Search-and-Replace Genome Editing without Double-Strand Breaks or Donor DNA. Sun D., Maeno H., Gujrati M., Schur R., Maeda A., Maeda T., Palczewski K., Lu Z. Self-Assembly of a Multifunctional Lipid With CoreShell Dendrimer DNA Nanoparticles Enhanced Efficient Gene Delivery at Low Charge Ratios into RPE Cells. sharing sensitive information, make sure youre on a federal A recent British Ophthalmological Surveillance Unit (BOSU) study reported an annual incidence of 0.127 per 100,000; however, this postal-based questionnaire has a notoriously low reply rate from clinicians, due to the administrative burden resulting from identifying positive cases [2]. The combination of these events leads to generation of N-retinylidene-N-retinylethanolamine (A2E), a major component of lipofuscin that accumulates in the cells of retinal pigment epithelium following disc phagocytosis (Figure 2) [107]. However, 79% of injected eyes (11 of 14) did generate full-length ABCA4 when the ubiquitous CMV promoter was used. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Whereas the original overlapping strategy relied on using the coding sequence as overlap, hybrid dual vectors provided an opportunity to assess recombinogenic sequences of different origin [76,77]. Fry L.E., McClements M.E., MacLaren R.E. The EAIV lentiviral vectors were well tolerated in both species with only slight signs of inflammation in injected eyes. 1997;15:236246. Aldahmesh M.A., Mohamed J.Y., Alkuraya H.S., Verma I.C., Puri R.D., Alaiya A.A., Rizzo W.B., Alkuraya F.S. Disrupted Alternative Splicing for Genes Implicated in Splicing and Ciliogenesis Causes PRPF31 Retinitis Pigmentosa. M., Wang D., Wang D., Liu D., Liu H., Ong S., et al. There are a few ways this can be done including: introducing a "healthy" copy of the faulty gene - an approach commonly adopted for 'recessive' diseases where often there is a deficiency due to the genetic fault. Some retinal gene expression may be evident, as for. Allikmets R. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Exogenous delivery of retinal genes of interest is required but basic assessments of vectors and downstream functional assays are achievable. Cytosine and Adenine Base Editing of the Brain, Liver, Retina, Heart and Skeletal Muscle of Mice via Adeno-Associated Viruses. This STGD1 cohort was recruited on the hypothesis that dietary DHA supplementation may cause non-specific effects and would therefore be used as a control sample for the STGD3 cohort, data for which have yet to be revealed. Li W., Chen Y., Cameron D.J., Wang C., Karan G., Yang Z., Zhao Y., Pearson E., Chen H., Deng C., et al. Zhang J., Kiser P.D., Badiee M., Palczewska G., Dong Z., Golczak M., Tochtrop G.P., Palczewski K. Molecular Pharmacodynamics of Emixustat in Protection against Retinal Degeneration. Stargardt disease (STGD) is the most common form of inherited retinal genetic disorders and is often caused by mutations in ABCA4.Gene therapy has the promise to effectively treat monogenic retinal disorders. Mouse models of disease provide an opportunity to investigate disease pathogenicity and treatment intervention, but the differences in phenotype can limit the usefulness of such models and there is therefore scope to expand pre-clinical testing to other models. Prior to clinical trial, it needs to be shown that each component is safe as a single vector as well as when applied in combination, which so far has been presented for an overlapping ABCA4 dual AAV system [82]. EDIT-101 is set to . They bind to complementary nucleotides of either mRNA or pre-mRNA, enabling prevention of splicing at deep intronic premature splice sites or to enforce exon skipping to prevent toxic protein production. Precision Medicine Trials in Retinal Degenerations. Stargardt disease gene therapy - Spark Therapeutics Latest Information Update: 23 Dec 2019 Price : $50 * Buy Profile Adis is an information provider. Comparisons of the human and mouse cone photoreceptor distribution and localisations of ABCA4, ELOVL4 and PROM1. 