Feeling Old? Time for a Mitochondrial Tune Up
Gene treatment targets mutations and defects in cellular powerhouses that contribute to aging and disease
By Liz Brown
Betterhumans Staff
Credit: NIH
Repair work: Prone to age-related damage, mitochondria could be fixed through DNA mending or replacement
Halting aging and the development of diseases such as Alzheimer's and Parkinson's may one day be as simple as seeing the doctor for a mitochondrial "tune up."
The tune up, currently in the early stages of development, would repair mutations that occur in mitochondria and are believed to contribute to many afflictions, from diabetes to heart disease.
From biology class, you may remember that mitochondria are the "powerhouses of the cell." These tiny organelles manufacture ATP, which is used as a source of energy. Besides manufacturing ATP, mitochondria are also involved in apoptosis, sending a "suicide" signal to cells.
Mitochondria are unique from other cell organelles because they contain their own DNA. This leaves them susceptible to genetic mutations in the form of DNA damage. Scientists believe that when a cell divides, mitochondria can lose important information, which can contribute to disease and aging.
Correcting defects
To combat this DNA damage, Shaharyar Khan and Rafal Smigrodzki of the University of Virginia are developing a therapy that could potentially prevent mitochondrial diseases and possibly many aspects of aging.
The therapy introduces engineered "correct" mitochondrial DNA to fix defects.
"In our current protocol, the DNA is mixed with a specially designed protein which coats it and enables it to pass through cell membranes to reach mitochondria," says Smigrodzki.
The method for delivery is called protofection. Already being tested in animals, protofection uses what are known as mitochondrial targeting sequences (MTS) to deliver treatment through the membrane of the mitochondria. These act like zip codes, making sure that treatment is delivered to the proper area of the organelle.
Delivering proteins
The approach is already showing promise for delivering therapeutic proteins to mitochondria in living animals.
Mark Payne of Wake Forest University School of Medicine in North Carolina, who is conducting similar research to the team in Virginia, says that researchers there have already delivered a test protein—green florescent protein—to most tissues in rats, including the brain, heart, liver, kidney and muscle.
Delivery of specific proteins could repair defects that cause specific diseases, much like repairing certain parts of a car. "We are currently working on two human diseases to determine if we can repair or stop the damage that occurs in the mitochondria," says Payne. One is a mitochondria defect that leads to sudden infant death syndrome (SIDS) and the other is involved in Friedreich's Ataxia, a rare genetic, neurodegenerative disease.
"Both of these diseases have transgenic animal models that we can test our hypothesis in," says Payne. "If we are successful in altering the disease course in the animal, we will perform additional testing and move towards human clinical trials," he says.
DNA replacement
While targeting individual proteins could help treat disease, Smigrodzki and Khan in Virginia have also begun tests on animals to see if they can successfully replace all mitochondrial DNA in a functioning animal. If all of the DNA can be replaced, it is possible that all mitochondrial diseases could be treated with a one-size-fits-all treatment rather than different treatments for different conditions.
"Currently, mitochondrial diseases are essentially untreatable," says Smigrodzki. "There is increasing evidence for significant mitochondrial involvement in Alzheimer's disease, Parkinson's disease and diabetes so mitochondrial replacement therapy could provide an effective causal (as opposed to current symptomatic) treatment."
However, Smigrodzki warns there is a long road of lab work ahead. "Once we prove the efficacy of protofection in animals, we need to show that it works in humans and then expand its use to other conditions, which should be enough to keep us busy for the next 15 to 20 years."
http://www.betterhumans.com/News/news.aspx?articleID=2005-02-23-3
By Liz Brown
Betterhumans Staff
Credit: NIH
Repair work: Prone to age-related damage, mitochondria could be fixed through DNA mending or replacement
Halting aging and the development of diseases such as Alzheimer's and Parkinson's may one day be as simple as seeing the doctor for a mitochondrial "tune up."
The tune up, currently in the early stages of development, would repair mutations that occur in mitochondria and are believed to contribute to many afflictions, from diabetes to heart disease.
From biology class, you may remember that mitochondria are the "powerhouses of the cell." These tiny organelles manufacture ATP, which is used as a source of energy. Besides manufacturing ATP, mitochondria are also involved in apoptosis, sending a "suicide" signal to cells.
Mitochondria are unique from other cell organelles because they contain their own DNA. This leaves them susceptible to genetic mutations in the form of DNA damage. Scientists believe that when a cell divides, mitochondria can lose important information, which can contribute to disease and aging.
Correcting defects
To combat this DNA damage, Shaharyar Khan and Rafal Smigrodzki of the University of Virginia are developing a therapy that could potentially prevent mitochondrial diseases and possibly many aspects of aging.
The therapy introduces engineered "correct" mitochondrial DNA to fix defects.
"In our current protocol, the DNA is mixed with a specially designed protein which coats it and enables it to pass through cell membranes to reach mitochondria," says Smigrodzki.
The method for delivery is called protofection. Already being tested in animals, protofection uses what are known as mitochondrial targeting sequences (MTS) to deliver treatment through the membrane of the mitochondria. These act like zip codes, making sure that treatment is delivered to the proper area of the organelle.
Delivering proteins
The approach is already showing promise for delivering therapeutic proteins to mitochondria in living animals.
Mark Payne of Wake Forest University School of Medicine in North Carolina, who is conducting similar research to the team in Virginia, says that researchers there have already delivered a test protein—green florescent protein—to most tissues in rats, including the brain, heart, liver, kidney and muscle.
Delivery of specific proteins could repair defects that cause specific diseases, much like repairing certain parts of a car. "We are currently working on two human diseases to determine if we can repair or stop the damage that occurs in the mitochondria," says Payne. One is a mitochondria defect that leads to sudden infant death syndrome (SIDS) and the other is involved in Friedreich's Ataxia, a rare genetic, neurodegenerative disease.
"Both of these diseases have transgenic animal models that we can test our hypothesis in," says Payne. "If we are successful in altering the disease course in the animal, we will perform additional testing and move towards human clinical trials," he says.
DNA replacement
While targeting individual proteins could help treat disease, Smigrodzki and Khan in Virginia have also begun tests on animals to see if they can successfully replace all mitochondrial DNA in a functioning animal. If all of the DNA can be replaced, it is possible that all mitochondrial diseases could be treated with a one-size-fits-all treatment rather than different treatments for different conditions.
"Currently, mitochondrial diseases are essentially untreatable," says Smigrodzki. "There is increasing evidence for significant mitochondrial involvement in Alzheimer's disease, Parkinson's disease and diabetes so mitochondrial replacement therapy could provide an effective causal (as opposed to current symptomatic) treatment."
However, Smigrodzki warns there is a long road of lab work ahead. "Once we prove the efficacy of protofection in animals, we need to show that it works in humans and then expand its use to other conditions, which should be enough to keep us busy for the next 15 to 20 years."
http://www.betterhumans.com/News/news.aspx?articleID=2005-02-23-3
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