Creating a plan of attack with the National Gaucher Foundation

Unfortunately there is a lot that I have been doing for the past few months that I can’t blog about.  But I have been talking to researchers all over the country, different lysosomal storage disease organizations, as well as trying to reach out to the media.  I really only post when it is something that is “nonpolitical” or published. 

Today, I had a wonderful conversation with the head of the National Gaucher Foundation for about 45 minutes.  They have been so incredibly supportive of our fight against GD23, and they have opened their arms wide open to our families.  For the past 10 years or so, there was an agreement that the Children’s Gaucher Research Fund would fund and support GD23 families, and the NGF would fund and support GD1 families.  So, to take us in with such passion and care after a decade, it has just been fantastic.

She and I are going to work together to come up with a sensible plan to get a real formalized research plan and structure together.  She has some ideas that she is going to work on during the next week, and I have a lot of ideas and contacts to bring into the mix.   I really think she and I will work well together.  She supports my passion and drive, yet I feel comfortable enough with her because she is not afraid to be honest with me about how things “work” and keeps my feelings in check as to not to get my hopes up. 

Our concept is instead of having a few researchers here and there doing their own thing, we are going to attempt to create a huge umbrella with all the Gaucher organizations and other related diseases working together,  get a common point where all the research information is kept updated, and work on finding research that could make a difference for kids like Hannah who are here today, still fighting. 

Bottom line, our goal is to get work towards finding a treatment for our kids.

With the power and expertise of the National Gaucher Foundation behind us, I really believe we have the chance to get some real research done.  Keep your fingers crossed…

Sly Syndrome: Delivering Medicine To Fight Rare Genetic Disorder

http://www.sciencedaily.com/releases/2007/07/070726085925.htm

ScienceDaily (July 27, 2007) — The scientist who discovered “Sly Syndrome” nearly four decades ago and a team of colleagues at Saint Louis University are a step closer to finding an approach to treat the rare genetic disease. Sly Syndrome causes bone defects, mental retardation, vision and hearing problems, heart disease and premature death.

They found that a potentially life-saving enzyme can be induced to cross the blood-brain barrier, a structure which protects the brain from foreign substances, if it is given with the hormone epinephrine.

Ever since William S. Sly, M.D., chairman of the department of biochemistry and molecular biology at Saint Louis University, discovered the rare genetic disease in 1969, he and his colleagues have conducted research to learn more about how to treat it.

He says their recent findings have significance beyond treating the extremely rare disease that bears his name.

“There are at most 100 living cases of Sly Syndrome. Nonetheless, this disease is a model for all the diseases in this group, some of which are much more common,” Sly says.

“Lysosomal storage diseases affect 1 in 7,000 live births, and 90 percent of those with the diseases have brain involvement. What we find with Sly Syndrome has some importance for all those diseases as well. It is potentially a big finding and an important first step.”

The discovery potentially points to a new way to get big molecules, such as certain medications, across the blood-brain barrier. It is reported in the Proceedings of the National Academy of Sciences online early edition the week of July 16.

SLU researchers found that the right amount of epinephrine probably works by stimulating transport by vesicles — blister-like wrappers that carry substances across the blood-brain barrier – so that the enzyme missing in patients who have Sly Syndrome can get into the brain.

Those who have Sly Syndrome lack the enzyme called beta-glucuronidase. Without this enzyme, protein-sugar molecules accumulate in the brain and other organs in the body. By replacing the missing enzyme, doctors believe they can treat the genetic disease.

The problem, though, was slipping the enzyme past the blood-brain barrier to where it needs to do its work.

“This is a disease that is simply made for testing drug delivery vehicles. If you can get the enzyme into the brain, the vehicle that delivered it could work to deliver other chemicals, too,” says William A. Banks, M.D., professor of geriatrics and pharmacological and physiological sciences at Saint Louis University, and a leading researcher on the blood-brain barrier.

Sly Syndrome, which occurs in fewer than one in 100,000 births, is a progressive disorder that ranges in severity from mild to deadly. It is among a group of genetic diseases call mucopolysaccharidoses.

“Some children who have this group of diseases are doomed to an early death because they don’t make a certain enzyme,” Banks says.

Enzyme replacement therapy — or putting the missing enzyme into the bodies of those who have Sly Syndrome — holds promise in treating the physical problems of the disease.

“In the case of Sly Syndrome, the missing enzyme is more than 1,000 larger than a sugar molecule and so huge it can’t get across the blood-brain barrier, which prevents it from reaching the brain.”

Scientists used a mouse model to figure out how to get the enzyme into the brain. They knew that injections of the missing enzyme into the brains of baby mice reached their target, but similar injections into mature mice did not. As the mice grew older, the transporter that brought the enzyme past the protective blood-brain barrier was lost.

