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

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

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

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

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

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

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

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

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

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

Ichraf Kraoua, MD 1, Jérôme Stirnemann, MD 2, Maria João Ribeiro, MD, PhD 3, Tiphaine Rouaud, MD 4, Marc Verin, MD, PhD 4, Agnès Annic, MD 5, Christian Rose, MD, PhD 6, Luc Defebvre, MD, PhD 5, Liliane Réménieras, MD 7, Michaël Schüpbach, MD 1, Nadia Belmatoug, MD 8, 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

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