The Dawn of In Vivo Gene Editing Era: A Revolution in the Making
Abstract
:1. Introduction
2. The Science of Gene Editing
2.1. Next-Generation Sequencing
2.2. Personalized Medicine
2.3. Targeting
3. Current Status
4. GE Tools
4.1. Nuclease Mediated
4.2. Prime Editing
4.3. Base Editing (BE)
4.4. Mitochondrial Base Editing
4.5. Nickase-Based Genome Engineering
4.6. Homologous Recombination
4.7. TFD-ODN Techniques
4.8. Argonautes
4.9. Integrase
4.10. Recombinase
5. Current Status
6. Challenges and Concerns
7. Regulatory
8. Delivery Tools
8.1. Overview
8.2. CRISPR
8.3. Vectors
8.4. AAV
8.5. Direct
8.6. LNPs
8.7. Nano Particles
8.8. Plasmid
8.9. Ribonucleoproteins (RNP)
9. Prospective Views
10. Conclusions
Funding
Conflicts of Interest
References
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Condition or Disease | GE Applications |
---|---|
Aging | Genetic modification of senescent cells has been proposed to counteract aging [33]. |
Alkaptonuria | A metabolic disorder that leads to a buildup of homogentisic acid, causing various symptoms, including dark-colored urine. Gene editing could correct the HGD gene, which causes this condition [34]. |
Alpha-1 Antitrypsin Deficiency | This genetic disorder can lead to lung and liver disease. Gene editing technologies can potentially correct the faulty SERPINA1 gene that causes it [35]. |
Alport Syndrome | A genetic disorder characterized by kidney disease, hearing loss, and eye abnormalities. Gene editing could correct the COL4A3, COL4A4, or COL4A5 genes, which cause this condition [36]. |
Amyotrophic Lateral Sclerosis (ALS) | A group of neurological diseases mainly involving the nerve cells (neurons) responsible for controlling voluntary muscle movement. Gene editing might correct the SOD1, TARDBP, FUS, or C9orf72 genes, which can cause this condition [37]. |
Angioedema | A rare genetic disorder characterized by recurrent episodes of severe swelling. Gene editing might correct the SERPING1 gene, which causes this condition [38]. |
Antimicrobial Resistance | Gene editing can potentially counteract the growing problem of antibiotic resistance by directly targeting and killing antibiotic-resistant bacteria or by making the bacteria sensitive to antibiotics again [39]. |
Atherosclerosis | Gene editing can potentially treat atherosclerosis, a disease where plaque builds up inside the arteries. Using gene editing techniques to modify the PCSK9 gene, which controls LDL cholesterol levels, could potentially lower the risk of atherosclerosis [40]. |
Autoimmune Diseases | With autoimmune diseases like rheumatoid arthritis and lupus, gene editing could modify immune cells and prevent them from attacking the body’s tissues [41]. |
Bardet-Biedl Syndrome | A disorder that affects many parts of the body and can cause obesity, loss of vision, kidney abnormalities, and extra fingers or toes. Gene editing could correct any 21 genes that cause this condition, such as BBS1, BBS2, or BBS10 [42]. |
Barth Syndrome | A genetic disorder characterized by muscle weakness, delayed growth, and sometimes intellectual disability. Gene editing could correct the TAZ gene, which causes this condition [43]. |
Beta Thalassemia | Gene editing techniques have been used in attempts to treat beta-thalassemia, a blood disorder that reduces the production of hemoglobin. Researchers have manipulated the BCL11A gene to enhance the production of fetal hemoglobin as a workaround [44]. |
Blindness | Researchers have used gene editing to restore sight in blind mice, which could eventually lead to treatments for certain forms of inherited blindness in humans [45]. |
Brain Function | Gene editing has been used in neuroscience to understand the function of different genes in the brain, which could eventually help us treat or even cure neurological disorders [46]. |
Canavan Disease | A progressive, fatal neurological disorder that begins in infancy. Gene editing could correct the ASPA gene, which causes this condition [47]. |
Cancer | CRISPR has been used to develop novel cancer therapies, such as genetically modifying a patient’s immune cells to target and fight cancer cells [48]. |
Chronic Granulomatous Disease | Gene editing has been used to correct the genetic mutations that cause chronic granulomatous disease, a disorder that affects the immune system [49]. |
