54 research outputs found
Molecular Therapies for Inherited Retinal Diseases
Get PDFFollowing the implementation of next-generation sequencing technologies (e.g., exome and genome sequencing) in molecular diagnostics, the majority of genetic defects underlying inherited retinal disease (IRD) can readily be identified. In parallel, opportunities to counteract the molecular consequences of these defects are rapidly emerging, providing hope for personalized medicine. ‘Classical’ gene augmentation therapy has been under study for several genetic subtypes of IRD and can be considered a safe and sometimes effective therapeutic strategy. The recent market approval of the first retinal gene augmentation therapy product (LuxturnaTM, for individuals with bi-allelic RPE65 mutations) by the FDA has not only demonstrated the potential of this specific approach, but also opened avenues for the development of other strategies. However, every gene—or even every mutation—may need a tailor-made therapeutic approach, in order to obtain the most efficacious strategy with minimal risks associated. In addition to gene augmentation therapy, other subtypes of molecular therapy are currently being designed and/or implemented, including splice modulation, DNA or RNA editing, optogenetics and pharmacological modulation. In addition, the development of proper delivery vectors has gained strong attention, and should not be overlooked when designing and testing a novel therapeutic approach. In this Special Issue, we aim to describe the current state of the art of molecular therapeutics for IRD, and discuss existing and novel therapeutic strategies, from idea to implementation, and from bench to bedside
Applications of antisense oligonucleotides for the treatment of inherited retinal diseases
No full textPreface of Special Issue "Molecular Therapies for Inherited Retinal Diseases"
No full textContains fulltext :
218308.pdf (Publisher’s version ) (Open Access)Inherited retinal diseases (IRDs) are a group of progressive disorders that lead to severe visual impairment or even complete blindness. IRDs display a vast heterogeneity, clinically as well as genetically, with over 250 genes identified in which mutations can cause one or more clinical subtypes of IRD. Long considered incurable diseases, intense research over the last two decades, combined with major technological advancements, have enabled the development of the first therapeutic approaches for these diseases. The approval of LuxturnaTM (voretigene neparvovec), a gene augmentation therapy vector for RPE65-associated IRD, by the US Food and Drug Administration and the European Medicines Agency, is considered a true milestone in the field, and has led to the development of similar, or different therapeutic strategies for many other subtypes of IRD. Despite these major achievements, there are still many aspects that can-and need to-be improved, including more insights into the relationship between genetic variation and cellular dysfunction, optimization of the vectors and sequences used, improving delivery methods, as well as understanding and modulating the (local) immune response. In addition, the extreme rarity of some genetic subtypes of IRDs poses an enormous challenge on the development of novel therapies, in terms of e.g., costs and regulatory affairs.[...]
The numerical solution of waveguide discontinuity problems
Get PDFA computational method for solving a wide range of transverse and longitudinal waveguide discontinuity problems is described. Results are obtained by the simultaneous solution of matrix equations, generated by Fourier analysis, which relate the complex amplitudes of orthogonal electric and magnetic field components. In some cases the solution is found to be sensitive to the way in
which infinite series of field functions are truncated, and it is shown how the optimum form of truncation can be determined for many configurations of practical importance.
Several examples showing the application of the method are
given, and comparison of results with those obtained by experiment, and by other analytical techniques, confirms its accuracy.
The application of the method in the design of discontinuities for higher-mode generation in multimode antennas is considered, particularly in connection with a multimode monopulse feed for a satellite-communication reflector antenna. Primary and secondary characteristics are determined theoretically for various modeconverter
configurations, allowing those giving satisfactory allround
performance to be selected. Comparison with conventional
feeds shows the multimode feed to be superior in many respects. A prototype multimode feed is constructed, and theoretical primary radiation patterns are compared with those obtained experimentally
Generation of iPSC lines from three Stargardt patients carrying bi-allelic ABCA4 variants
No full textStargardt disease, a progressive retinal disorder, is associated with bi-allelic variants in ABCA4, a protein that is expressed in the retina. Induced pluripotent stem cell lines (RMCGENi005-A, SCTCi018-A, SCTCi017-A) were generated by lentivirus reprogramming of fibroblasts derived from Stargardt patients carrying different bi-allelic ABCA4 variants. All the generated lines showed pluripotent characteristics and no chromosomal aberrations. The availability of these lines will allow us to generate patient-derived photoreceptor precursor cells and retinal organoids to further study ABCA4 and thereby, Stargardt disease in relevant model systems carrying the patient’s genetic background
Generation of three isogenic control lines from patient-derived iPSCs carrying bi-allelic ABCA4 variants underlying Stargardt disease
No full textStargardt disease, a progressive retinal disorder, is associated with bi-allelic variants in ABCA4. Employing the CRISPR/Cas9 approach, we generated isogenic control lines (RMCGENi005-A-1, RMCGENi018-A-1, RMCGENi017-A-1) for each of three induced pluripotent stem cell lines (RMCGENi005-A, RMCGENi018-A, RMCGENi017-A) derived from Stargardt patients carrying compound heterozygous ABCA4 variants. All of the generated lines showed pluripotent characteristics, no chromosomal aberrations and no indication of off-targets. The availability of these isogenic control lines will allow us to have a fair comparison between health and disease state within our studies on Stargardt disease
Joining forces to develop individualized antisense oligonucleotides for patients with brain or eye diseases:the example of the Dutch Center for RNA Therapeutics
Get PDFAntisense oligonucleotides (ASOs) offer versatile tools to modify the processing and expression levels of gene transcripts. As such, they have a high therapeutic potential for rare genetic diseases, where applicability of each ASO ranges from thousands of patients worldwide to single individuals based on the prevalence of the causative pathogenic variant. It was shown that development of individualized ASOs was feasible within an academic setting, starting with Milasen for the treatment of a patient with CLN7 Batten’s disease in the USA. Inspired by this, the Dutch Center for RNA Therapeutics (DCRT) was established by three academic medical centers in the Netherlands with a track record in ASO development for progressive, genetic neurodegenerative, neurodevelopmental, and retinal disorders. The goal of the DCRT is to bundle expertise and address national ethical, regulatory, and financial issues related to ASO treatment, and ultimately to develop individualized ASOs for eligible patients with genetic diseases affecting the central nervous system in an academic, not-for-profit setting. In this perspective, we describe the establishment of the DCRT in 2020 and the achievements so far, with a specific focus on lessons learned: the need for processes and procedures, the need for global collaboration, the need to raise awareness, and the fact that N-of-1 is N-of-a-few.</p
Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders
No full textCone photoreceptor disorders form a clinical spectrum of diseases that include progressive cone dystrophy (CD) and complete and incomplete achromatopsia (ACHM). The underlying disease mechanisms of autosomal recessive (ar)CD are largely unknown. Our aim was to identify causative genes for these disorders by genome-wide homozygosity mapping. We investigated 75 ACHM, 97 arCD, and 20 early-onset arCD probands and excluded the involvement of known genes for ACHM and arCD. Subsequently, we performed high-resolution SNP analysis and identified large homozygous regions spanning the PDE6C gene in one sibling pair with early-onset arCD and one sibling pair with incomplete ACHM. The PDE6C gene encodes the cone alpha subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5'-GMP, and thereby plays an essential role in cone phototransduction. Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs. Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families. One patient had a frameshift mutation and a splice defect; the other two had a splice defect and a missense variant (p.M455V). Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD. Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes
Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
No full textContains fulltext :
70831.pdf (Publisher’s version ) (Open Access
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