Grupos

Tuesday, August 08, 2006

ALS Therapy Delivers Antisense Drug Directly to Nervous System - rod @ 05:58 PST

Delivering agents across the blood-brain barrier likely to be effective treatment for other neurodegenerative diseases

SAN DIEGO, CA -- July 28, 2006 -- Researchers from the University of California, San Diego (UCSD) School of Medicine, the Center for Neurologic Study and Isis Pharmaceutical Corporation have designed and tested a molecular therapy in animals that they hope will be a major development in the fight to treat amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease.

The study conducted in the laboratory of Don Cleveland, PhD, UCSD Professor of Medicine, Neurosciences and Cellular and Molecular Medicine and member of the Ludwig Institute for Cancer Research, shows that therapeutic molecules known as antisense oligonucleotides can be delivered to the brain and spinal cord through the cerebrospinal fluid (CSF) at doses shown to slow the progression of ALS in rats. The study will be published July 27 in advance of publication in the August issue of Journal of Clinical Investigation.

With colleagues Timothy Miller, MD, PhD, UCSD Department of Neurosciences, and Richard A. Smith, MD, of the Center for Neurologic Study, Cleveland found that when effective doses of the antisense therapy were delivered, far less of a protein that causes a hereditable form of amyotrophic lateral sclerosis was produced.

ALS is a progressive disease that attacks motor neurons that reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body. Estimated to affect some 30,000 Americans, most people are diagnosed with ALS between the ages of 40 and 70. Typically, ALS patients live only three to five years after initial diagnosis.

Neurotoxicity from an accumulation of mutant proteins is believed to be at the root of many neurodegenerative diseases. ALS can be caused by a mutation in a protein called SOD1, and the antisense drug effectively silences the gene that codes for this mutant protein – found in the cells of patients with inherited forms of ALS.

In this disease, selective killing of spinal cord "motor neurons" occurs. Motor neurons are long and complex nerve cells that control voluntary movement. Degeneration of motor neurons in ALS leads to progressive loss of muscle control, paralysis and untimely death.

Healthy "neighbor" or supporting non-neuronal cells also have a protective effect on damaged mutant motor neurons, slowing the progression of ALS even when the nerve cells carry the mutant gene. The researchers speculate that the non-neuronal cells play a vital role in nourishing the motor neurons and in scavenging toxins from the cellular environment.

The onset and progression of disease in inherited ALS is determined by the motor neurons and microglia, small immune cells in the spinal cord, which migrate through nerve tissue and remove damaged cells and debris. Damage to motor neurons determines timing of disease onset. Microglia – the neighborhood, or "helper" cells – are then activated to help nourish the motor neurons and clean out debris like a vacuum cleaner. But because these neighboring cells are also damaged, they hurt instead of help, thus speeding disease progression.

When the UCSD researchers isolated and shut off mutant SOD1genes in the motor neuron cells only, the disease onset slowed, but the course of the disease eventually caught up to the control rodents. When mutant genes in only the microglia were silenced, the scientists found almost no effect on disease onset, however the disease progression was significantly slowed.

This discovery – authored by UCSD investigators Severine Boillee, Koji Yamanaka, Cleveland and others and published in the June 2 issue of the journal Science – confirms the importance of the new therapeutic approach, which delivers an antisense drug directly to the whole nervous system, including non-neuronal cells.

"Limiting mutant damage to microglia robustly slowed the disease's course, even when all motor neurons were expressing high levels of a SOD1 mutant," said Cleveland. "Our research suggests that what starts ALS and what keeps it going are two separate phases; it also suggests that with the right therapy, ALS could become a manageable, chronic disease."

Within a year, Cleveland hopes the first clinical trial will be initiated in humans. In order to deliver the antisense drug directly to the nervous system, surgeons will insert a small pump into a patient using a fairly routine surgery that has already been approved for management of pain. A small catheter is then implanted into the area surrounding the spinal cord, in order to pump antisense oligonucleotide drugs directly into the nervous system.