Cystic Fibrosis | Gene editing technologies could correct the CFTR gene mutation that leads to cystic fibrosis, a disease affecting the lungs and digestive system [50]. |
Cystinosis | A genetic disorder characterized by an accumulation of the amino acid cystine within cells, leading to various symptoms and complications. Gene editing technologies are being explored to correct the CTNS gene, which causes this condition [51]. |
Diabetes | In Type 1 diabetes, the immune system destroys insulin-producing cells. Researchers are exploring gene editing as a potential approach to protect these cells from the immune system or to create new insulin-producing cells [52]. |
Duchenne Muscular Dystrophy | A severe type of muscular dystrophy. Gene editing has shown promise in correcting the gene mutation that causes this condition [53]. |
Dystonia | A movement disorder in which a person’s muscles contract uncontrollably. Gene editing could correct any of the 20+ known genes that can cause this condition, such as TOR1A, THAP1, or GNAL [54]. |
Epidermolysis Bullosa | Gene editing technologies can potentially correct the genetic mutations that cause epidermolysis bullosa, a group of genetic conditions that cause the skin to be very fragile and to blister easily [55]. |
Familial Exudative Vitreoretinopathy | A hereditary disorder that can cause progressive vision loss. Gene editing could correct the FZD4, LRP5, TSPAN12, NDP, or ZNF408 genes, which cause this condition [56]. |
Fanconi Anemia | A rare genetic disease resulting in bone marrow failure. Gene editing could correct the FANCC gene, one of the known genes that causes this condition when mutated [57]. |
Fragile X Syndrome | A genetic disorder causing intellectual disability, behavioral and learning challenges, and various physical characteristics. Gene editing has been proposed as a potential way to correct the FMR1 gene that causes this condition [58]. |
Gaucher Disease | A genetic disorder that affects the body’s ability to break down fats. Gene editing technologies are being explored to correct the GBA gene mutations that cause this condition [59]. |
Glycogen Storage Disease Type Ia | A metabolic disorder caused by the deficiency of glucose-6-phosphatase, the enzyme necessary for the final step of gluconeogenesis and glycogenolysis. Gene editing technologies are being explored to correct the G6PC gene mutations that cause this condition [60]. |
Gorlin Syndrome | A genetic condition affecting many body parts increases the risk of developing various cancerous and noncancerous tumors. Gene editing could correct the PTCH1 gene, which causes this condition [61]. |
Hemophilia A and B | A rare bleeding disorder in which a person lacks or has low levels of specific proteins is called “clotting factors”. Gene editing might correct the F8 or F9 genes, which cause Hemophilia A and B, respectively [62]. |
Hemorrhagic Telangiectasia | A genetic disorder of blood vessel formation causes multiple direct connections between arteries and veins. Gene editing could correct the ENG, ACVRL1, or SMAD4 gene, which can cause this condition [63]. |
HIV/AIDS | Gene editing technology has been used to eradicate HIV from infected cells. This is achieved by targeting the viral DNA integrated into the host genome [64]. |
Huntington’s Disease | This inherited disease causes the progressive breakdown of nerve cells in the brain. Gene editing could potentially correct or deactivate the gene that causes Huntington’s disease [65]. |
Hypertrophic Cardiomyopathy | A disease in which the heart muscle becomes abnormally thick, making it harder for the heart to pump blood. Gene editing might correct the MYH7 gene, which causes this condition [66]. |
Hypophosphatasia | A metabolic disease that disrupts mineralization, processes in which minerals such as calcium and phosphorus are deposited in developing bones and teeth. Gene editing could correct the ALPL gene, which causes this condition [67]. |
Immunodeficiencies | Gene editing may provide treatments for primary immunodeficiencies, like severe combined immunodeficiency (SCID), where gene alterations affect the immune system’s development and function [68]. |
Infertility | Gene editing technology may be utilized to treat genetic disorders that cause infertility, offering hope to many individuals and couples wishing to have children [69]. |