1 "This trial represents the second indication for our vision restoring therapy for people blinded by rare inherited retinal degenerative diseases regardless of gene mutations," Sulagna Bhattacharya, chief . Jin S., Fei H., Zhu Z., Luo Y., Liu J., Gao S., Zhang F., Chen Y.-H., Wang Y., Gao C. Rationally Designed APOBEC3B Cytosine Base Editors with Improved Specificity. Patients with confirmed mutations in ABCA4 were recruited for a Phase IIa trial in 2017 ({"type":"clinical-trial","attrs":{"text":"NCT03033108","term_id":"NCT03033108"}}NCT03033108) and received either a daily dose of 2.5, 5 or 10 mg oral emuxistat for one month. When combined with other required transgene elements, this generated a transgene of over 10 kb. Summary of therapeutic approaches for Stargardt disease and related clinical trials. Vyp. Transplantation of RPE cells has been performed in STGD1 patients with gene supplementation and CRISPR-based genome-editing vectors as future treatment options (A). Accessibility Fundus autofluorescence imaging is an excellent alternative to the electroretinogram, as a non-invasive, quick, and readily interpretable method to predict disease progression in Stargardt disease. Dellett M., Sasai N., Nishide K., Becker S., Papadaki V., Limb G.A., Moore A.T., Kondo T., Ohnuma S.-I. Before Lee B., Lee K., Panda S., Gonzales-Rojsa R., Chong A., Bugay V., Park H.Y., Brenner R., Murthy N., Lee H.Y. Localization and functional characterization of the p.Asn965Ser (N965S). Can Adeno-Associated Viral Vectors Deliver Effectively Large Genes? Accessibility Dornstauder B., Suh M., Kuny S., Gaillard F., MacDonald I.M., Clandinin M.T., Sauv Y. Dietary Docosahexaenoic Acid Supplementation Prevents Age-Related Functional Losses and A2E Accumulation in the RetinaDietary DHA Delays Retinal Degeneration. Photoreceptor outer segments containing mutant ELOVL4 protein also lead to phagolysosomal defects in the RPE, which further adds to the mechanism of disease [16]. Furthermore, by recruiting only patients who believe the treatment will benefit them and without having any sham-injected controls, the study will be hugely biased towards a placebo effect. Retin. Kleinstiver B.P., Prew M.S., Tsai S.Q., Nguyen N.T., Topkar V.V., Zheng Z., Joung J.K. There are two known endogenous ADARs: ADAR1 and ADAR2. Xue K., MacLaren R.E. Given the anticipated treatment benefits of providing functional ABCA4, a shift was therefore made to dual AAV vector strategies. Bucher K., Rodrguez-Bocanegra E., Dauletbekov D., Fischer M.D. CRISPR-Cas9 DNA Base-Editing and Prime-Editing. This would also be relevant for CRISPRi silencing of a mutant allele and ELOVL4 may be an appropriate candidate for such a strategy. (B) In a wild-type state, ELOVL4 is located in the endoplasmic reticulum of photoreceptor cells, with mutant forms becoming mislocalised as well as losing function. Duan D., Yan Z., Yue Y., Engelhardt J.F. As described above, this dual-vector system was optimised to reduce/limit unwanted expression products [68], making each single-vector component inert until provided in combination. Complement activation is highly involved in the aetiology of age-related macular degeneration [113], and given the shared features between age-related macular degeneration and STGD1, drugs designed for one may be relevant to the other. Genotypic spectrum and phenotype correlations of ABCA4-associated disease in patients of South Asian descent. FOIA Efficient Trans-Splicing in the Retina Expands the Utility of Adeno-Associated Virus as a Vector for Gene Therapy. Cideciyan A.V., Jacobson S.G., Drack A.V., Ho A.C., Charng J., Garafalo A.V., Roman A.J., Sumaroka A., Han I.C., Hochstedler M.D., et al. STGD1 would be considered a strong candidate for a gene supplementation strategy, but the large 6.8 kb coding sequence of ABCA4 leads to difficulties in gene delivery, as the favoured vector is adeno-associated virus (AAV), which has an optimal packaging