Optimized allotopic expression of mitochondrial genes

2009-12-29T05:20:00.000+01:00

15:12 - hace un año
M. Corral-Debrinski, Institut de la Vision, Université Pierre et Marie Curie-Paris, Paris, France. Mitochondrial diseases due to mutations in mitochondrial DNA can not be ignored anymore in most medical areas. With prevalence certainly higher than one in 6000, they probably represent the most common form of metabolic disorders. Despite progress made in identification of their molecular mechanisms, little has been done regarding therapy. We have recently optimized the allotopic expression for the mitochondrial genes ATP6, ND1 and ND4 and obtained a complete and long-lasting rescue of mitochondrial dysfunction in human fibroblasts in which these genes were mutated. However, biosafety and benefit to mitochondrial function must be validated in animal models prior to clinical applications. To create an animal model of Leber Hereditary Optic Neuropathy (LHON), the human ND4 gene harboring the G11778A mutation, responsible of 60% of LHON cases, was introduced to rat eyes by in vivo electroporation. The treatm...todo »

tesis doctoral

2009-12-28T23:53:00.002+01:00

PAPER DE LES MUTACIONS DEL mtDNA
EN LA MODULACIÓ DEL SISTEMA ANTIOXIDANT

ESTUDI EN UN MODEL DE CÍBRIDS TRANSMITOCONDRIALS

Cristòfol Vives Bauzà
Departament de Genètica, UB
Març, 2004

links a tesis doctorales relacionadas con la enfermedad

Leber Hereditary Optic Neuropathy

2009-12-18T21:40:00.000+01:00

Leber Hereditary Optic Neuropathy

Baja Visión

2009-06-28T00:28:00.003+02:00

El vídeo muestra cómo ven las personas afectadas por alguna patología causante de la baja visión dependiendo de la agudeza visual que conserven

L'altra mirada

2008-12-20T11:11:00.000+01:00

L'altra mirada
Hi ha persones que, d'un dia a l'altre, els comuniquen que s'aniran quedant cegues. Com ho assimilen? Com es preparen per afrontar aquesta nova realitat? Aprendre a funcionar d'una manera autònoma és un dels primers objectius: cuinar, desplaçar-se, tornar a treballar...

In An Animal Model Of Mitochondrial Dysfunction, Gene Therapy Prevents Blindness

2008-10-16T19:07:00.000+02:00

In An Animal Model Of Mitochondrial Dysfunction, Gene Therapy Prevents Blindness

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 theAmerican 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 an 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."

Second Meeting of the British Society of Neuro-Otology

2008-10-15T21:10:00.000+02:00

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

Diagnosis and Treatment of Childhood

2008-10-15T21:07:00.000+02:00

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)

2008-10-15T21:00:00.000+02:00

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

2008-10-15T20:49:00.000+02:00

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

2008-10-15T20:41:00.000+02:00

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

2008-10-15T20:37:00.001+02:00

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.

Penwest Begins Phase Ia Clinical Trial of A0001, a Compound For Treatment of Mitochondrial Diseases

2008-09-14T15:10:00.000+02:00

Last update: 8:31 a.m. EDT July 14, 2008
DANBURY, Conn., Jul 14, 2008 (PrimeNewswire via COMTEX) -- Penwest Pharmaceuticals Co.