Joubert Syndrome | A genetic disorder characterized by decreased muscle tone, difficulties with coordination, abnormal eye movements, and breathing problems. Gene editing could correct any of the 35 genes that cause this condition, such as AHI1, CEP290, or TMEM67 [70]. |
Juvenile Polyposis Syndrome | A genetic condition characterized by multiple polyps in the gastrointestinal tract. Gene editing could correct the BMPR1A or SMAD4 genes, which cause this condition [71]. |
Leber Congenital Amaurosis | An eye disorder that primarily affects the retina. Gene editing could correct any of the 14 known genes that can cause this condition, such as GUCY2D, RPE65, or CEP290 [72]. |
Leukemia | Specific genetic mutations cause certain forms of leukemia. Gene editing could potentially correct these mutations, leading to improved treatment outcomes [73]. |
Li-Fraumeni Syndrome | A rare, hereditary disorder that significantly increases the risk of developing several types of cancer, particularly in young adults and children. Gene editing could correct the TP53 gene, which causes this condition [74]. |
Long QT Syndrome | A disorder of the heart’s electrical activity can cause sudden, uncontrollable, and irregular heartbeats (arrhythmias), which may lead to premature death. Gene editing could correct any of the 17 known genes that can cause this condition, such as KCNQ1, KCNH2, or SCN5A [75]. |
Lynch Syndrome | A genetic condition that increases the risk of many types of cancer, particularly colorectal cancers. Gene editing could correct the MSH2, MLH1, MSH6, or PMS2 genes, which cause this condition [76]. |
Marfan Syndrome | A genetic disorder affecting the body’s connective tissue. Gene editing has been proposed to correct the faulty gene that causes this syndrome [77]. |
Mitochondrial Diseases | Mitochondrial diseases often result from mutations in the mitochondrial DNA. Scientists have used gene editing techniques to selectively eliminate mutated mitochondrial DNA and prevent these diseases [78]. |
Mucopolysaccharidosis | A group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans. Gene editing could correct any of the 11 known genes that cause these conditions [79]. |
Multiple System Atrophy | A rare neurodegenerative disorder characterized by autonomic dysfunction, parkinsonism, and ataxia. Gene editing could investigate and possibly correct the underlying genetic contributors to this condition, which are not yet fully understood [80]. |
Muscular Dystrophy | Scientists have used gene editing to correct the mutation that causes Duchenne muscular dystrophy in animal models, and clinical trials are in the works [53]. |
Neurodegenerative Disorders | Gene editing can be employed to study and potentially treat neurodegenerative disorders like Parkinson’s, Alzheimer’s, and Huntington’s disease by targeting the specific genes involved in these conditions [81]. |
Neurofibromatosis | Genetic disorders that cause tumors to form on nerve tissue. Gene editing could correct the NF1 or NF2 genes that cause these conditions [82]. |
Niemann-Pick Disease | A group of severe inherited metabolic disorders in which sphingomyelin accumulates in cell lysosomes. Gene editing could correct the SMPD1 gene, which causes types A and B of this disease [83]. |
Oculocutaneous Albinism | A group of conditions that affect the coloring (pigmentation) of the skin, hair, and eyes. Gene editing could correct the OCA2 gene, causing some forms of this condition [84]. |
Osteogenesis Imperfecta | This group of genetic disorders mainly affects the bones, resulting in bones that break easily. Gene editing could correct or compensate for the faulty genes causing these conditions [85]. |
Osteopetrosis | A group of rare, genetic bone disorders that result in the bone being overly dense. Gene editing could correct the TCIRG1, CLCN7, or SNX10 genes, which cause this condition [86]. |
Pantothenate Kinase-Associated Neurodegeneration (PKAN) | A type of neurodegeneration with brain iron accumulation. Gene editing could correct the PANK2 gene, which causes this condition [87]. |
Paraganglioma and Pheochromocytoma | Rare neuroendocrine tumors originate in the adrenal glands or near specific nerves and blood vessels. Gene editing could correct the SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, RET, NF1, TMEM127, or MAX genes, which can cause these conditions [88]. |
