Little Miss Hannah » Gaucher’s Disease

CGRF Considers $500,000 in Research

Carrie — Tue, 02 Nov 2010 09:49:24 +0000

The Children’s Gaucher Research Fund (CGRF) is currently reviewing research proposals and is considering the funding of between $300,000 and $600,000 in scientific research. The dollar amount of funding will be dependent upon the quality and the compelling nature of the submitted proposals. The CGRF released a “Call for Research” on July 10, 2010, encouraging investigators from around the world to submit scientific research proposals in an effort to find a cure for neuronopathic Gaucher disease. Eleven research proposals were received from scientific laboratories in England, Israel, Italy, The Netherlands, and the United States. Members of our Scientific Advisory Board as well as peer review from investigators outside of the Scientific Advisory Board are currently in the process of reviewing these proposals for potential funding.

In years past the CGRF has released similar “Calls for Research”, however the response in 2010 has far surpassed previous interest. This is a testament to the fact that science is accelerating – more is being learned about these brain diseases in children – and more scientific laboratories have an interest in pursuing avenues that may lead to a cure.

These advances in medical science are compelling, and it gives the CGRF further motivation to continue in our quest to raise funds to support this important research. It is your donations that fund this important research – donations can be made online at www.childrensgaucher.org. We truly appreciate your continued support.

100% of donations received by the Children’s Gaucher Research Fund go directly to Medical Research.

The Scientist Magazine: A Rare Chance

Mommy — Wed, 03 Feb 2010 04:03:14 +0000

http://www.the-scientist.com/article/display/57100/

Print Issue: Volume 24 | Issue 2 | Page 18

By Alison McCook

A rare chance

Over the course of 5 days last summer, an army of researchers and clinicians examined, poked, and prodded 1-year-old Hannah Ostrea at the National Institutes of Health (NIH). Experts in neurology, rehabilitation medicine, physical therapy, speech pathology, and anesthesiology gave the little girl an EEG, a test of her heart’s electrical activity (EKG), an MRI, a CT scan, X-rays, and a throat exam (laryngoscopy). All this testing was meant not only to help Hannah but in the hope that her rare disease could reveal something about another condition that affects 1 million Americans: Parkinson’s.

Hannah has Gaucher’s disease, and within hours of her birth, it was obvious something was wrong. Looking past her thick head of dark hair, and the fact that she could down an entire bottle of formula in 5 minutes, clinicians quickly saw that her spleen was massive, and her platelet counts were rock bottom. Her liver was expanding—in a few months it looked like she had a volleyball in her stomach. These are the classic signs of Gaucher’s, a rare, recessive genetic disorder in which the body does not produce enough of a lysosomal enzyme that breaks down the fatty substance glucocerebroside, causing it to glob up in cells of the liver, spleen, and other organs—including, sometimes, the brain.

But researchers have never seen the combination of mutations Hannah carries, so doctors couldn’t determine if she had the Type 2 or Type 3 form. Children with Type 2 typically die before their third birthdays, while those with Type 3 can live much longer. “They [wouldn’t] give us a prognosis,” Hannah’s mom, Carrie Ostrea, says. “They came out and said that to us. Which is fine by me.”Hannah has many classic Gaucher’s symptoms, such as developmental delays, and the inability to easily shift her eyes from side to side or up and down. But she also has some puzzling symptoms. For one, she only blinks once every 30 minutes or so—“you’ll have a staring contest with her,” Ostrea laughs. This is not a symptom of Gaucher’s disease, but it is a symptom of Parkinson’s.

Indeed, in recent years, researchers have been noting more and more crossover between the two diseases, and the hope is that insights into one will reveal secrets of the other.

In an October issue of the New England Journal of Medicine, Ellen Sidransky at the NIH and her colleagues found that Parkinson’s patients were five times more likely to carry a mutation in the gene associated with Gaucher’s disease. Furthermore, Parkinson’s patients with the mutation in the Gaucher’s gene tended to develop Parkinson’s earlier, and were more likely to have family members with Parkinson’s (N Engl J Med, 361:1651–61, 2009). It’s unknown how many people have signs of both diseases, Sidransky notes, but it’s “clearly dozens and dozens.”

Still, Parkinson’s and Gaucher’s are more different than they are alike. One comes from a deficiency of the lysosomal enzyme that breaks down glucocerebroside, the other likely from a deficiency of dopamine, and it’s largely unclear why the two diseases are linked, says Sidransky. Perhaps the lysosome plays a role in Parkinson’s; the protein misfolding that underlies Parkinson’s may be aggravated by mutations in the Gaucher’s gene.

