miércoles, 15 de octubre de 2008
Diagnosis and Treatment of Childhood
Leber’s Hereditary Optic Neuropathy (LHON)
Leber’s Hereditary Optic Neuropathy (LHON)
LHON is a genetic disease that results in the degeneration of nerve cells in the retina and optic nerve, leading to the rapid loss of central vision and blindness. The disease affects young adult males predominantly.
The effects of LHON are rapid and severe, with the damage to retinal and optic neurons cells leading to blindness within a few months after the onset of symptoms. The symptomatic phase of the disease begins with blurring of central vision. Both eyes are usually affected within several months of symptom onset in the first eye. Within 12 months over 97% of patients will experience vision loss in the second eye, most often leaving them severely visually impaired.
Santhera has been granted orphan drug designation in the US and Europe for SNT-MC17 in LHON.
Clinical development of SNT-MC17 (INN: idebenone) in LHON
Santhera is currently recruiting patients for a Phase IIa (proof-of-concept) at the University of Munich in Germany and at the University of Newcastle in the UK.
The study, which is a double-blind, randomized and placebo-controlled trial, is designed to assess the efficacy of SNT-MC17 in the treatment as well as the prevention of vision loss in LHON patients. 84 LHON patients will be recruited for the study and they will be treated for a period of six months. Patients experiencing vision loss for up to 5 years are eligible to enroll.
SNT-MC17 for treatment of Leber's Hereditary Optic Neuropathy / Leber hereditäre Optikusneuropathie / Neuropathie Optique Héréditaire de Leber
Axonal loss and neuroprotection in optic neuropathies
Gene therapy prevents blindness in an animal model of mitochondrial dysfunction
The most common forms of metabolic disorders are due to mutations in mitochondrial DNA (mtDNA). Mitochondria are the cell's energy producers, and mitochondrial diseases involve tissues with high energy needs, such as retina, brain, heart, muscle, liver, and endocrine systems. Although 300 mtDNA alterations have been identified as the genetic cause of mitochondrial diseases, there are not, as of yet, any effective treatments available. "Despite progress made in identification of their molecular mechanisms, little has been done regarding therapy," says senior author Dr. Marisol Corral-Debrinski from the Pierre and Marie Curie University in Paris.
Dr. Corral-Debrinski and colleagues recently perfected a strategy for expression of mitochondrial genes transferred to the nucleus; such expression is called allotropic expression. "We obtained a complete and long-term restoration of mitochondrial function in human fibroblasts in which the mitochondrial genes ATP6, ND1, and ND4 were mutated," explains Dr. Corral-Debrinski. ND1 and ND4 are mutated in nearly all cases of Leber hereditary optic neuropathy (LHON). LHON is the most common mitochondrial disorder and is characterized by a loss of vision.
The researchers sought to create and animal model of LHON to further test their technique and work toward clinical application of their strategy. They introduced the human ND4 gene with the mutation present in the majority of LHON patients into rat eyes. The treatment caused retinal ganglion cells (RGCs) to degenerate significantly when compared to those from control eyes and was associated with decreased visual performance. Importantly, reintroducing normal ND4 led to prevention of RGC loss and visual impairment, effectively rescuing the animals from impending blindness.
"These data represent the 'proof of principle' that optimized allotropic expression is effective in vivo and can be envisaged as a therapeutic approach for mtDNA-related diseases," concludes Dr. Corral-Debrinski. "The next step towards our goal of clinical trials for preventing blindness in patients suffering from LHON disease will be to assess the long-term safety of our approach in large animals."
The researchers include Sami Ellouze, Sébastien Augustin, Aicha Bouaita, Crystel Bonnet, Manuel Simonutti, Valérie Forster, Serge Picaud, Jose-Alain Sahel and Marisol Corral-Debrinski, of the Institut de la Vision, Université Pierre et Marie Curie-Paris, Paris, France.
Experience of the LHON Treatment Trial
Progression of Visual Field Defects in Leber Hereditary Optic Neuropathy: Experience of the LHON Treatment Trial
Nancy J. Newman MDa, b, c, , , Valérie Biousse MDa, b, Steven A. Newman MDd, M. Tariq Bhatti MDe, Steven R. Hamilton MDf, Bradley K. Farris MDg, Robert L. Lesser MDh and Roger E. Turbin MDi
Accepted 22 December 2005.
Purpose
To describe the visual fields of patients with Leber hereditary optic neuropathy (LHON), a maternally inherited disorder characterized by bilateral, often sequential vision loss, before and during progressive visual deterioration.
Design
Prospective longitudinal follow-up of serial visual fields in patients enrolled onto an open-label, nonrandomized pilot study of topical brimonidine purite as prophylactic treatment after first eye involvement in LHON.
Methods
Nine molecularly confirmed primary mutation patients with LHON with monocular vision loss for less than six months and normal visual function in the other eye were followed prospectively for up to two years. Visual fields were performed on automated perimetry at baseline and on many follow-up visits.
Results
Despite normal visual acuity at baseline in all patients, seven patients had some minimal changes in the central visual field of the second eye. All patients had subsequent deterioration of visual acuity, mean deviation, and foveal sensitivity in their second eye. The earliest pattern of abnormality was typically a cecocentral defect enlarging to become a central defect, often with a superior or inferior predilection. The visual field defects in the two eyes of any given patient were remarkably similar.
Conclusions
LHON may be a bilateral condition at onset more frequently than appreciated. Automated static perimetry of the “normal” eye may reveal subclinical findings that typically worsen rapidly over weeks to months to similar central scotomatous damage. Quantitative automated static perimetry is helpful in elucidating the natural history of LHON and in understanding the underlying pathology and pathophysiology of this disease.