Peutz-Jeghers Syndrome | A genetic condition characterized by the development of noncancerous growths called hamartomatous polyps in the gastrointestinal tract and a significantly increased risk of developing certain types of cancer. Gene editing could correct the STK11 gene, which causes this condition [89]. |
Polycystic Kidney Disease | A genetic disorder characterized by the growth of numerous cysts in the kidneys. Gene editing might correct the PKD1 or PKD2 genes, which cause this condition [90]. |
Pompe Disease | A metabolic disorder is caused by the buildup of a complex sugar called glycogen within cells. Gene editing could correct the GAA gene, which causes this condition [91]. |
Prader-Willi Syndrome | This complex genetic condition affects many body parts, causing weak muscle tone, feeding difficulties, poor growth, and delayed development. Using gene editing to reactivate the silenced paternal copy of the genes could provide a cure [92]. |
Progeria | Gene editing technology has shown promise in treating Progeria (also known as Hutchinson-Gilford Progeria Syndrome), a rare, fatal genetic disorder characterized by an appearance of accelerated aging in children. Gene editing can potentially correct the mutation in the LMNA gene associated with this disease [93]. |
Retinal Diseases | Gene editing holds promise in treating inherited retinal diseases. Scientists have successfully used gene editing techniques to correct a mutation causing Leber congenital amaurosis, inherited blindness, breakdown, and loss of cells in the retina. Gene editing might correct any of the 60+ known genes that can cause this condition, such as RHO, RPGR, or USH2A [94]. |
Rett Syndrome | A rare genetic disorder causing severe cognitive and physical impairments. Gene editing could potentially reactivate the silenced MECP2 gene that causes Rett syndrome [95]. |
Sanfilippo Syndrome | A type of Mucopolysaccharidosis, Sanfilippo syndrome is characterized by the body’s inability to break down certain sugars properly. Gene editing technologies are being developed to correct the SGSH gene, which causes this condition [96]. |
Sickle Cell Disease | Gene editing has shown promise in correcting the genetic mutation responsible for sickle cell disease, which causes misshapen red blood cells [97]. |
Spastic Paraplegia | A group of inherited disorders characterized by progressive weakness and stiffness of the legs. Gene editing could correct the SPG11 gene, which causes one of the more common types of this disease [98]. |
Spinocerebellar Ataxias | These genetic diseases are characterized by degenerative changes in the part of the brain related to movement control. Gene editing techniques have been applied in experimental models to correct the associated genetic mutations [99]. |
Tuberous Sclerosis Complex | A genetic disorder characterized by the growth of numerous noncancerous (benign) tumors in many body parts. Gene editing could correct the TSC1 or TSC2 genes that cause this condition [100]. |
Tyrosinemia Type 1 | A rare genetic disorder characterized by multistep disruptions that break down the amino acid tyrosine. Gene editing could correct the FAH gene mutations causing this condition [101]. |
Waardenburg Syndrome | A group of genetic conditions that can cause hearing loss and changes in coloring (pigmentation) of the hair, skin, and eyes. Gene editing could correct the PAX3 or MITF genes, which cause this condition [102]. |
Werner Syndrome | A disorder characterized by the premature appearance of features associated with normal aging. Gene editing could correct the WRN gene, which causes this condition [103]. |
Wilson Disease | A condition where copper builds up in the body, potentially leading to life-threatening organ damage. Gene editing might correct the ATP7B gene mutations causing Wilson’s disease [104]. |
Wolfram Syndrome | A genetic disorder characterized by diabetes mellitus and progressive vision loss. Gene editing could correct the WFS1 or CISD2 genes, which cause this condition [105]. |
X-Linked Agammaglobulinemia | Gene editing can potentially correct mutations in the BTK gene, which cause X-linked agammaglobulinemia, an immune system disorder that leaves the body prone to infections [106]. |
Xenotransplantation | Researchers have used gene editing to remove retroviruses from pig genomes, bringing us one step closer to pig-to-human organ transplants [107]. |
Zellweger Spectrum Disorder | A group of conditions that can affect many body parts. Gene editing could correct any 12 PEX genes known to cause these conditions [108]. |