Gaucher’s itself is an interesting model for trying to understand single-gene diseases, Sidransky adds. She and her colleagues like to invite patients with rare presentations of a disease to the NIH to study them and hopefully learn something about an entirely different condition. “I’ve always been convinced that focusing on one thing and becoming an expert helps you see connections” between that one question you’re investigating and other unanswered—perhaps even more significant—questions.

The NIH visits can be long, but Hannah held up fairly well, her mother says. She didn’t like waking up from the EEG and being tied down, and didn’t like the heart ultrasound, but the neuro-ophthalmologist got her to laugh hysterically by turning his video camera around so she could look at herself. “She just thought that was the funniest thing in the world,” Ostrea says.

Genzyme to Evaluate to-BBB’s Technology for Delivering Biologics to the Brain

Mommy — Sat, 07 Nov 2009 00:10:19 +0000

This could be HUGE!!! I’m waiting to hear back from Genzyme to get more details — Cerezyme, Genzyme’s product, delivered to the brain! That could be what we have been waiting for!!!!

http://www.genengnews.com/news/bnitem.aspx?name=67331403

Nov 3 2009, 11:02 AM EST

Genzyme to Evaluate to-BBB’s Technology for Delivering Biologics to the Brain
GEN News Highlights

Genzyme and Netherlands-based to-BBB established a research collaboration to evaluate the use of the latter’s G-Technology™ to transport biologics against neurodegenerative diseases across the blood brain barrier (BBB).

G-Technology has been developed to transport different classes of drugs directly across this barrier using glutathione-coated liposomes. The company’s research partnership with Genzyme follows on from a similar agreement with MedImmune, signed in September.
Liposomal formulation allows the encapsulation of a wide range of compounds and biological molecules without changing their function and protecting them against degradation and immune responses, according to to-BBB. Coating liposomes with PEG further ensures a prolonged circulation time in plasma. Conjugation of glutathione to the tips of the PEG molecules targets the liposomes toward the active glutathione transporters on the blood-brain barrier, the firm explains.

to-BBB’s lead in-house project is 2B3-101, a G-Technology formulated doxorubicin, currently in preclinical development. A Phase I/II trial is expected to start during the second half of 2010. Additional preclinical-stage in-house projects are ongoing in diseases including Alzheimer’s and lysosomal storage diseases.

The Parkinson’s Disease – Gaucher Disease link

Mommy — Fri, 23 Oct 2009 04:05:13 +0000

What we have known for a few months has finally started hitting the mainstream media now as well as some other medical sites. There are just a few….

Question is, now how can we capitalize on this and get the Parkinson’s community to start paying attention to our Gaucher kids?

Gaucher disease linked to Parkinson’s – Los Angeles Times
Mutant Gene Raises Risk of Parkinson’s (WebMD)
Glucocerebrosidase Mutations in Parkinson’s Disease New England Journal of Medicine (subscription)
Study Conclusively Ties Rare Disease Gene To Parkinson’s – Medical News Today

10/26, Golf Tournament and Auction, San Jose, CA!

Mommy — Fri, 16 Oct 2009 13:13:52 +0000

Coldwell Banker Residential Brokerage will hold its 13th annual Gregory Austin Macres Memorial Golf Tournament on Oct. 26 at the Palo Alto Hills Golf & Country Club, 3000 Alexis Drive. Registration is $135 and is open until Monday. A raffle and silent auction will also be held at the event.

The event is a fundraiser for the Children’s Gaucher Research Fund. Children’s Gaucher Disease is a progressive debilitating genetic disease that attacks children and causes a variety of systemic and neurological medical complications. The public is encouraged to participate in the tournament and may register by contacting their local Coldwell Banker Residential Brokerage office or sales associate. For more information on the Children’s Gaucher Research Fund, please visit www.childrensgaucher.org.

For more information on the Gregory Austin Macres Memorial Golf Tournament, call 925-275-3085.

A possible delivery system that crosses the blood-brain barrier!!!!

Mommy — Tue, 22 Sep 2009 12:54:17 +0000

Kyle’s mom and I are off to get the researchers’ opinions of this hopeful breakthrough!

University of Iowa scientists use blood-brain barrier as therapy delivery system
Enzyme delivered through the bloodstream corrects deficiencies in the brain

The blood brain barrier is generally considered an obstacle to delivering therapies from the bloodstream to the brain. However, University of Iowa researchers have discovered a way to turn the blood vessels surrounding brain cells into a production and delivery system for getting therapeutic molecules directly into brain cells.

Working with animal models of a group of fatal neurological disorders called lysosomal storage diseases, the UI team found that these diseases cause unique and disease-specific alterations to the blood vessels of the blood brain barrier. The scientists used these distinct alterations to target the brain with gene therapy, which reversed the neurological damage caused by the diseases.

