1,721,129 research outputs found
Gene Therapy - Evolution and Therapeutic Applications (Slides)
No full textPrinciples of gene therapy; Gene therapy paradigms; In vivo v/s ex vivo gene therap
Genetic Manipulation for Inherited Neuodegenerative Diseases - Myth or Reality? (slideshow)
No full textThe genetic revolution of the past 25 years has transformed our understanding of the genetic basis of human neurodegenerative diseases. The causative genes for a large number of well-recognised clinical entities have been identified and the pace of discovery will only accelerate further as next-generation whole-genome sequencing becomes routinely available to clinicians. In addition to classical monogenetic diseases with high penetrance, it is now clear that the majority of common late-onset neurodegenerative disorders are heavily determined by a complex cluster of genetic variants, each contributing to the overall risk of developing overt clinical disease, and in some cases having a synergistic deleterious interaction with environmental triggers. Unfortunately, the significant advances made in deciphering the genetic factors that contribute to the underlying neuropathological process have so far resulted in limited therapeutic benefits for patients. A number of factors have contributed to this frustrating translational gap and the challenges that remain are daunting. This review will provide a critical overview of genetic strategies that are being pioneered to halt or reverse disease progression in inherited neurodegenerative diseases. This field of research covers a vast area and only the most promising treatment paradigms will be discussed with a particular focus on inherited eye diseases, which have paved the way for innovative gene therapy paradigms, and mitochondrial diseases, which are currently generating a lot of debate centred on the bioethics of germline manipulation
Chronic Progressive External Ophthalmoplegia Secondary to Nuclear-Encoded Mitochondrial Genes
No full textTreatment of Hereditary Optic Neuropathies
No full textHereditary optic nerve disorders result in significant chronic visual morbidity and the minimum prevalence of affected individuals in the population has been estimated at 1 in 10,000.1 Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA) are the two classical paradigms for this group of disorders and they comprise nearly half of all the inherited optic atrophy cases seen in clinical practice. LHON is caused by mitochondrial DNA (mtDNA) point mutations whereas in DOA, the majority of cases are due to pathogenic mutations in the OPA1 gene, which codes for an inner mitochondrial membrane protein. Strikingly, both LHON and DOA share the same characteristic pathological features with selective degeneration of the retinal ganglion cell (RGC) layer leading to progressive optic nerve degeneration and the onset of visual symptoms. RGCs are therefore exquisitely sensitive to mitochondrial dysfunction and the elucidation of the mechanisms involved is opening the way for therapeutic interve ions targeting different stages of the disease process. In this review, recent advances in our understanding of LHON and DOA will be discussed, in addition to the practical management of this group of patients and emerging treatment options
Harnessing the Power of Genetic Engineering for Patients With Mitochondrial Eye Diseases
No full textMitochondrial diseases affect at least 1 in 4,300 people and as a group, it represents the most common form of inherited neuromuscular diseases in the population (1,2). The associated clinical phenotype is extremely heterogeneous, ranging in severity from early-onset, frequently fatal, childhood encephalomyopathies to late-onset, progressive neurodegenerative syndromes that result in significant chronic morbidity and impaired quality of life. Ocular involvement is a prominent feature and over half of all patients with an underlying mitochondrial cytopathy will manifest one or more ophthalmologic manifestations with a particular predilection for the optic nerve, the outer retina, and the extraocular muscles. Vision is the most precious of our senses and unsurprisingly, the risk of blindness is a major cause of concern for patients and their families. The first pathogenic mutations associated with mitochondrial disease were identified in 1988 and the intervening years have witnessed an exponential increase in the number of causative genes and a better understanding of the disease mechanisms that contribute to cell loss and clinical deterioration. Despite these remarkable achievements, effective treatments for patients with mitochondrial disease still remain elusive and the translational gap remains to be bridged. Although one cannot underestimate the scale of the challenges involved, we have now reached a confluence of scientific and technological breakthroughs that could herald the dawn of a new era of personalized genetic medicine. In this review, we will cover potentially transformative therapeutic strategies for patients with mitochondrial eye diseases, including the unknowns and the ethical considerations
Harnessing the Power of Genetic Engineering for Patients With Mitochondrial Eye Diseases
No full textMetabolomic and Biomarker Profiling in Mitochondrial Optic Neuropathies (video)
No full textMitochondrial optic neuropathies constitute an important cause of registrable blindness in both the paediatric and adult population. The two classical paradigms are Leber hereditary optic neuropathy (LHON), which is a primary mitochondrial DNA (mtDNA) disorder, and autosomal dominant optic atrophy (DOA) secondary to pathogenic mutations within the nuclear gene OPA1 (3q28-q29) that encodes for a mitochondrial inner membrane protein. Recessive and dominant WFS1 mutations have also emerged as an important cause of both isolated and syndromic optic atrophy. WFS1 (4p16.1) encodes for the transmembrane endoplasmic reticulum (ER) protein Wolframin that plays a critical role in calcium homeostasis and interorganellar cross-talk at areas of ER mitochondria; contacts. The defining neuropathological feature of all these mitochondrial optic neuropathies is the preferential loss of retinal ganglion cells (RGCs), but the marked phenotypic variability observed in this patient group and the disease mechanisms that ultimately contribute to RGC loss still need to be clarified further
Metabolomic and Biomarker Profiling in Mitochondrial Optic Neuropathies (abstract)
No full textMitochondrial optic neuropathies constitute an important cause of registrable blindness in both the paediatric and adult population. The two classical paradigms are Leber hereditary optic neuropathy (LHON), which is a primary mitochondrial DNA (mtDNA) disorder, and autosomal dominant optic atrophy (DOA) secondary to pathogenic mutations within the nuclear gene OPA1 (3q28-q29) that encodes for a mitochondrial inner membrane protein. Recessive and dominant WFS1 mutations have also emerged as an important cause of both isolated and syndromic optic atrophy. WFS1 (4p16.1) encodes for the transmembrane endoplasmic reticulum (ER) protein Wolframin that plays a critical role in calcium homeostasis and interorganellar cross-talk at areas of ER mitochondria; contacts. The defining neuropathological feature of all these mitochondrial optic neuropathies is the preferential loss of retinal ganglion cells (RGCs), but the marked phenotypic variability observed in this patient group and the disease mechanisms that ultimately contribute to RGC loss still need to be clarified further
Gene Therapy - Evolution and Therapeutic Applications (Video)
No full textPrinciples of gene therapy; Gene therapy paradigms; In vivo v/s ex vivo gene therap
- …