“We found that the right amount of epinephrine allowed the enzyme to pass into the brain of older mice, which means we reinduced the way to get the enzyme where it is needed,” Banks says.

Epinephrine is a drug that treats cardiac arrest and is given to open the airways of asthma patients who have difficulty breathing. Discovering epinephrine as the transportation key to unlock the blood-brain barrier for the missing enzyme was “a shot in the dark,” Banks says.

 “High doses of epinephrine can destroy the blood brain barrier and let everything into the brain, which is toxic,” Banks says. “We tested three things. One didn’t work at all. One worked partially and epinephrine worked incredibly well.”

The finding changes how scientists look at getting medications through the blood-brain barrier, he says, and could have implications for treating other diseases such as Alzheimer’s disease and obesity.

Instead of viewing the blood-brain barrier as an obstacle to fight, researchers should consider it something to finesse, using its special features to help in drug delivery, Banks adds.

“The field has approached the problem as if you have a Volkswagen that can get across the street and you put your cargo on it so the cargo can get there too. We’ve found that trying to transport the cargo changes the Volkswagen and the Volkswagen can no longer get across.”

The research was funded by the National Institutes of Health, The Sanfilippo Syndrome Medical Research Foundation and VA Merit Review.

NIH Therapeutics for Rare and Neglected Diseases Program

http://rarediseases.info.nih.gov/TRND/

The need and opportunity for Therapeutics for Rare and Neglected Diseases (TRND) are enormous. Of the 7,000 human diseases, fewer than 300 are of interest to the biopharmaceutical industry, due to limited prevalence and/or commercial potential. More than 6,000 of these diseases are rare (defined by the Orphan Drug Act as <200,000 U.S. prevalence), and the remainder are neglected because they affect impoverished or disenfranchised populations. Researchers have now defined the genetic basis of more than 2,000 rare diseases and identified potential drug targets for many rare and neglected diseases (RND).

TRND received $24 million in the National Institutes of Health (NIH) budget for fiscal year 2009. TRND is a collaborative drug discovery and development program with governance and oversight provided by the Office of Rare Diseases Research (ORDR). Program operations will be within the intramural research program adjacent to the NIH Chemical Genomics Center (NCGC) and will be administered by the National Human Genome Research Institute (NHGRI).

 

Frequently Asked Questions
TRND (PDF – 30)
Rare Diseases (PDF – 21KB)
Neglected Diseases (PDF – 36KB)

News

TRND Press Release (PDF – 80KB)

GBA gene (glucosidase, beta; acid)

http://ghr.nlm.nih.gov/gene=gba

What is the official name of the GBA gene?

The official name of this gene is “glucosidase, beta; acid (includes glucosylceramidase).”

GBA is the gene’s official symbol. The GBA gene is also known by other names, listed below.

What is the normal function of the GBA gene?

The GBA gene provides instructions for making an enzyme called beta-glucocerebrosidase. This enzyme is active in lysosomes, which are structures inside cells that act as recycling centers. Lysosomes use digestive enzymes to break down toxic substances, digest bacteria that invade the cell, and recycle worn-out cell components. Based on these functions, enzymes in the lysosome are sometimes called housekeeping enzymes. Beta-glucocerebrosidase is a housekeeping enzyme that helps break down a large molecule called glucocerebroside into a sugar (glucose) and a simpler fat molecule (ceramide).

How are changes in the GBA gene related to health conditions?

Gaucher disease – caused by mutations in the GBA gene
More than 200 mutations in the GBA gene have been identified in people with Gaucher disease. These mutations occur in both copies of the gene in each cell. Most of the GBA mutations responsible for Gaucher disease change a single protein building block (amino acid) in beta-glucocerebrosidase, altering the structure of the enzyme and preventing it from working normally. Other mutations delete or insert genetic material in the GBA gene or lead to the production of an abnormally short, nonfunctional version of the enzyme.

Mutations in the GBA gene greatly reduce or eliminate the activity of beta-glucocerebrosidase in cells. As a result, glucocerebroside is not broken down properly. This molecule and related substances can build up in white blood cells called macrophages in the spleen, liver, bone marrow, and other organs. Tissues and organs are damaged by the abnormal accumulation and storage of these substances, causing the characteristic features of Gaucher disease.

Parkinson disease – associated with the GBA gene
Growing evidence suggests an association between GBA mutations and Parkinson disease or Parkinson-like disorders that affect movement and balance (parkinsonism). People with Gaucher disease have mutations in both copies of the GBA gene in each cell, while those with a mutation in just one copy of the gene are called carriers. Some studies suggest that people with Gaucher disease and GBA mutation carriers have an increased risk of developing Parkinson disease or parkinsonism.