Product | Developer | Indication |
---|---|---|
ABECMA (idecabtagene vicleucel) | Celgene Corporation | Adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. |
ADSTILADRIN | Ferring Pharmaceuticals A/S | Adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors |
BREYANZI | Juno Therapeutics, Inc. | Adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have: Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or Relapsed or refractory disease after two or more lines of systemic therapy. |
CARVYKTI (ciltacabtagene autoleucel) | Janssen Biotech, Inc. | Adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. |
ELEVIDYS delandistrogene moxeparvovec | Sarepta Therapeutics, Inc. | Ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene. |
GINTUIT (Allogeneic Cultured Keratinocytes and Fibroblasts in Bovine Collagen) | Organogenesis Incorporated | It is an allogeneic cellularized scaffold product indicated for topical (non-submerged) application to a surgically created vascular wound bed in mucogingival conditions in adults. |
HEMGENIX | CSL Behring LLC | HEMGENIX is an adeno-associated virus vector-based gene therapy indicated for adults with Hemophilia B (congenital Factor IX deficiency) who use Factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, spontaneous severe bleeding episodes. |
IMLYGIC (talimogene laherparepvec) | BioVex, Inc. | For the local unresectable cutaneous, subcutaneous, and nodal lesions in patients with recurrent melanoma after initial surgery. |
KYMRIAH (tisagenlecleucel) | Novartis Pharmaceuticals Corporation | KYMRIAH is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for adult patients with relapsed or refractory follicular lymphoma after two or more lines of therapy |
LANTIDRA (donislecel) | CellTrans Inc. | Adults with Type 1 diabetes who cannot approach target hba1c because of repeated episodes of severe hypoglycemia despite intensive diabetes management and education. |
LAVIV (Azficel-T) | Fibrocell Technologies | Improvement of the appearance of moderate to severe nasolabial fold wrinkles in adults. |
LUXTURNA | Spark Therapeutics, Inc. | Patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. |
MACI (Autologous Cultured Chondrocytes on a Porcine Collagen Membrane) | Vericel Corp. | Repair single or multiple symptomatic, full-thickness cartilage defects of the knee with or without bone involvement in adults. MACI is an autologous cellularized scaffold product. |
OMISIRGE (omidubicel-onlv) | Gamida Cell Ltd. | Adults and pediatric patients 12 years and older with hematologic malignancies are planned for umbilical cord blood transplantation following myeloablative conditioning to reduce the time to neutrophil recovery and the incidence of infection. |
PROVENGE (sipuleucel-T) | Dendreon Corp. | Asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone refractory) prostate cancer. |
RETHYMIC | Enzyvant Therapeutics GmbH | For immune reconstitution in pediatric patients with congenital athymia. |
ROCTAVIAN (valoctocogene roxaparvovec-rvox) | BioMarin Pharmaceutical Inc | Adults with severe hemophilia A (congenital factor VIII deficiency with factor VIII activity <1 IU/dL) without pre-existing antibodies to adeno-associated virus serotype five detected by an FDA-approved test. |
SKYSONA (elivaldogene autotemcel) | Bluebird bio, Inc. | To slow the progression of neurologic dysfunction in boys 4–17 years of age with early, active cerebral adrenoleukodystrophy (CALD). |
STRATAGRAFT | Stratatech Corporation | Adults with thermal burns containing intact dermal elements for which surgical intervention is clinically indicated (deep partial-thickness burns). |
TECARTUS (brexucabtagene autoleucel) | Kite Pharma, Inc. | Adult patients with relapsed or refractory mantle cell lymphoma (MCL). New Indication for this supplement: Adult patients with relapsed or refractory (r/r) B-cell precursor acute lymphoblastic leukemia (ALL) |
VYJUVEK | Krystal Biotech, Inc. | Wounds in patients six months of age and older with dystrophic epidermolysis bullosa with mutation(s) in the collagen type VII alpha one chain (COL7A1) gene |
YESCARTA (axicabtagene ciloleucel) | Kite Pharma, Incorporated | Adult patients with large B-cell lymphoma refractory to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy. Axicabtagene ciloleucel is not indicated in patients with primary central nervous system lymphoma. |