The investigators noted that if the antisense approach works for ALS – by delivering therapeutic agents for neurodegenerative diseases across the highly impermeable blood-brain barrier – it would likely also work in other neurodegenerative conditions, including Alzheimer's, Parkinson's and Huntington's diseases.

"We know we're on target with the pathogenic mechanism," said Cleveland. The remaining question is whether the genetic-based therapy will be tolerated. "If tolerated, this sets the stage for broader treatment of neurodegenerative disease, especially Huntington's disease, where there is currently no treatment, but key genes involved in promoting disease are known."

Cleveland was just elected to the National Academy of Science and Smith is a Skaggs Scholar at the Scripps Research Institute. Both are consultants Isis Pharmaceuticals Inc. (NASDAQ, ISIS), a Carlsbad, California-based company whose scientists helped identify the novel therapy and will manufacture drug for clinical trials. The work was supported by funding from the ALS Association.


SOURCE: University of California, San Diego

Fonte: ALSA.

Normando Oliveira.

 

.......................TRADUTOR ON LINE.......................

 

Tuesday, August 08, 2006 

ALS Therapy Delivers Antisense Drug Directly to Nervous System - rod @ 05:58 PST       

Delivering agents across the blood-brain barrier likely to be effective treatment for other neurodegenerative diseases   

SAN DIEGO, CA -- July 28, 2006 -- Researchers from the University of California, San Diego (UCSD) School of Medicine, the Center for Neurologic Study and Isis Pharmaceutical Corporation have designed and tested a molecular therapy in animals that they hope will be a major development in the fight to treat amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease.    The study conducted in the laboratory of Don Cleveland, PhD, UCSD Professor of Medicine, Neurosciences and Cellular and Molecular Medicine and member of the Ludwig Institute for Cancer Research, shows that therapeutic molecules known as antisense oligonucleotides can be delivered to the brain and spinal cord through the cerebrospinal fluid (CSF) at doses shown to slow the progression of ALS in rats. The study will be published July 27 in advance of publication in the August issue of Journal of Clinical Investigation.    With colleagues Timothy Miller, MD, PhD, UCSD Department of Neurosciences, and Richard A. Smith, MD, of the Center for Neurologic Study, Cleveland found that when effective doses of the antisense therapy were delivered, far less of a protein that causes a hereditable form of amyotrophic lateral sclerosis was produced.    ALS is a progressive disease that attacks motor neurons that reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body. Estimated to affect some 30,000 Americans, most people are diagnosed with ALS between the ages of 40 and 70. Typically, ALS patients live only three to five years after initial diagnosis.    Neurotoxicity from an accumulation of mutant proteins is believed to be at the root of many neurodegenerative diseases. ALS can be caused by a mutation in a protein called SOD1, and the antisense drug effectively silences the gene that codes for this mutant protein – found in the cells of patients with inherited forms of ALS.    In this disease, selective killing of spinal cord "motor neurons" occurs. Motor neurons are long and complex nerve cells that control voluntary movement. Degeneration of motor neurons in ALS leads to progressive loss of muscle control, paralysis and untimely death.    Healthy "neighbor" or supporting non-neuronal cells also have a protective effect on damaged mutant motor neurons, slowing the progression of ALS even when the nerve cells carry the mutant gene. The researchers speculate that the non-neuronal cells play a vital role in nourishing the motor neurons and in scavenging toxins from the cellular environment.    The onset and progression of disease in inherited ALS is determined by the motor neurons and microglia, small immune cells in the spinal cord, which migrate through nerve tissue and remove damaged cells and debris. Damage to motor neurons determines timing of disease onset. Microglia – the neighborhood, or "helper" cells – are then activated to help nourish the motor neurons and clean out debris like a vacuum cleaner. But because these neighboring cells are also damaged, they hurt instead of help, thus speeding disease progression.    When the UCSD researchers isolated and shut off mutant SOD1genes in the motor neuron cells only, the disease onset slowed, but the course of the disease eventually caught up to the control rodents. When mutant genes in only the microglia were silenced, the scientists found almost no effect on disease onset, however the disease progression was significantly slowed.    This discovery – authored by UCSD investigators Severine Boillee, Koji Yamanaka, Cleveland and others and published in the June 2 issue of the journal Science – confirms the importance of the new therapeutic approach, which delivers an antisense drug directly to the whole nervous system, including non-neuronal cells.    "Limiting mutant damage to microglia robustly slowed the disease's course, even when all motor neurons were expressing high levels of a SOD1 mutant," said Cleveland. "Our research suggests that what starts ALS and what keeps it going are two separate phases; it also suggests that with the right therapy, ALS could become a manageable, chronic disease."    Within a year, Cleveland hopes the first clinical trial will be initiated in humans. In order to deliver the antisense drug directly to the nervous system, surgeons will insert a small pump into a patient using a fairly routine surgery that has already been approved for management of pain. A small catheter is then implanted into the area surrounding the spinal cord, in order to pump antisense oligonucleotide drugs directly into the nervous system.    The investigators noted that if the antisense approach works for ALS – by delivering therapeutic agents for neurodegenerative diseases across the highly impermeable blood-brain barrier – it would likely also work in other neurodegenerative conditions, including Alzheimer's, Parkinson's and Huntington's diseases.    "We know we're on target with the pathogenic mechanism," said Cleveland. The remaining question is whether the genetic-based therapy will be tolerated. "If tolerated, this sets the stage for broader treatment of neurodegenerative disease, especially Huntington's disease, where there is currently no treatment, but key genes involved in promoting disease are known."    Cleveland was just elected to the National Academy of Science and Smith is a Skaggs Scholar at the Scripps Research Institute. Both are consultants Isis Pharmaceuticals Inc. (NASDAQ, ISIS), a Carlsbad, California-based company whose scientists helped identify the novel therapy and will manufacture drug for clinical trials. The work was supported by funding from the ALS Association.     

