Protein research - looks promising

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Protein research - looks promising

Postby bromley » Tue Apr 24, 2007 1:39 am

There's quite a lot of protein work being undertaken in various labs. This looks promising as it's about protecting nerves,

Ian


Deactivating protein may protect nerve fibres in MS 24 April 2007

OHSU findings could lead to first drug to treat progressive, disabling form of disease.

Oregon Health & Science University neuroscientists are eyeing a protein as a potential therapeutic target for multiple sclerosis because de-activating it protects nerve fibers from damage.

OHSU researchers, working with colleagues at the Portland Veterans Affairs Medical Center and the University of Padova in Italy, have shown that genetically inactivating a protein called cyclophilin D can protect nerve fibres in a mouse model of multiple sclerosis. Cyclophin D is a key regulator of molecular processes in the nerve cell's powerhouse, the mitochondrion, and can participate in nerve fibre death. Inactivating cyclophilin D strengthens the mitochondrion, helping to protect nerve fibres from injury. The findings are published today, 24/04/07, in Proceedings of the National Academy of Sciences.

"We're extremely excited," said Michael Forte, Ph.D., senior scientist at the Vollum Institute at OHSU and the study's lead author. "While we can't genetically inactivate cyclophilin D in people, there are drugs out there that can block the protein. Our research predicts that drugs that block cyclophilin D should protect nerve fibres from damage in MS."

Such a drug would be the first therapy specifically for secondary-progressive MS, one of the more debilitating forms of MS involving an initial period of relapsing and remitting, followed by a steady worsening of symptoms. It affects half of the estimated 2 million people with MS.

The only available therapies for MS are anti-inflammatory drugs, which reduce the inflammation believed to spur certain T-cells in the body to attack myelin, the fatty sheath insulating nerve fibres in the brain and spinal cord. The fibres can't conduct impulses, leading to paralysis, memory loss, dizziness, fatigue, pain and imbalance. Over time, the nerve fibres themselves degenerate, leading to permanent functional deficits.

"All MS drugs available right now are anti-inflammatory," said study co-author Dennis Bourdette, M.D., professor and chairman of neurology in the OHSU School of Medicine, and director of the OHSU MS Centre of Oregon. "What is desperately needed is a therapeutic that protects the nerve fibres from degeneration."

In recent years, scientists have increasingly viewed MS as a neurodegenerative disorder rather than simply an inflammatory one. Loss of nerve cells, injury to nerve fibres and atrophy within the central nervous system occur progressively from the start of the disease, eventually leading to permanent disability, especially in patients who've had MS for many years.

"What puts people in wheelchairs from MS is not an inflammatory attack on myelin of the central nervous system. It's the severing of the axons (nerve fibres), which is a permanent thing," Forte said.

Inflammation triggers a chain of molecular events that leads to progressive nerve fibre deterioration in MS, including the development of free radicals such as reactive oxygen and nitrogen that slow the cell's energy generation capability. It also throws off mitochondrial function by causing calcium to build up in the cell, reducing levels of ATP that serves as the cell's fuel source.

But scientists believe that cyclophilin D is responsible for causing the unregulated opening of a pore in the mitochondrion's membrane that allows the calcium overload. The OHSU team showed that mice lacking cyclophilin D still developed an MS-like disease, but unlike their counterparts possessing the protein, the mutant mice partially recovered. Scientists found their nerve fibres remained intact, and they resisted the free radicals and calcium overload.

"What we've done is make it so the mitochondria can tolerate higher loads of calcium before they die," Forte said. "The mutant mice are protected from axonal damage associated with this MS-like disease in mice."

The scientists are now testing drugs that could be used to shut down the cyclophilin D protein and the mitochondrion pore it activates. "If you basically inhibited that protein with a drug, you would see the same axonal preservation that you saw in the mutant mouse," Forte said.

One class of compounds Forte and Bourdette are particularly interested in is non-immunosuppressive derivative of cyclosporin A (CsA). Some nonimmunsuppressive derivatives of cyclosporin A are in human trials for other conditions. Because these drugs are already being tested in humans, they could be rapidly tested in MS. Bourdette believes that a cyclophilin D antagonist could potentially become available as a treatment for MS within five years.

"We don't have to invent the drugs to target this protein. They already exist," Bourdette said.

Such a therapy can't come soon enough for 36-year-old West Linn, Ore. resident Laura Wieden, who has suffered since 1995 from relapsing-remitting MS that's caused weakness in both legs and forced her to ride a Segway personal transportation device or a wheelchair. "For me, it's fabulous," she said. "If you can prevent MS, that's great, but what about the millions of people who have it? They need something that keeps the cells from dying. This just holds so much promise."

Wieden's father, Dan Wieden, co-founder of Portland-based Wieden + Kennedy advertising agency, set up a fund in his daughter's name – the Laura Fund for Innovation in Multiple Sclerosis Research – to support MS research that pushes traditional boundaries to discovery. The discovery by Forte, Bourdette and their team, which was funded in part by the foundation, fits the bill, he said.