ZOLGENSMA (onasemnogene abeparvovec-xioi) | Novartis Gene Therapies, Inc. | Adult and pediatric patients with ß-thalassemia who require regular red blood cell (RBC) transfusions |
ZYNTEGLO (betibeglogene autotemcel) | Bluebird Bio, Inc. | Spinal muscular atrophy (type I) |
Attribute | Meganucleases | Zinc Finger Nucleases | TALENs | CRISPR/Cas9 |
---|---|---|---|---|
Enzyme | Endonuclease | Fok1-nuclease | Fok1-nuclease | Cas9 nuclease |
Target site | LAGLIDADG proteins | Zinc-finger binding sites | RVD tandem repeat region of TALE protein | PAM/spacer sequence |
Recognition sequence size | 12–45 bp | 9–18 bp | 14–20 bp | 3–8 bp/20 bp |
Targeting limitations | MN cleaving site | Difficult to target non-G-rich sites | 5′ targeted base must be a T for each TALEN monomer | The targeted site must precede a PAM sequence |
Advantage | High specificity; Relatively easy to deliver in vivo | Small protein size; Relatively easy in vivo delivery | High specificity; Relatively easy to engineer; targets mitochondrial DNA more efficiently and causes fewer off-target effects than MNs and ZFNs. | Easy to engineer; Easy to multiplex |
Disadvantage | Target locus must be put into the genome; complex to construct; difficult to multiplex; ineffectiveness and potential genotoxicity. The targeted locus must also contain the unique cleavage site for each endonuclease. | Expensive, time-consuming, labor-intensive, difficult to choose the target sequence, needing the coding gene to be custom-built for each target site, and highly off-target gene editing. All ZF domains must also be active. | Challenging to multiplex; not relevant in the case of DNA methylcytosine; a few in vivo deliveries; We should all be engaged; TALEs are nevertheless constrained by their repetitive sequences, which make it difficult to construct them using polymerase chain reaction (PCR), and by the fact that they are unable to target methylated DNA due to the possibility that cytosine methylation will impede TALE binding and alter recognition by its typical RVD. | Lower specificity; Limited in vivo delivery |
DNA-recognition mechanism | HR-introduced Protein-DNA interactions | DSB-introduced by Protein-DNA interactions | DSB-introduced by Protein-DNA interactions | DSB introduced by RNA-guided protein-DNA interactions |
Target specificity | High Positional mismatches are only occasionally accepted. Protein engineering is necessary for re-targeting. | High preference for G-rich sequences Positional mismatches are only occasionally accepted. Protein engineering is necessary for re-targeting. | High Requires a T at each of its target’s five ends. Some positional inconsistencies are accepted. Retargeting necessitates intricate molecular cloning. | Moderate The two base pairs that PAM recognizes must come before the RNA-targeted sequence. Positional mismatches are only occasionally accepted. A new RNA guide is necessary for re-targeting. There is no need for protein engineering. |
Multiplexing | + | + | + | ++++ |
Delivery | accessible by transduction of viral vectors and electroporation | accessible by viral vector transduction and electroporation | simple in vitro conception Due to TALEN DNA’s size and the recombination likelihood, it is challenging in vivo. | simple in vitro The big Cas9′s inadequate packing by viral vectors is the cause of the mild difficulties of distribution in vivo. |
Use as a gene activator | No | Yes endogenous gene activation minimal impacts off-target To target specific sequences, engineering work may be necessary | Yes endogenous gene activation has minimal impacts on off-target There are no time restrictions. | Yes endogenous gene activation minimal impacts off-target “NGG” PAM is necessary adjacent to the target sequence. |
Use as gene inhibitor | No | Yes Works by repressing chromatin to prevent transcriptional elongation. minimal impacts off-target To target specific sequences, engineering work may be necessary. | Yes Works by repressing chromatin to prevent transcriptional elongation. minimal impacts off-target There are no time restrictions. | Yes Works by repressing chromatin to prevent transcriptional elongation. minimal impacts off-target “NGG” PAM is necessary adjacent to the target sequence. |
Cost | High | High | High | Reasonable |
Popularity | Low | Low | Moderate | High |
