

Keyword(s):

Gene Therapy ◽

Dna Repair ◽

Animal Models ◽

Molecular Biology ◽

Small Molecules ◽

Genome Editing ◽

Drug Targets ◽

Targeted Mutagenesis ◽

Dna Repair Mechanisms ◽

Repair Mechanisms

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) genome editing has become a standard method in molecular biology, for the establishment of genetically modified cellular and animal models, for the identification and validation of drug targets in animals, and is heavily tested for use in gene therapy of humans. While the efficiency of CRISPR mediated gene targeting is much higher than of classical targeted mutagenesis, the efficiency of CRISPR genome editing to introduce defined changes into the genome is still low. Overcoming this problem will have a great impact on the use of CRISPR genome editing in academic and industrial research and the clinic. This review will present efforts to achieve this goal by small molecules, which modify the DNA repair mechanisms to facilitate the precise alteration of the genome.

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