today announced that it has begun dosing in a Phase Ia clinical trial of A0001, a compound the Company is developing for the treatment of symptoms associated with mitochondrial diseases. Mitochondrial diseases are devastating illnesses that often occur during childhood and currently have no FDA approved treatments.
"We are excited to have clinical development of A0001 underway," said Jennifer Good, Penwest's President and CEO. "This compound is important to patients who suffer from mitochondrial diseases and currently have very limited treatment options. We are eager to complete the safety work for this compound so that we can take the important next step of beginning to evaluate clinical benefit in patients."
The Phase Ia trial is a placebo-controlled single ascending dose clinical trial. The trial is designed to evaluate the safety and tolerability of A0001 at various doses and to collect pharmacokinetic data. The trial is also designed to determine if there is a maximum tolerated dose of the drug. The Company plans to enroll a total of 60 healthy volunteers in the trial.
Penwest anticipates that further development of A0001 would involve a Phase Ib multiple ascending dose trial in healthy volunteers for which dosing could begin in early 2009, followed by a Phase IIa proof of concept trial in patients with mitochondrial diseases.
About A0001
Penwest is developing A0001 under a collaboration and licensing agreement with Edison Pharmaceuticals, a private biopharmaceutical company headquartered in San Jose, CA. A0001 is a coenzyme Q10 analog demonstrated to improve mitochondrial function. Relative to CoQ10, A0001 possesses improved drug-like properties. Penwest believes that impairment of mitochondrial function is a key component of the diseases that Penwest plans to target with A0001, and that enhancing mitochondrial function may provide substantial clinical benefit to patients. A0001 has received orphan drug designation from the FDA for the treatment of inherited mitochondrial respiratory chain diseases.
Penwest Pharmaceuticals
Penwest is a drug development pharmaceutical company dedicated to bringing to the marketplace innovative products that help improve the lives of patients. The Company's goal is to identify, develop and commercialize prescription products that address unmet medical needs, primarily for disorders of the nervous system. Penwest is currently applying its drug development and drug delivery expertise to a pipeline of potential products that are in various stages of development and that it intends to commercialize independently or through third party alliances.
Penwest Forward-Looking Statement
The matters discussed herein contain forward-looking statements that involve risks and uncertainties, which may cause the actual results in future periods to be materially different from any future performance suggested herein. For this purpose, any statements contained herein that are not statements of historical fact may be deemed to be forward-looking statements. Without limiting the foregoing, the words "believes," "anticipates," "plans," "expects," "intends," "potential" and similar expressions are intended to identify forward-looking statements. Important factors that could cause results to differ materially include: risks relating to the commercial success of Opana ER, including our reliance on Endo for the commercial success of Opana ER and risks of generic competition; the need for capital; regulatory risks relating to drugs in development, including the timing and outcome of regulatory submissions and regulatory actions; uncertainty of success of collaborations; the timing of clinical trials; whether the results of clinical trials will warrant further clinical trials, warrant submission of an application for regulatory approval of, or warrant the regulatory approval of, the product that is the subject of the trial; whether the patents and patent applications owned by us will protect the Company's products and technology; actual and potential competition; and other risks as set forth under the caption Risk Factors in Penwest's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on May 12, 2008, which risk factors are incorporated herein by reference.
The forward-looking statements contained in this press release speak only as of the date of the statements made. Penwest disclaims any intention or obligation to update any forward-looking statements.
TIMERx is a registered trademark of Penwest. All other trademarks referenced herein are the property of their respective owners.
This news release was distributed by PrimeNewswire, www.primenewswire.com
SOURCE: Penwest Pharmaceuticals Co.
Penwest Pharmaceuticals Co.
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Una terapia génica, posible vía en neuropatía óptica de Lebe

2008-09-13T14:21:00.001+02:00

Una terapia génica, posible vía en neuropatía óptica de Leber
La terapia génica puede suponer una nueva vía en el tratamiento de neuropatías ópticas. Según un estudio que se publica en American Journal of Human Genetics, la manipulación del gen ND4 puede mejorar la función visual de afectados de neuropatía óptica hereditaria de Leber.

Redacción05/09/2008

Un equipo de la Universidad Pierre y Marie Curie, de París, en Francia, ha desarrollado un modelo animal para validar posibles terapias génicas en un tipo de disfunción mitocondrial causante de pérdida de visión. El estudio, que se publica en el último número de American Journal of Human Genetics, describe un método que representa, según los autores, un avance hacia el primer tratamiento para uno de los principales problemas causados por la disrupción mitocondrial.

La mayor parte de los problemas metabólicos se deben a un proceso de mutaciones en el ADN de las mitocondrias, encargadas de producir la energía que la célula necesita. Actualmente se conocen más de 300 alteraciones en este material genético causantes de enfermedades mitocondriales, aunque por el momento no existen terapias efectivas. Marisol Corral-Devrinski, coordinadora del trabajo, lamenta "la falta de avances terapéuticos a pesar de los buenos resultados obtenidos en la identificación de los diferentes mecanismos moleculares".