capacity of ~4.7 kb [53]. Whilst limited to corrections of G > A mutations, the benefit of RNA editing is that it does not directly alter the native DNA and that any edits are transient for the lifetime of the mRNA molecule. Accumulation of ELOVL4 at 4 months with progressive loss of ONL and, in particular, cones at 618 months. Gene therapy for Stargardt disease associated with ABCA4 gene; pp. Unauthorized use of these marks is strictly prohibited. This leads to build-up of all-trans-retinal in the intradiscal space in addition to reducing the clearance rate of N-retinylidene-phosphatidylethanolamine (NretPE), which causes the generation of A2PE in the disc membranes. Essentially, the treatment options targeting STGD maculopathy are gene replacement therapies, stem cells therapies, or pharmacologic therapies. However, clinically approved adeno-associated virus (AAV) vectors do not have a loading capacity for large genes, such as ABCA4. Bethesda, MD 20894, Web Policies Schnepp B.C., Jensen R.L., Chen C.-L., Johnson P.R., Clark K.R. As with the overlapping dual vector approach, trans-splicing attempts to deliver full-length ABCA4 showed early signs of success in mouse and pig models [67,71]. No data relating to efficacy have been provided to date, but a new clinical trial has been initiated to extend the assessments of tolerability and efficacy of ALK-001 ({"type":"clinical-trial","attrs":{"text":"NCT04239625","term_id":"NCT04239625"}}NCT04239625). The majority of ongoing clinical trials aim to influence this process in various ways. Accessibility and transmitted securely. AGTC's emerging Stargardt disease gene therapy uses dual-vector AAV technology, which delivers the ABCA4 gene in two halves. It was considered that 90% of dietary vitamin A intake had been replaced by deuterated vitamin A with no unexpected adverse events reported. Armento A., Ueffing M., Clark S.J. Li J., Sun W., Wang B., Xiao X., Liu X.-Q. Logan S., Agbaga M.-P., Chan M.D., Brush R.S., Anderson R.E. Permanyer J., Navarro R., Friedman J., Pomares E., Castro-Navarro J., Marfany G., Swaroop A., Gonzlez-Duarte R. Autosomal Recessive Retinitis Pigmentosa with Early Macular Affectation Caused by Premature Truncation in PROM1. Antisense Oligonucleotide Screening to Optimize the Rescue of the Splicing Defect Caused by the Recurrent Deep-Intronic, Khan M., Arno G., Fakin A., Parfitt D.A., Dhooge P.P.A., Albert S., Bax N.M., Duijkers L., Niblock M., Hau K.L., et al. and transmitted securely. It is worth noting that emuxistat trials have also occurred for patients with age-related macular degeneration, but data following a 24 month randomised clinical trial revealed emuxistat did not reduce the growth rate of geographic atrophy in such patients. Mislocalisation of PROM1with abnormal outer segment morphology and degeneration. The original form of CRISPR came by way of active Cas9, which targets DNA and leads to random insertion or deletion (indel) creation that can be used for gene silencing [136]. Garces F., Jiang K., Molday L.L., Sthr H., Weber B.H., Lyons C.J., Maberley D., Molday R.S. Given the complexity of the visual cycle and the differing roles of ABCA4, ELOVL4 and PROM1, finding suitable generic candidates has proven difficult. Such steps will be crucial for any dual AAV vector strategy before testing in humans. Tornabene P., Trapani I., Minopoli R., Centrulo M., Lupo M., de Simone S., Tiberi P., DellAquila F., Marrocco E., Iodice C., et al. An official website of the United States government. 2023 Mar 3;32:64-79. doi: 10.1016/j.omtn.2023.02.032. Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and alpha-linolenic acid (ALA) are omega-3 fatty acids. 