"It goes to prove that sometimes the big breakthroughs do not come from the more traditional lines of inquiry," he said. "What I appreciate about our relationship with OHSU is that there seems to be a sense of urgency about these projects. And it's been beneficial for us to develop a more personal relationship with the researchers. That way it becomes not just an academic exercise, but a very passionate inquiry on their part."

Source: Oregon Health & Science University
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Postby dignan » Tue Apr 24, 2007 8:51 am

Very interesting find Bromley. OHSU..."nonimmunosuppressant derivative of cyclosporin A...Dennis Bourdette...it looks like they've done some work on this. It might not be one of the drugs mentioned in this abstract, but it all sounds very promising. There is another recent abstract (I'm not posting it) about the use of a derivative of cyclosporin A in spinal cord injury from a different group of researchers. Seems like an area to watch.



FK506 and a nonimmunosuppressant derivative reduce axonal and myelin damage in experimental autoimmune encephalomyelitis: neuroimmunophilin ligand-mediated neuroprotection in a model of multiple sclerosis.

J Neurosci Res. 2004 Aug 1;77(3):367-77.
Gold BG, Voda J, Yu X, McKeon G, Bourdette DN.
Center for Research on Occupational and Environmental Toxicology (CROET), Oregon Health and Science University, Portland, Oregon 97239-3098, USA. gold@ohsu.edu

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) in which demyelination and axonal loss result in permanent neurologic disability. We examined the neuroprotective property of the immunosuppressant FK506 (tacrolimus), FK1706 (a nonimmunosuppressant FK506 derivative) and cyclosporin A (CsA) in a chronic relapsing experimental autoimmune encephalomyelitis (EAE) model of MS.

Female SJL/J mice were immunized by subcutaneous (s.c.) injection with proteolipid protein 139-151 peptide in complete Freund's adjuvant. At the onset of paralysis, 12-14 days after immunization, mice received daily s.c. injections of FK506 (0.2, 1, and 5 mg/kg), FK1706 (5 mg/kg), CsA (2, 10, and 50 mg/kg), saline or vehicle (30% dimethylsulfoxide) for 30 days.

FK506 (at a dose of 5 mg/kg) reduced the severity of the initial disease and suppressed relapses. FK1706 did not significantly alter the clinical course and CsA (at a dose of 50 mg/kg) lessened the severity of the initial episode of EAE but did not alter relapses. In the thoracic spinal cord, FK506 (5 mg/kg), FK1706 (5 mg/kg), and CsA (50 mg/kg) significantly (P < 0.001) reduced the extent of damage in the dorsal, lateral, and ventral white matter by a mean of up to 95, 68, and 30%, respectively. A nonimmunosuppressant dose of FK506 (0.2 mg/kg) also significantly (P < 0.001) reduced the extent of damage in the spinal cord by a mean of up to 45%. Other dosages of these compounds were ineffective.

FK506 markedly protects against demyelination and axonal loss in this MS model through immunosuppression and neuroprotection.

Pubmed URL
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Postby Muu » Wed Apr 25, 2007 2:08 pm

Thanks for finding and posting this Brom.
As a SPMS'er I have an interest in potential treatments for neuroprotection. Despite my best efforts it can get a little disheartening to read and become excited about potential treatments, only to realize that, yet again, it's something that won't help those of us that have moved on to the SP stage. So this was good to read.
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Postby gwa » Sat Apr 28, 2007 4:46 pm

This discovery appears to be very important.

Maybe Tonyjegs can discuss the ramifications of blocking the protein and how this knowledge could help all of us.

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Postby robbie » Sun Apr 29, 2007 5:31 am

So when will this be available?, it sounds good, when can we ask our neurologist for it?, when can it start to help?, will there be trials for it?,how do we follow the development of this drug?,It is great to read about but to actually take it and have it do something that would be priceless. :D
Had ms for over 19 years now.
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Postby dignan » Mon Apr 30, 2007 7:38 am

Here's the Pubmed abstract that goes with the original article in this post.



Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis.

Proc Natl Acad Sci U S A. 2007 Apr 26;
Forte M, Gold BG, Marracci G, Chaudhary P, Basso E, Johnsen D, Yu X, Fowlkes J, Bernardi P, Bourdette D.
Vollum Institute and Department of Neurology, Oregon Health and Science University, Portland, OR 97239;