Online resources | Database and Engineering for LAGLIDADG Homing Endonucleases (http://homingendonuclease.net/, accessed on 7 July 2021) | The Zinc Finger consortiums include software tools and protocols (http://www.zincfingers.org/, accessed on 7 July 2021) ZFNGenome—resources for locating ZFN target sites (https://bindr.gdcb.iastate.edu/ZFNGenome/, accessed on 7 July 2021) | Mojo Hand (http://www.talendesign.org/, accessed on 7 July 2021) or E-TALEN (http://www.e-talen.org/E-TALEN/, accessed on 7 July 2021) for TALEN design CHOPCHOP (https://chopchop.cbu.uib.no/, accessed on 7 July 2021) target site selection | Guide design: Zlab (https://zlab.bio/guide-design-resources, accessed on CRISPOR: http://crispor.tefor.net/, accessed on 7 July 2021; Benchling: https://www.benchling.com, accessed on 7 July 2021 AddGene: https://www.addgene.org/crispr, accessed on 7 July 2021; https://crispr.bme.gatech.edu, accessed on 7 July 2021 http://www.rgenome.net/cas-offinder/, accessed on 7 July 2021 |
Field | Future Developments |
---|---|
Fastest Development | |
Agriculture | The GMOs are already on the table. GE will further revolutionize agriculture by creating more nutritious crops resistant to pests and diseases or adaptable to changing climate conditions [297]. Creating disease-resistant crops [180,298] that bring greater food security [299]. |
Biocomputing | Using DNA in place of silicon chips is already in the early stages of development for data storage and processing [300]. Computers will be built inside living cells to perform complex computations [301]. |
NGS | The next-generation sequencing (NGS) technologies will expand fast and become available at the point of use in clinics, allowing more relevant and critical diagnosis, designing personalized therapies, and preventing long-term illnesses. The cost of this diagnosis will be fully reimbursed since it will prove to be the most significant measure in reducing the cost of healthcare. |
Bioenergy and Environment | Algae and certain bacteria can be edited to produce biofuels more efficiently, and gene editing can also help in bioremediation, where organisms are modified to clean up environmental pollutants [302,303]. Industrial yeasts can produce biofuels and various other chemicals; GE can improve the efficiency and versatility of these yeasts [304]. Gene editing can produce more efficient biofuels or bioplastics by altering microbial pathways, contributing to a more sustainable future [305]. |
Biomaterials | Create organisms that produce new biomaterials with unique properties, opening various industrial and scientific applications [306]. |
Biosensors | Engineer cells to detect specific molecules or conditions, creating biosensors for various applications, from medical diagnostics to environmental monitoring [307]. |
Conservation Efforts | Gene editing could aid conservation by introducing genetic diversity into endangered populations or by engineering invasive species to limit their reproduction [308]. By creating precise genetic modifications, scientists can study evolutionary pathways, development processes, and the intricate interactions of genes in real time [309]. |
CRISPR/Cas9 | CRISPR/Cas 9 has revolutionized the field of genetics and holds immense potential for various applications, from medical treatments to agricultural advancements. Beyond editing, the CRISPR system will be adapted for diagnostics. Platforms like SHERLOCK (Specific High-sensitivity Enzymatic Reporter UnLOCKing) can detect specific DNA or RNA sequences in pathogens [310]. |
Environment | Editing the genes of certain bacteria to make them produce biodegradable plastics offering an environmentally friendly alternative to conventional plastics [311]. To bolster conservation efforts by creating white-footed mice immune to the bacteria causing Lyme disease [308]. Gene drives using CRISPR/Cas9 systems have been proposed to control disease vectors, such as mosquitoes that spread malaria [312]. |
Nutrition | Gene editing can enhance the nutritional content of food crops, potentially addressing malnutrition problems in areas of the world where specific nutrient deficiencies are common [313]. To create versions of common foods that do not trigger allergic reactions. For example, researchers have used gene editing to create a variety of wheat that does not produce the proteins that cause most wheat allergies [314]. |