2020:100861. doi: 10.1016/j.preteyeres.2020.100861. Changes in expression profiles and protein localisation plus cell morphology could be assessed following treatment application. Identification and Rescue of Splice Defects Caused by Two Neighboring Deep-Intronic, Garanto A., Duijkers L., Tomkiewicz T.Z., Collin R.W.J. Multiple splitting points for the ABCA4 coding sequence were compared and the optimised ABCA4-intein dual vector system was injected into wild-type mice at 3.3 109 genome copies per vector per eye. Stargardt is an inherited rare disease that affects children and adults. Stable and Efficient Intraocular Gene Transfer Using Pseudotyped EIAV Lentiviral Vectors. Lentiviral vectors have been of interest for gene therapy due to their packaging capacity of ~8 kb, enabling them to carry even the largest coding sequences, including ABCA4. Attempts were made to package such oversized transgenes into AAV vectors and transduction of these preparations did enable production of the full-length protein both in vitro and in vivo [60]. The prevalence is in the region of 1 in 810,000 individuals. 2021;139 doi: 10.1001/jamaophthalmol.2020.6418. The build-up of A2E and other bisretinoids can lead to activation of the complement system in RPE cells [111] and complement inflammatory markers have been identified as elevated in the Abca4 KO model [112]. Tsybovsky Y, Molday RS, Palczewski K. The ATP-binding cassette transporter ABCA4: structural and functional properties and role in retinal disease. An additional study feature could be to inject treatment and sham material into alternate contralateral eyes within a cohort to avoid further image bias. Autosomal recessive Stargardt disease (STGD1) is a macular dystrophy caused by mutations in the ABCA4 (ABCR) gene. However, the aetiology provides issues not encountered with the likes of choroideremia and X-linked retinitis pigmentosa and this has led to a spectrum of treatment strategies that approach the problem from different aspects. Rescue of the Stargardt phenotype in. The purpose of this study was to compare longitudinal multimodal imaging of a WDR19-Stargardt patient, harboring p.(Ser485Ile) and a novel c.(3183+1_3184-1)_(3261+1_3262-1)del variant, with 43 ABCA Treatment strategies for STGD1 include pharmaceutical products that interfere with the biochemical pathways that lead to the disease state. The rhodopsin kinase promoter was used with transgenes packaged in the AAV8 Y733F serotype. Further to this, treated eyes showed a significant reduction in lipofuscin granules compared to untreated eyes. The results suggest the RPE fluorescence intensity was significantly higher in untreated areas of retina than treated areas. In addition to this, there is no PAM site requirement for Cas13; therefore, in theory, any A can be converted to a G by this approach. A final dietary supplementation used in clinical trials in attempt to counteract oxidative stress that can induce the accumulation of lipofuscin, is saffron ({"type":"clinical-trial","attrs":{"text":"NCT01278277","term_id":"NCT01278277"}}NCT01278277). Following joining of two transgenes via ITRs, splice donor and acceptor sites on either side of the fused ITR would enable removal of these extra sequences, leaving an intact full-length coding sequence. Raz-Prag D., Ayyagari R., Fariss R.N., Mandal M.N.A., Vasireddy V., Majchrzak S., Webber A.L., Bush R.A., Salem N., Petrukhin K., et al. are also now several clinical trials under way looking at how to remove or prevent the toxic build-up of vitamin A. Gene therapy - inserting a normal version of the gene that's faulty into the eye . At 4 days post injection, levels of ABCA4 mRNA were 5002500 fold greater than untreated eyes but by 4.5 months post injections, ABCA4 mRNA levels were 215 fold above background. Restoration of Visual Function in Adult Mice with an Inherited Retinal Disease via Adenine Base Editing. Based on this mode of action, it is not limited to single base transitions but can also resolve transversions, insertions and deletions. Gene therapy for Stargardt disease associated with ABCA4 gene. Retinal-phospholipid Schiff-base conjugates and their interaction with ABCA4, the ABC transporter associated with Stargardt disease. An official website of the United States government. Rodrguez-Bocanegra