Multiple sclerosis (MS) is the leading cause of neurological disability in young adults, affecting some two million people worldwide. Traditionally, MS has been considered a chronic, inflammatory disorder of the central white matter in which ensuing demyelination results in physical disability [Frohman EM, Racke MK, Raine CS (2006) N Engl J Med 354:942-955]. More recently, MS has become increasingly viewed as a neurodegenerative disorder in which neuronal loss, axonal injury, and atrophy of the CNS lead to permanent neurological and clinical disability. Although axonal pathology and loss in MS has been recognized for >100 years, very little is known about the underlying molecular mechanisms. Progressive axonal loss in MS may stem from a cascade of ionic imbalances initiated by inflammation, leading to mitochondrial dysfunction and energetic deficits that result in mitochondrial and cellular Ca(2+) overload. In a murine disease model, experimental autoimmune encephalomyelitis (EAE) mice lacking cyclophilin D (CyPD), a key regulator of the mitochondrial permeability transition pore (PTP), developed EAE, but unlike WT mice, they partially recovered. Examination of the spinal cords of CyPD-knockout mice revealed a striking preservation of axons, despite a similar extent of inflammation. Furthermore, neurons prepared from CyPD-knockout animals were resistant to reactive oxygen and nitrogen species thought to mediate axonal damage in EAE and MS, and brain mitochondria lacking CyPD sequestered substantially higher levels of Ca(2+). Our results directly implicate pathological activation of the mitochondrial PTP in the axonal damage occurring during MS and identify CyPD, as well as the PTP, as a potential target for MS neuroprotective therapies.
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Cyclophilins

Postby TonyJegs » Wed May 02, 2007 4:00 pm

Well, and again there is an attempt to cut the whole cell death process in pieces and claim that this particular piece is outmost important.

There are two antagonistic cyclophilins, A and D. Cyclophilin A is overexpressed in cancer/tumor cell and this is the reason of their tremendous survival. If you got knocked out Cyclophilin D, you will get overexpression of Cyclophilin A automatically.
Cyclophilin D is responsible for the permeability transition pore (PTP) in mitochondria formation for calcium (Ca2+) cellular overload during cell’s drastic events. Even if it is knocked out, the PTP will be open anyway (!), but the twice amount of calcium will be required for cell death. And it is a big difference, esp. in timing of cell death, which skillfully exploited for making various statements.

Anti-cancer drug Cyclosporin A has pleiotropic nature, it means - works on both, A and D. That why its effectiveness is only 30%. Survival of axons/or neurons mostly depends where they are located in the lesion (doesn’t matter of what origin), because other mechanisms (and their inducing factors) are much more powerful comparing to Rho’s or cyclophilins.
By the way, permeability transition in mitochondria leads to cell necrosis, but not to its apoptosis. These definitions are often mixed and misused.

Get it right. If the damage of tissue or separate cell is over the physiological limit, this tissue or this cell must due. This is a Law of Nature. In case of artificial survival the damage inside the cell is so significant that it cursed to die later anyway, but this will require lots of efforts from the tissue (or from whole body) later.

Kind regards,
Tony
"All truth passes through three stages.
First it is ridiculed.
Second it is violently opposed.
Third it is accepted as being self-evident."
Schopenhauer
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Postby gwa » Thu May 03, 2007 6:01 am

Tony,

Is it safe to say that you are not impressed with this new discovery?

gwa
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Cyclophilins

Postby TonyJegs » Thu May 03, 2007 8:49 am

I wouldn’t call it a new discovery. Cyclophilins are around from mid 80-ties, and there are present in every single cell of the body. Last three years there were attempts made from several labs to explore possible benefits by modulating their activity. Maybe they will be ‘hot’ again for a while.
I don’t think that this ‘new wave’ will have a significant impact on MS treatment protocols, but you never know nowadays for sure, what will be approved and recommended by authorities.

Kind regards,
Tony
"All truth passes through three stages.
First it is ridiculed.
Second it is violently opposed.
Third it is accepted as being self-evident."
Schopenhauer
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Postby gwa » Thu May 03, 2007 10:59 am

Tony,

Any idea what will have a significant impact on MS treatment?

gwa
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Postby TonyJegs » Thu May 03, 2007 11:28 pm

So far I value only myeloid precursor cells as a likely agent with big perspective for MS; they were appeared here in one of the trends in connection with TREM-2 protein.
I really wish to say more ‘brighter’ news about current or proposed drugs, but in reality their value varies from pure scum to minimally effective.

I would like to say a little bit more about cure and MS; about what you can do right now, without waiting for a ‘magic pill’.

I usually encourage MS people to be more positive by telling them that if you survive first 2 years, then the chance that you have a very bad form of MS is out, so prepare yourself for a long (decades long) deal with what you got.
Try to get the best individualized treatment during relapse and get it fast; try to get the best rehabilitation available after every relapse for few months long (at least); try to be stress-free, avoid extreme’s; try to fix any other health problem beyond MS, esp. teeth; try to live emotionally balanced life, and then the quality of your life will be definitely improved.
If you are “the fighter”, then fight MS vigorously but methodically (!); do it every single day, step-by-step. Analyze your body, pay attention to any changes, even minor, try to understand what is good for you, what is bad, then cut all ‘bad’s’ once and forever; do that everyday, and then you’ll be much better ‘equipped’ and in much better shape for the hard times which could come one day.

There are books about recovery from MS, true stories; sometimes it really takes time, so use your time wisely. Remember, maybe you couldn’t achieve everything you want, but achieving of something good is always possible.

Kind regards,
Tony
"All truth passes through three stages.
First it is ridiculed.
Second it is violently opposed.
Third it is accepted as being self-evident."
Schopenhauer
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