The findings, which were published Sept. 13 in Nature Medicine’s Advance Online Publication (AOP), could lead to a new non-invasive approach for treating neurological damage caused by lysosomal storage diseases.

“This is the first time an enzyme delivered through the bloodstream has corrected deficiencies in the brain,” said lead investigator Beverly Davidson, Ph.D., UI professor of internal medicine, neurology, and molecular physiology and biophysics. “This provides a real opportunity to deliver enzyme therapy without surgically entering the brain to treat lysosomal storage diseases.

“In addition, we have discovered that these neurological diseases affect not just the brain cells that we often focus on, but also the blood vessels throughout the brain. We have taken advantage of that finding to delivery gene therapy, but we also can use this knowledge to better understand how the diseases impact other cell types such as neurons,” she added.

Lysosomal storage diseases are individually quite rare, but as a group they affect approximately 1 in 8,000 live births. The diseases are caused by deficiencies in enzymes that break down larger molecules. Without these enzymes, the large molecules accumulate inside cells and cause cell damage and destruction.

Enzyme replacement therapy has been successful in treating one form of lysosomal storage disease called Gaucher disease. However, storage diseases that affect the central nervous system remain untreatable because it has not been possible, to this point, to get the missing enzymes past the blood-brain-barrier and into the brain.

“Our discovery allowed us to test the idea that the brain cells might be able to make use of the reintroduced enzyme to stop or reverse the damage caused by the accumulated materials,” said Davidson, who also is the Roy J. Carver Professor in Internal Medicine. “In the treated mice, the affected brain cells go back to looking normal, the brain inflammation goes away and the impaired behaviors that these mice have is corrected.”

To develop their gene therapy targeting system, Davidson and colleagues used a technique called phage panning to identify peptides that hone in on the blood vessels surrounding the brain. Surprisingly, they found that peptides that targeted the brain blood vessels in mice with lysosomal storage diseases were distinct from the peptides that targeted brain blood vessels in healthy mice. Moreover, the peptides that targeted blood vessels in different diseases were distinct from each other, suggesting that each disease causes specific alterations to the blood vessels.

The team modified a deactivated virus used for gene therapy so that the virus expressed copies of the unique brain-targeting peptide on its outer coat, and also carried the genetic blueprint for the missing enzyme.

The study showed that the modified virus targeted the blood vessels in the brain and caused the blood vessel cells to produce the enzyme. Most importantly, the researchers found that the enzyme was secreted into the brain tissue in sufficient quantities to correct the disease symptoms and problems.

The team was able to use this approach to treat two types of lysosomal storage disease in mice, suggesting that the approach could be used for other types of lysosomal storage disease and possibly other neurological disorders.

Management of neuronopathic Gaucher disease: Revised recommendations

Mommy — Wed, 12 Aug 2009 03:23:39 +0000

http://www.springerlink.com/content/k0053551261l9n07/

The original guidelines drawn up for the management of the neuronopathic forms of Gaucher disease were felt to be in need of revision; in particular, the role of high-dose enzyme replacement therapy (120 IU/kg of body weight every 2 weeks) in stabilizing neurological disease. The existing published evidence was analysed; it was concluded that it did not support the role of high-dose ERT, although this might be required to treat severe visceral disease.

Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: A biological link between Gaucher disease and parkinsonism

Mommy — Mon, 10 Aug 2009 12:07:45 +0000

http://www.ncbi.nlm.nih.gov/pubmed/19576930?dopt=Abstract

The Parkinson’s Institute, 675 Almanor Ave., Sunnyvale, CA 94085, USA.

A growing body of experimental and clinical literature indicates an association between Gaucher disease and parkinsonism, raising the possibility that convergent mechanisms may contribute to neurodegeneration in these disorders. The aim of this study was to determine whether there is a relationship between alpha-synuclein (alpha-syn), a key protein in Parkinson’s disease pathogenesis, and abnormalities in glucocerebroside (GC) catabolism that lead to the development of Gaucher disease. We inhibited glucocerebrosidase (GCase) with conduritol B epoxide (CBE) in neuroblastoma cells and mice to test whether a biological link exists between GCase activity and alpha-syn. After CBE exposure, enhanced alpha-syn protein was detected in differentiated cells challenged with CBE as compared to vehicle, with no change in alpha-syn mRNA. In the mouse model, after one injection of CBE, elevated nigral alpha-syn levels were also detected. Analyses by Western blot and confocal microscopy revealed that normal alpha-syn distribution was perturbed after CBE exposure with its accumulation apparent within nigral cell bodies as well as astroglia. These findings raise the possibility that alpha-syn may contribute to the cascade of events that promote neuronal dysfunction in Gaucher disease and are the first to implicate this protein as a plausible biological intersection between Gaucher disease and parkinsonism using a pharmacological model.

