Julia's Hope--Grants

2006 JULIA'S HOPE PILOT GRANTS

The purpose of this program is to support innovative research toward treatment of Sanfilippo Syndrome and other MPS disorders. The grant is designed to bring sponsored research to a level at which additional, ongoing support may be secured through larger grants from NIH or other sources.

The application form for grants awarded in July 2006 will be available in February 2006
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Current Research Supported By SSMRF

2005

Title: Targeting Sulphamidase to the Brain

Investigators: Dr. Bert de Boer, Leiden University; Drs. William Banks and William Sly, St. Louis University

Amount of Grant: $100,000

This project will test the delivery of sulphamidase to the brain using the CRM-197 carrier protein.

2004

1. Title: Transport of Sulfamidase Across the Blood-Brain Barrier
Investigator: Dr. Willam Banks and Dr. WIlliam Sly, St. Louis University School of Medicine
Amount of Grant: $94,300

Progress Report #1

Progress Report #2

Progress Report #3

2003

1. Title: Alterations in Blood Brain Barrier Permeability Following Intravenous Injections of Microbubbles During Transcranial Ultrasound.
Investigator: Dr. Thomas Porter, University of Nebraska Medical Center
Amount of Grant: $19,840

2. Title: Microglia as Therapeutic Tools for Central Nervous System disease in Sanfilippo Syndrome
Investigator: Dr. Kostantin Dobrenis, Albert Einstein College of Medicine, Bronx, NY
Amount of Grant: $40,000

Summary

The hypotheses we wish to test are [1] that cells of the monocyte-microglial lineage show enhanced infiltration of the CNS in MPSIIIA, and [2] that microglia have the capacity to transfer sulfamidase, the disease-deficient enzyme, to CNS neural cells with corrective benefit. The specific aims are:
1. To intravenously inject monocytic cells and microglia into MPSIIIA mice and assess recipients for the extent of invasion of cells into the CNS. We will determine whether blood monocytic cells enter the diseased brain in significant and greater number than in normal animals and whether they reach the brain parenchyma. We will also test whether invasion of injected microglia is greater than that of monocytic cells. The experiments will employ intrinsic genetically-tagged and conditionally immortalized cells obtained from transgenic mice, and will utilize our MPSIIIA mouse model.
2. To assess microglia for secretion of sulfamidase and for the capacity to effect therapeutic changes in MPSIIIA CNS cells. Purified normal mouse microglial cultures will be used to measure intracellular and secreted sulfamidase activity, as we have done for several other enzymes. Secreted enzyme will be evaluated for mannose-6-phosphate (M6P) receptor-mediated uptake, important to obtaining effective enzyme transfer. In coculture studies with MPSIIIA mouse CNS cells, we will test for microglial cross-correction of neurons. Reduction of heparan sulfate storage, as well as alleviation of secondary disease-related elevation of b-glucuronidase and GM2 ganglioside elevation, will be used as measures of efficacy.
Collectively, these experiments will help determine the strengths and limits of hematopoietic-cell based therapy, and identify the strategies that are required to make this approach effective for treatment of CNS disease in MPSIII.

3. Title: The Sleeping Beauty Transgene Vehicle: a potential new therapy for MPS IIIA.
Investigators: Dr. John Hopwood and Dr. Kim Hemsley, Women's and Children's Hospital, Adelaide, Australia; Dr. Cliff Steer and Dr. Betsy Kren, University of Minnesota.
Amount of Grant: $42,000 (plus matching funds generously provided by the National MPS Society)

Lay Summary
Introduction to the problem:

LSD are diseases in which cells in the body are missing one particular protein which is important for recycling within the cell. Two thirds of LSD involve the brain and spinal cord and this results in the cells in these areas being unable to break down waste products, and leads to the accumulation of toxic substances in the brain and a devastating effect on the neurological development of the child. Symptoms progress to severe mental retardation and death by inanition in the 2nd decade is usual. An example of an LSD that affects the brain is Sanfilippo syndrome type A (or mucopolysaccharidosis type IIIA - MPSIIIA).