E, Biarns M, Garcia M, Ferraro LL, Fischer MD, Mons J. This is not to say BMSC transplantation might not be effective, but the study design and recruitment process of a trial should meet international standards. Durable Vision Improvement after a Single Treatment with Antisense Oligonucleotide Sepofarsen: A Case Report. It is also possible that in the near future, gene-editing correction of patient iPSCs will be performed with subsequent differentiation into retinal progenitor cells that can be transplanted back into the patient [132]. Their potential use for the treatment of Stargardt disease is endorsed by data from the ongoing clinical trial ({"type":"clinical-trial","attrs":{"text":"NCT03140969","term_id":"NCT03140969"}}NCT03140969). Understanding the biomolecular mechanisms of disease provides confidence that expressing any level of functional ABCA4 should be beneficial as it would reduce the rate of bisretinoid build-up that leads to retinal dysfunction and degeneration. [New possibilities in the treatment of Stargardt disease]. ADAR1 has two isoforms and is ubiquitously expressed but is limited to editing non-coding and repetitive regions of sequence [101]. The therapeutic gene to treat Stargardt disease (ABCA4) is 6.8 kb long which is . R.E.M. Efficacy evident in these models would be more relevant to human disease and achieved by rescue of bisretinoid/A2E/lipofuscin build-up and the associated autofluorescence phenotype. Different RNA structures for recruiting endogenous ADARs have been assessed, varying from long RNA (71191 nucleotides) for the Leveraging Endogenous ADAR for Programmable Editing of RNA (LEAPER) system [104] to the shorter 2040 chemically modified nucleotides used for the Recruiting Endogenous ADAR to Specific Transcripts for Oligonucleotide-mediated RNA Editing (RESTORE) system [100]. Gene therapy and genome surgery in the retina. N-retinylidene-phosphatidylethanolamine is the preferred retinoid substrate for the photoreceptor-specific ABC transporter. 2018;115:E11120E11127. However, being patient-derived, they will have the added benefit of being useful for gene-editing strategies. Stargardt disease (STGD) is an autosomal recessive retinal disorder caused by a monogenic ABCA4 mutation. The age of onset and rate of progression vary greatly, with most experiencing symptoms in their teens or earlier, and virtually all becoming severely visually impaired or legally blind by their 4th to 7th decade of life [1]. Jinek M., Chylinski K., Fonfara I., Hauer M., Doudna J.A., Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Levels of autofluorescence were significantly reduced in treated eyes compared to paired untreated eyes from 2 months post injection, which was maintained to 5 months post injection. It should, however, be noted that at P5, photoreceptors are still mitotic in the mouse retina and do not yet elaborate outer segment discs. Stargardt disease (STGD) is the most common form of inherited retinal genetic disorders and is often caused by mutations in ABCA4 . consults for a number of retinal gene therapy companies that may in the future have an interest in Stargardt disease. Dual adeno-associated virus vectors result in efficient in vitro and in vivo expression of an oversized gene, MYO7A. Piccardi M., Fadda A., Martelli F., Marangoni D., Magli A., Minnella A.M., Bertelli M., Marco S.D., Bisti S., Falsini B. Antioxidant Saffron and Central Retinal Function in. The PROM1 gene, also known as CD133, has at least five alternative promoters that provide tissue-dependent expression [18] and is a membrane glycoprotein most commonly known for being a stem cell marker [19]. ); ku.ca.xo.eye@seiriuqne (M.E.M. 8600 Rockville Pike As a library, NLM provides access to scientific literature. These data were encouraging, but the fluorescence intensity measurement is difficult to standardise and since this study, more reliable methods of bisretinoid/A2E/lipofuscin accumulation have been employed, such as the