PMID: 19576930 [PubMed - as supplied by publisher]

Uncoupling between CD1d upregulation induced by retinoic acid and conduritol-B-epoxide and iNKT cell responsiveness

Mommy — Sat, 08 Aug 2009 01:22:03 +0000

http://www.ncbi.nlm.nih.gov/pubmed/19651460?dopt=Abstract

IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal; ICBAS – Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Portugal.

Gaucher disease (GD) is associated with upregulation of CD1d and MHC-class II expression by monocytes. While the physiological impact of CD1d upregulation remains uncertain, it has been proposed that MHC-class II upregulation is associated with inflammation. Hereby, we show that the decrease in MHC-class II expression seen in GD patients under therapy correlates positively with chitotriosidase activity, a marker of inflamed macrophages. We also show that retinoic acid (RA) and the beta-glucocerebrosidase inhibitor conduritol-B-epoxide (CBE) lead to upregulation of CD1d expression by THP-1 cells, which correlated with an increase in mRNA expression. In vitro co-culture experiments showed that RA treated THP-1 cells were more stimulatory for CD4(+) than for CD8(+) T cells, as determined by CFSE loss, in comparison to untreated THP-1 cells. Interestingly, even though addition of exogenous isoglobotrihexosylceramide (iGb3), a physiological CD1d ligand, augmented the percentage of dividing CD4(+) T cells, we could not detect a significant expansion of CD4(+)Valpha24(+) invariant Natural Killer T (iNKT) cells. In contrast, addition of alpha-galactosylceramide (alpha-GC) induced expansion of Valpha24(+) iNKT cells as determined by using alpha-GC-loaded human CD1d dimers. These results strengthen the existence of a cross-talk between monocyte lipid accumulation, inflammation and changes in cell surface CD1d and MHC-class II in monocytes, which may result in inappropriate recognition events by immune cells and perpetuate chronic inflammation.

PMID: 19651460 [PubMed - as supplied by publisher]

Parkinsonism in Gaucher’s disease type 1: Ten new cases and a review of the literature

Mommy — Tue, 30 Jun 2009 05:09:25 +0000

http://www3.interscience.wiley.com/journal/122441884/abstract?CRETRY=1&SRETRY=0

Frédéric Sedel (frederic.sedel@psl.aphp.fr)

Ichraf Kraoua, MD¹, Jérôme Stirnemann, MD², Maria João Ribeiro, MD, PhD³, Tiphaine Rouaud, MD⁴, Marc Verin, MD, PhD⁴, Agnès Annic, MD⁵, Christian Rose, MD, PhD⁶, Luc Defebvre, MD, PhD⁵, Liliane Réménieras, MD⁷, Michaël Schüpbach, MD¹, Nadia Belmatoug, MD⁸, Marie Vidailhet, MD^{1 9}, Frédéric Sedel, MD, PhD^{¹ *}
¹Federation of Nervous System Diseases, Reference Center for Lysosomal Diseases, Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, France ²Department of Internal Medicine, Jean Verdier Hospital, Assistance Publique-Hôpitaux de Paris, Paris X111 University, France ³Service Hospitalier Frédéric Joliot, I2BM, DSV, CEA, Orsay, France ⁴Department of Neurology, University Hospital of Rennes, Rennes, France ⁵Department of Neurology, University Hospital of Lille, Lille, France ⁶Department of Onco-Haematology, Saint Vincent de Paul Hospital, Lille, France ⁷Department of Haematology, University Hospitals of Limoges, Limoges, France ⁸Department of Internal Medicine, Reference Center for Lysosomal Diseases, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, France ⁹INSERM U679, Pierre et Marie Curie (Paris 6) University, France
	email:

^*Correspondence to Frédéric Sedel, Federation of Nervous System Diseases and Reference Centre for Lysosomal Diseases, Salpêtrière Hospital, 47 Boulevard de l’Hôpital, 75651 Paris cedex 13, France

Potential conflict of interest: None reported.

Funded by:
Genzyme

Keywords

Gaucher • glucocerebrosidase • parkinsonism • Parkinson’s disease • Lewy body dementia

Abstract

Parkinsonism has been described in patients with Gaucher’s disease (GD). We reviewed the 10 cases of patients with both parkinsonism and GD recorded in the French national GD registry, as well as 49 previously published cases. Relative to the general population, parkinsonism in GD patients (1) was more frequent, (2) occurred at an earlier age, (3) responded less well to levodopa, and (4) was more frequently associated with signs of cortical dysfunction. Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) were ineffective on GD-associated parkinsonism, suggesting that parkinsonism itself is not an indication for ERT or SRT in this setting. © 2009 Movement Disorder Society