Mice have been found with this disorder and the pattern of waste accumulation is similar to that seen in human patients with MPSIIIA. We can use the mouse model of MPSIIIA to test novel treatments for LSD that affect the brain. Success in the mouse model will result in trials of the treatment in the MPSIIIA dog model and hopefully this treatment can one day be used in children with MPSIIIA.

A treatment that is effective in MPSIIIA should also treat other LSD that affect the brain/spinal cord.

Who we [the investigators] are:

The present study investigates a potential new treatment for LSD that affect the brain. The proposed project brings together two world-leading research groups - Professor John Hopwood's research team in Adelaide, Australia, who have extensive experience in the field of lysosomal storage disorders and their treatment, and Professor Cliff Steer's team in Minnesota, USA, who have recently described and developed technology for repairing defective genes in animal models of biochemical disorders like MPSIIIA. By combining the two group's experiences, we believe that we may be able to produce a novel new treatment for LSD that affect the brain.

What we [the investigators] will do:

A 'naked DNA vector' that has a fluorescent tag (so that it can be located within the body) has been constructed by Betsy T. Kern and colleagues in the Department of Medicine, University of Minnesota Medical School. In the first part of the study, we will inject this reporter construct into the brain and blood circulation of MPSIIIA mice and we will be able to detect the fluorescent protein expressed from the introduced transgene after it has entered the cells of the brain and other organs. We are interested in assessing how far the vector travels within the body following injection in newborn and young adult mice, and for how long the transgene is expressed.

In the second part of the study, we plan to insert a 'wild-type' copy of a gene (which codes for the lysosomal enzyme sulphamidase that is missing in MPSIIIA) into the vector replacing the fluorescent DsRed2 gene. Injection of that vector into the brain/blood circulation of MPSIIIA mice will introduce the 'normal gene' into the mouse tissues. This will in theory allow the disorder to be treated, as the cells that receive the 'wild-type trans-gene, will now be able to start producing normal levels of sulphamidase. This should result in clearance of the toxic chemicals that have accumulated, and a reduction in the symptoms of MPSIIIA.

2002

Title: Assisted Enxyme Replacement Therapy in Mucopolysaccharodosis IIIA Mice Investigator: Dr. John Hopwood, Women's and Children's Hospital, Adelaide, Australia Amount of Grant: $75,000

Lay Summary from Dr. Hopwood

Sanfilippo syndrome is a rare degenerative disorder of the central nervous system that belongs to a group of genetic diseases known as the lysosomal storage disorders. Children with Sanfilippo syndrome lack an essential enzyme (sulphamidase). This absence leads to the accumulation of toxic substances in the brain, which have a devastating effect on the neurological development of the child. Symptoms are progressive and lead to severe mental retardation and early death. Mice have been found with this disease and the pattern of waste accumulation is similar to that seen in human Sanfilippo type A patients with the same disease. The behaviour of these Sanfilippo mice mimic the human disease in that the mice display a hyperactive, aggressive nature that resembles that observed in Sanfilippo patients. The sulphamidase protein that is deficient has been produced recombinantly. For this recombinant protein to be effective in breaking down the waste products it must be able to reach the major sites of pathology ie. brain. This is complicated because these cells are tightly held together and will not allow molecules into the brain from circulating blood. However, it has been proposed that the coupling of these proteins to p97, shown to pass into the brain from circulation, will enable "piggy back" entry of proteins normally excluded. We plan to take advantage of this by giving the recombinant sulphamidase/p97 conjugate protein at various dose rates to mice from birth, therefore allowing the protein to enter the brain. At the end of the study (18 weeks) the mice will undergo a neurological test known as the Morris water maze. This involves the mice having to learn and remember the location of a hidden platform. This will allow us to determine if the recombinant protein is effective in preventing/restoring the learning and memory deficits characteristic in the MPS IIIA mice.