SOURCE: University of California, San Diego

PESQUISA - ÓXIDO NITRIC.

20:18 @ 30/08/2006

Research Update — from ALSA’s National Office


August 29, 2006

The ALS Association Funds Studies to Clarify the Role of Inflammation in ALS

Roberta Friedman, Ph.D., Research Department Information Coordinator

[QUICK SUMMARY: The ALS Association is funding a continued line of investigation that will build on new evidence that an aspect of inflammation may actually help rather than harm in the progression of ALS.]

The ALS Association is funding research that will follow up on unexpected findings that a player in nerve cell communication and in the tissue response to damage, a molecule called nitric oxide, may actually prolong life in mice that have many aspects of the human disease, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease).

This project is funded through The ALS Association’s program to recruit and retain experts in critical areas relevant to ALS. Cold Spring Harbor Laboratories researcher Grigory Enikolopov, Ph.D., will expand on his findings on the action of nitric oxide by increasing or decreasing its production in the SOD1 mutant mouse model of ALS using available compounds that act on nitric oxide production.

The planned studies could help solve a key controversy over the role of nitric oxide in ALS. Clarity on the role of nitric oxide would contribute to the search for an effective ALS treatment.

Nitric oxide is basic to several nerve cell processes, such as cell to cell communication, response to damage, and the orderly removal of damaged cells called programmed cell death (apoptosis). Work to date by Enikolopov, funded by The Greater New York Chapter of The Association, has followed the logic that nitric oxide would be harmful to people with ALS, a notion supplied by findings in some but not all labs working with this molecule. But Enikolopov has instead found that removing nitric oxide from the picture does not help lab mice that model ALS.

Mice expressing the mutation associated with some forms of ALS crossed with mice lacking nitric oxide (a genetic knockout of nitric oxide production in nerve cells) did not survive longer in contrast to some earlier studies in other labs. Instead, Enikolopov’s team has now gathered evidence that this breeding strategy in fact produces accelerated death and that nitric oxide may be beneficial in mice with the ALS-linked mutation to copper-zinc superoxide dismutase (SOD1).

New studies will now seek to confirm if increasing nitric oxide production extends lifespan in the SOD1 mice. The investigators will see at which stage in the disease nitric oxide production will help most and which way of changing supplies of nitric oxide will work best. Drugs that are approved by the FDA for other conditions can change nitric oxide production or availability. So any evidence that one of these might work in ALS can be quickly translated into clinical trials in this disease.