Symptoms of Parkinson disease and parkinsonism result from the loss of nerve cells that produce dopamine. Dopamine is a chemical messenger that transmits signals within the brain to produce smooth physical movements. It remains unclear how GBA mutations lead to these disorders. Researchers speculate that GBA mutations may contribute to the faulty breakdown of toxic substances in nerve cells by impairing the function of lysosomes, or mutations may enhance the formation of abnormal protein deposits. As a result, toxic substances or protein deposits could accumulate and kill dopamine-producing nerve cells, leading to abnormal movements and balance problems.

other disorders – associated with the GBA gene
Emerging research suggests an association between GBA mutations and a disorder called dementia with Lewy bodies. Lewy bodies are abnormal deposits of the protein alpha-synuclein that form in some dead or dying nerve cells. Specifically, they occur in nerve cells that produce a chemical messenger called dopamine. The features of this disorder are variable, but symptoms typically include a loss of intellectual functions (dementia), visual hallucinations, and fluctuations in attention. Affected individuals may also experience changes that are characteristic of Parkinson disease such as trembling or rigidity of limbs, slow movement, and impaired balance and coordination.

People with mutations in both copies of the GBA gene in each cell develop Gaucher disease, while those with a mutation in just one copy of the gene are called carriers. Research suggests that carriers have an increased risk of developing dementia with Lewy bodies, although it remains unclear how GBA mutations increase this risk. Researchers speculate that GBA mutations can alter the structure of beta-glucocerebrosidase and impair the function of lysosomes. As a result, alpha-synuclein may not be processed properly, allowing the formation of Lewy bodies.

Where is the GBA gene located?

Cytogenetic Location: 1q21

Molecular Location on chromosome 1: base pairs 153,470,866 to 153,481,111
The GBA gene is located on the long (q) arm of chromosome 1 at position 21.

The GBA gene is located on the long (q) arm of chromosome 1 at position 21.

More precisely, the GBA gene is located from base pair 153,470,866 to base pair 153,481,111 on chromosome 1.

See How do geneticists indicate the location of a gene? in the Handbook.

Where can I find additional information about GBA?

You and your healthcare professional may find the following resources about GBA helpful.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

What other names do people use for the GBA gene or gene products?

  • Acid beta-glucosidase
  • Alglucerase
  • beta-D-glucosyl-N-acylsphingosine glucohydrolase
  • Beta-glucocerebrosidase
  • D-Glucosyl-N-acylsphingosine glucosylhydrolase
  • GBA1
  • GLCM_HUMAN
  • GLUC
  • Glucocerebrosidase
  • Glucocerebroside beta-Glucosidase
  • glucosphingosine glucosylhydrolase
  • Glucosylceramidase
  • Glucosylceramide beta-Glucosidase
  • Imiglucerase

Where can I find general information about genes?

The Handbook provides basic information about genetics in clear language.

These links provide additional genetics resources that may be useful.

What glossary definitions help with understanding GBA?

acids ; amino acid ; bacteria ; bone marrow ; carrier ; cell ; ceramides ; dementia ; digestive ; dopamine ; enzyme ; gene ; glucose ; hallucinations ; Lewy bodies ; lysosome ; macrophage ; molecule ; mutation ; nerve cell ; parkinsonism ; protein ; symptom ; tissue ; toxic ; white blood cells

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

See also Understanding Medical Terminology.

References (14 links)

Calcium signaling in neurodegeneration

http://www.molecularneurodegeneration.com/content/4/1/20

Calcium is a key signaling ion involved in many different intracellular and extracellular processes ranging from synaptic activity to cell-cell communication and adhesion. The exact definition at the molecular level of the versatility of this ion has made overwhelming progress in the past several years and has been extensively reviewed.

In the brain, calcium is fundamental in the control of synaptic activity and memory formation, a process that leads to the activation of specific calcium-dependent signal transduction pathways and implicates key protein effectors, such as CaMKs, MAPK/ERKs, and CREB. Properly controlled homeostasis of calcium signaling not only supports normal brain physiology but also maintains neuronal integrity and long-term cell survival.

Emerging knowledge indicates that calcium homeostasis is not only critical for cell physiology and health, but also, when deregulated, can lead to neurodegeneration via complex and diverse mechanisms involved in selective neuronal impairments and death. The identification of several modulators of calcium homeostasis, such as presenilins and CALHM1, as potential factors involved in the pathogenesis of Alzheimer’s disease, provides strong support for a role of calcium in neurodegeneration.

These observations represent an important step towards understanding the molecular mechanisms of calcium signaling disturbances observed in different brain diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases.