Second Meeting of the British Society of Neuro-Otology

http://www.bsno.org.uk/Oct28-2002-abstracts.pdf

Diagnosis and Treatment of Childhood

Mitochondrial cytopathies are caused by genetic alterations of nuclear- or mitochondrial-encoded genes involved in the synthesis of subunits of the electron transport chain.

Mutations of mitochondrial DNA are associated with a wide range of clinical presentations [1–4]. The ubiquitous nature of mitochondria and the role of the mitochondria in cellular

metabolism result in the potential for any tissue in the body to be affected [5–7,8••,9]. Although some children with mitochondrial disease present with life-threatening lactic acidosis in the newborn period, the majority of children come to clinical attention for nonspecific problems, including failure to thrive, developmental delay, seizures, hypotonia, and loss of developmental milestones. The diagnosis of these disorders is made through careful clinical evaluation, coupled

with biochemical, morphologic, and molecular biologic techniques. Genetic counseling is difficult due to unique aspects of mitochondrial genetics. Despite advances in our understanding of mitochondrial biochemistry and genetics, treatment options remain limited.

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

Leonard A. Levin, MD, PhD

ABSTRACT • RÉSUMÉ

Most optic neuropathies do not have effective treatments. 

Examples are ischemic optic neuropathy, Leber hereditary optic neuropathy, optic neuritis, and traumatic optic neuropathy. In some cases, the pathophysiology of the optic nerve injury is not fully understood. 

For example, while the demyelinative aspects of optic neuritis have been studied, the mechanism by which the axonal loss occurs is less apparent. 

In other cases, although the pathophysiology of the optic neuropathy may be understood, there is difficulty treating the disease, for example, with traumatic optic neuropathy. 

In response to this therapeutic dearth, the concept of neuroprotection has arisen. Neuroprotection is a therapeutic paradigm for preventing death of neurons from injury and maintaining function. In optic neuropathies, the corresponding neuron is the retinal ganglion cell.

These cells are unable to divide, and optic neuropathies irrevocably result in their death; therefore, the primary target of neuroprotection are retinal ganglion cells and their axons. This review emphasizes that most optic neuropathies are axonal and thus good targets for neuroprotection.

Il n’y a pas de traitement efficace pour la plupart des neuropathies optiques, notamment la neuropathie optique ischémique, la neuropathie optique héréditaire de Leber, la névrite optique et la neuropathie optique traumatique. Dans certains cas, la pathophysiologie du dommage au nerf optique n’est pas entièrement élucidée. Par exemple, si on a étudié les aspects démyélinisants de la névrite optique, le mécanisme par lequel survient la perte des axones demeure moins apparent. 

Dans d’autres cas, bien qu’on puisse comprendre la pathophysiologie de la neuropathie optique, il est difficile de traiter la maladie, comme on le voit par exemple dans le cas de la neuropathie optique traumatique. Face à la pénurie de traitements, est survenue la notion de

neuroprotection. 

Il s’agit là d’un paradigme thérapeutique pour prophylaxie, ou prévention de la mort des

neurones due à des blessures afin de maintenir la fonction physiologique. Pour les neuropathies optiques, le neurone correspondant est la cellule ganglionnaire de la rétine. Les neuropathies optiques résultent irrévocablement de la mort des cellules ganglionnaires, qui sont incapables de division. 

Celles-ci et leurs axones deviennent donc les premières cibles de la neuroprotection pour les maladies optiques. Cette revue souligne que la plupart des neuropathies optiques sont axonales, donc de bonnes cibles pour la neuroprotection.

Gene therapy prevents blindness in an animal model of mitochondrial dysfunction

Scientists have created an animal model suitable for testing and validating gene therapies for treatment of a common mitochondrial dysfunction that causes loss of vision. The research, published by Cell Press in the September issue of the American Journal of Human Genetics, describes an innovation that represents a significant advance toward development of the first treatment for one of the many devastating disorders caused by mitochondrial disruption.

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."

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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 MD^{a, b, c, ,} , Valérie Biousse MD^a, b, Steven A. Newman MD^d, M. Tariq Bhatti MD^e, Steven R. Hamilton MD^f, Bradley K. Farris MD^g, Robert L. Lesser MD^h and Roger E. Turbin MDⁱ

^aDepartment of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia ^bDepartment of Neurology, Emory University School of Medicine, Atlanta, Georgia ^cDepartment of Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia ^dDepartment of Ophthalmology, University of Virginia, Charlottesville, Virginia^eDepartments of Ophthalmology, Neurology, and Neurosurgery, University of Florida, Gainesville, Florida ^fSwedish Neuroscience Institute, Seattle, Washington ^gDean A. McGee Eye Institute, Oklahoma City, Oklahoma ^hDepartments of Ophthalmology and Visual Science and Neurology, Yale University School of Medicine, New Haven, ConnecticutⁱInstitute of Ophthalmology and Visual Sciences, University of Medicine and Dentistry of New Jersey, Newark, New Jersey

Accepted 22 December 2005.  

Available online 8 June 2006. 

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.