The researchers have found an interaction of nitric oxide with the glutamate messenger system in the nervous system. Glutamate is also implicated in ALS, and this converging picture may help in designing new therapeutics that will help in the disease. For further information about the roles of inflammation and glutamate in ALS, click here and here.

To refer to the earlier Association studies funded on this topic.

Fonte: ALSA.

 

................................TRADUTOR ON LINE..................................

Update da pesquisa - do escritório nacional de ALSA

Agosto 29, 2006  

Os estudos dos fundos da associação de ALS para esclarecer o papel do Inflammation em ALS  Roberta Friedman, Ph.D., coordenador da informação do departamento da pesquisa  [SUMÁRIO RÁPIDO: A associação de ALS está financiando uma linha continuada da investigação que construa na evidência nova que um aspecto do inflammation pode realmente ajudar melhor que prejudicar na progressão de ALS.]   

A associação de ALS está financiando a pesquisa que continuação nos findings inesperados que um jogador em uma comunicação da pilha do nervo e na resposta aos danos, uma molécula do tecido chamada óxido nitric, pode realmente prolongar a vida nos ratos que têm muitos aspectos da doença humana, sclerosis de lateral amyotrophic (ALS, sabido também como a doença de Lou Gehrig).    

Este projeto é financiado com o programa da associação de ALS para recrutar e reter peritos nas áreas críticas relevantes a ALS. O investigador frio Grigory Enikolopov dos laboratórios do porto da mola, Ph.D., expandirá em seus findings na ação do óxido nitric aumentando ou diminuindo sua produção no modelo do rato do mutant SOD1 de ALS usando os compostos disponíveis que agem na produção nitric do óxido. 

Os estudos de planeamento podiam ajudar resolver uma controvérsia chave sobre o papel do óxido nitric em ALS. A claridade no papel do óxido nitric contribuiria à busca para um tratamento eficaz de ALS. 

O óxido Nitric é básico a diversos processos da pilha do nervo, tais como a pilha a uma comunicação da pilha, a resposta aos danos, e a remoção em ordem das pilhas danificadas chamadas morte programada da pilha (apoptosis). Trabalhar para datar por Enikolopov, financiado pelo capítulo mais grande de New York da associação, seguiu a lógica que o óxido nitric seria prejudicial aos povos com ALS, noção fornecida por findings em algum mas não todos os laboratórios que trabalham com esta molécula. Mas Enikolopov encontrou preferivelmente que remover o óxido nitric do retrato não ajuda aos ratos do laboratório que ALS modelo. 

Os ratos que expressam o mutation associado com alguns formulários de ALS cruzado com os ratos que faltam o óxido nitric (um knockout genetic da produção nitric do óxido em pilhas do nervo) não sobreviveram mais por muito tempo no contraste a algum mais cedo estudam em outros laboratórios. Instead, a equipe de Enikolopov tem recolhido agora a evidência que esta estratégia produzir no fato produz a morte acelerada e que o óxido nitric pode ser benéfico nos ratos com o dismutase ALS-ligado do superoxide do cobre-zinco do mutation (SOD1). 

Os estudos novos procurarão agora confirmar se a produção nitric crescente do óxido estender o lifespan nos ratos SOD1. Os investigators verão em que estágio na produção nitric do óxido da doença ajudará a a maioria e que maneira de mudar fontes do óxido nitric trabalhará melhor. As drogas que são aprovadas pelo FDA para outras circunstâncias podem mudar a produção ou a disponibilidade nitric do óxido. Assim toda a evidência que um destes pôde trabalhar em ALS pode rapidamente ser traduzida em experimentações clínicas nesta doença. 

Os investigadores encontraram uma interação do óxido nitric com o sistema do mensageiro do glutamate no sistema nervoso. O Glutamate é implicado também em ALS, e este retrato converging pode ajudar em projetar o therapeutics novo que ajudará na doença. Para uma informação mais adicional sobre os papéis do inflammation e do glutamate em ALS.