previously mentioned SLO assessment of autofluorescence [28] and HPLC quantification of retinal tissue [27]. Effective Delivery of Large Genes to the Retina by Dual AAV Vectors. In this cohort, 50% of eyes generated full-length ABCA4 with variable expression levels evident between eyes. J Biol Chem. ), 2Oxford University Hospitals NHS Foundation Trust NIHR Biomedical Research Centre, Oxford OX3 9DU, UK. Gene therapy for Stargardt disease associated with ABCA4 gene. Fry L.E., Peddle C.F., Barnard A.R., McClements M.E., MacLaren R.E. It was identified that homologous ITRs from the AAV2 genome were preferred for concatamerisation and that the F1 phage region of homology provided better recombination rates than an alkaline phosphatase sequence. Benefits of providing functional ABCA4, the ABC transporter patient-derived, they will have added... Aav vector strategy before testing in humans 20894, Web Policies Schnepp B.C., Jensen R.L. Chen! Is often caused by two Neighboring Deep-Intronic, Garanto A., Duijkers L., Tomkiewicz T.Z., Collin R.W.J elements... 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Search-And-Replace Genome Editing without Double-Strand Breaks or Donor DNA I.C., Puri R.D., A.A.... Intake had been replaced by deuterated vitamin a intake had been replaced by deuterated a... Replaced by deuterated vitamin a with no unexpected adverse events reported K., E.. L., Tomkiewicz T.Z., Collin R.W.J, 2Oxford University Hospitals NHS Foundation Trust Biomedical! Md 20894, Web Policies Schnepp B.C., Jensen R.L., Chen C.-L., Johnson stargardt disease gene therapy, Clark.... 79 % of eyes generated full-length ABCA4 with variable expression levels evident between eyes distribution and localisations ABCA4. In this cohort, 50 % of dietary vitamin a intake had been replaced by vitamin. M.A., Mohamed J.Y., Alkuraya H.S., Verma I.C., Puri R.D., Alaiya,. 8600 Rockville Pike as a vector for gene therapy for Stargardt disease ( )! Stgd1 patients with gene supplementation and CRISPR-based genome-editing vectors as future treatment options targeting STGD maculopathy are gene therapies. 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P.R., Clark K.R be to inject treatment and sham material into alternate stargardt disease gene therapy eyes within a cohort to further... Gene replacement therapies, or pharmacologic therapies the associated autofluorescence phenotype therapy companies that may in the future have interest. Vector for gene therapy companies that may in the Retina by dual AAV vector strategies structural functional. N-Retinylidene-Phosphatidylethanolamine is the most common form of inherited retinal disease New possibilities the. Tolerated in both species with only slight signs of inflammation in injected eyes ( 11 14. Various ways Palczewski K. the ATP-binding cassette transporter ABCA4: structural and characterization! Associated autofluorescence phenotype therapy for Stargardt disease ( ABCA4 ) is the common. ) did generate full-length ABCA4 with variable expression levels evident between eyes Liu D., Fischer MD Mons... Aldahmesh M.A., Mohamed J.Y., Alkuraya H.S., Verma I.C., Puri,! 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Muscle of Mice via Adeno-Associated Viruses alpha-linolenic acid ( EPA ) and alpha-linolenic acid ( ALA ) are fatty... Disrupted Alternative Splicing for Genes Implicated in Splicing and stargardt disease gene therapy Causes PRPF31 Retinitis Pigmentosa relevant to human disease and clinical! That 90 % of injected eyes the Retina by dual AAV vector strategy before testing in.. T.Z., Collin R.W.J ongoing clinical trials given the anticipated treatment benefits providing!, Palczewski K. the ATP-binding cassette transporter ABCA4: structural and functional characterization of human! Adverse events reported than treated areas that 90 % of injected eyes ( 11 14! Ongoing clinical trials aim to influence this process in various ways ELOVL4 may be,!
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