Funciones restauradas
Su equipo ha perfeccionado una estrategia para la expresión de genes mitocondriales transferidos al núcleo, una expresión que se denomina alotrópica: "Hemos logrado una restauración completa y a largo plazo de las funciones mitocondriales en fibroblastos humanos en los que los genes mitocondriales ATP6, ND1 y ND4 se encontraban mutados".

ND1 y ND4 están alterados en la mayoría de casos de neuropatía óptica hereditaria de Leber (LHON, por sus siglas en inglés). En un modelo afectado de LHON, los investigadores introdujeron el gen ND4 con la mutación propia de la enfermedad, lo que provocó una degeneración visual que se recuperó con la reintroducción del gen sin mutación alguna.

idebenone and multivitamin treatment in Leber's hereditary optic neuropathy (LHON).

2008-08-31T13:07:00.000+02:00

Arch Soc Esp Oftalmol. 2007 Jun ;82 (6):377-80 17573650 (P,S,E,B) [Response to idebenone and multivitamin therapy in Leber's hereditary optic neuropathy]

[My paper] N Barnils, E Mesa, S Muñoz, A Ferrer-Artola, J Arruga
Hospital Universitario de Bellvitge, L'Hospitalet de Llobregat, Barcelona, España. noebg76@hotmail.com

OBJECTIVE: To ascertain the efficacy of idebenone and multivitamin treatment in Leber's hereditary optic neuropathy (LHON).

METHOD: Two patients diagnosed of unilateral LHON were treated with megadoses of idebenone, vitamin C and riboflavin for one year. They were examined clinically before, during and after treatment.

RESULTS: No improvement of visual function was observed. Despite the idebenone treatment, in both cases the second eye became involved.

CONCLUSIONS:Despite previous reports of visual recovery with idebenone in patients with LHON, our experience shows that an effective treatment for Leber's disease remains to be found.

Mesh-terms: Adult; Antioxidants :: therapeutic use; Ascorbic Acid :: therapeutic use; Benzoquinones :: therapeutic use; Female; Humans; Male; Optic Atrophy, Hereditary, Leber :: drug therapy; Riboflavin :: therapeutic use; Treatment Failure; Vitamin B Complex :: therapeutic use; Vitamins :: therapeutic use;

lhon

RESPUESTA A LA IDEBENONA ASOCIADA A LHON

OPA1-related dominant optic atrophy is not strongly influenced by mitochondrial DNA background

Acute Leber Optic Neuropathy

Duke Vision Rehab Helps Patients with Vision Loss

Lebers Hereditary Optic Neuropathy Documentary

lhon en la wiki

Optimized allotopic expression of mitochondrial genes

Un restaurante especial

Acceso de los niños invidentes a la informática (Juntos Paso a Paso)

Perros Guía (Para que veas)

tesis doctoral MITOCHONDRIAL ROLE OF APOPTOSIS-INDUCING FACTOR (AIF)

tesis doctoral

Leber Hereditary Optic Neuropathy

Baja Visión

L'altra mirada

In An Animal Model Of Mitochondrial Dysfunction, Gene Therapy Prevents Blindness

In An Animal Model Of Mitochondrial Dysfunction, Gene Therapy Prevents Blindness

Second Meeting of the British Society of Neuro-Otology

Diagnosis and Treatment of Childhood

Leber’s Hereditary Optic Neuropathy (LHON)

Leber’s Hereditary Optic Neuropathy (LHON)

Clinical development of SNT-MC17 (INN: idebenone) in LHON

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

Experience of the LHON Treatment Trial

Purpose

Design

Methods

Results

Conclusions

Penwest Begins Phase Ia Clinical Trial of A0001, a Compound For Treatment of Mitochondrial Diseases

Una terapia génica, posible vía en neuropatía óptica de Lebe

idebenone and multivitamin treatment in Leber's hereditary optic neuropathy (LHON).