Personalized Medicine | With an understanding of individual genetic makeup, treatments can be tailored specifically to the genetic profile of each patient, offering better outcomes [315]. |
Synthetic Biology and Biomanufacturing | New organisms can be designed to produce complex organic compounds, pharmaceuticals, or even materials for manufacturing [316]. |
Vaccination | Creating attenuated strains of pathogens for more effective vaccines [317]. |
Slower Development | |
Drug Development | Creating models of human diseases in animals, providing a platform to test new drugs more efficiently using modeling that is not currently available [5]. |
Modifying Microbiomes | The collection of microbes living in and on us, the microbiome, plays a crucial role in our health; they can be modified to promote health and combat diseases [318]. |
Organ Transplants | Using animals like pigs, gene editing can help produce organs suitable for human transplantation [107]. Modify donor organs to increase compatibility with recipients, potentially reducing organ rejection rates [319]. |
Slowest Development | |
Animal Welfare | Improve the well-being of animals; for instance, pigs can be edited to be resistant to diseases, or chickens can be edited to only produce female offspring for egg production [320]. Researchers can use gene editing to create cell cultures or organoids that mimic human tissues for drug testing and disease modeling as an alternative to live animal testing [321]. |
Gene Therapeutics | Targeting and repairing the faulty genes by GE will likely eradicate diseases like cystic fibrosis, Duchenne muscular dystrophy, and sickle cell anemia, which are prime candidates [322]. Beyond editing DNA sequences, tools are being developed to modify the epigenome, which could offer treatments for diseases where epigenetic changes play a role [323]. Many rare genetic disorders, often neglected by mainstream research due to their low prevalence, could be targeted and potentially cured using gene editing [16]. |
Infectious Diseases | To bring extinct species back to life, or “de-extinction”. This would involve using DNA from preserved specimens to edit the genes of a closely related existing species [324]. While controversial, gene editing technologies like CRISPR have raised the possibility of enhancing human abilities beyond normal levels, or “human enhancement” [325]. |
Life Augmentation | By targeting genes involved in aging processes, gene editing may offer strategies to extend healthy human lifespan or combat age-related diseases [326]. For conditions like congenital blindness or deafness due to specific gene mutations, gene editing offers a path to restore these senses [327]. There is potential (albeit controversial) for gene editing to enhance human capabilities, such as increased strength, improved cognitive function, or resistance to diseases [328]. The possibility of enhancing cognitive abilities through gene editing is being explored. While this poses vast ethical dilemmas, it could revolutionize cognitive disorders or brain injury treatments [329]. |
Neurodegenerative Diseases | Gene editing offers promise in the treatment or delay of neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Huntington’s by targeting the causative genes or modifying disease pathways [65]. |
Least Likely | |
Species Modulation | “Designer babies” (e.g., in China in 2018) and species modulations are highly possible since modifications can be passed on to subsequent generations [195]. There is a global consensus to prevent this, but as history will tell, it is impossible to contain a knowledge base. This will happen sooner or later, which may be the pivotal step in human evolution; it is of little concern to the process, whether it is brought in by long-time mutations or planned. We may be responsible for our evolution, not as an accident but as a random evolution design. |
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Niazi, S.K. The Dawn of In Vivo Gene Editing Era: A Revolution in the Making. Biologics 2023, 3, 253-295. https://doi.org/10.3390/biologics3040014
Niazi SK. The Dawn of In Vivo Gene Editing Era: A Revolution in the Making. Biologics. 2023; 3(4):253-295. https://doi.org/10.3390/biologics3040014
Chicago/Turabian StyleNiazi, Sarfaraz K. 2023. "The Dawn of In Vivo Gene Editing Era: A Revolution in the Making" Biologics 3, no. 4: 253-295. https://doi.org/10.3390/biologics3040014