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Research options
We live in a time of rapid development in medical science. Therapies that didn't exist yesterday are saving people today. We need to support research that will bring about effective therapies and even a cure for Sanfilippo Syndrome. Although the incidence of MPS III C is 1 in 1.4 million (Sanfilippo as a whole 1 in 70,000), the incidence of all Lysosomal Storage Diseases is 1 in 5000. A breakthrough in ERT, Gene Therapy, or breaching the Blood-Brain Barrier for one disease may prove to be beneficial to others. Enzyme
Replacement Therapy is a treatment in which a missing enzyme is injected into a patient who is missing or deficient
in that particular enzyme. It has shown promise in other Lysosomal Storage Diseases such as Gaucher, Fabry, MPS I and MPS
II. Once the enzyme is replaced, the substrates can be broken down and recycled. ERT does not treat the underlying disease,
only the symptoms. Since Sanfilippo Syndrome is primarily a neurological disease, medications or enzymes injected intravenously are blocked at the Blood-Brain Barrier (BBB). Scientists are studying the process of intrathecal injection, in which enzymes are injected into the spinal fluid, thus bypassing the BBB (see our notes on this here). More research must also be done with small molecules that can breach the BBB as well. Time is of the essence, as ERT can help stabilize a patient or even reverse some of the somatic effects of the disease. However, once damage has been done to the brain, it is irreversible. Shire is conducting a clinical trial at Manchester for IT ERT for MPS IIIA. There is a natural history study going on in Minnesota with a clinical trial to begin
perhaps in late 2012. Gene Therapy. Like ERT, gene therapy addresses the enzyme deficiency in patients. It is currently being investigated for MPS in animal and in-vitro models. This research is still in its early stages. Adeno-associated viral and retroviral vectors (AAV) have shown promise in some LSDs. There is a proposed clinical trial for MPS IIIB in the Netherlands and France using this technology. This trial is being held up due to what appear to be legal disagreements between the parties involved. Another group in London and Paris has injected AAV vector into the brain of MPS IIIA mice and shown stable correction of primary and secondary pathology. The enzyme for type C - acetyl-CoAlpha-glucosaminide
acetyltransferase - is unlike the other three
known Sanfilippo enzymes in that it is NOT soluble. It is theorized that it would not to be able to spread throughout
the cells of the brain and rest of the body. If this is true, ERT, AAV as well as Stem Cell Transplant may face even greater
challenges against Type C. Substrate Deprivation. This therapy, based on inhibition of synthesis of the compounds that cannot be degraded in cells of the patients, has been shown to be effective in several animal models of various diseases, and recent reports demonstrate its efficacy in the treatment of patients suffering from Niemann-Pick C disease and Sanfilippo disease. Genistein aglycone is a substrate inhibitor that may help stabilize a patient. Genistein is a soy isoflavone that has been shown to block GAG production in patient cells in culture from several MPS subtypes. Soy extracts of genistein contain mainly genistin, which is the sugar form of genistein. This is what one can buy in a health-food store (SoyFem). What they have used for testing in MPS III B mice at Manchester is genistein aglycone: pure genistein. This is important because it has been shown that genistin is broken down by the gut bacteria. Genistein aglycone has been shown to have a better bio viability than genistein in soy extract form - it can get into the blood better, therefore it can get into the brain better. If genistein aglycone is used, more can get into the blood for the same dose. Genistein aglycone appears to correct the pathological heperan sulfate in the brain and primary storage of the MPS III B mice. It can reduce the neuro inflammation in the brain and perhaps to some extent improve some of the secondary pathology as well. It appears to fully correct most of the behavioral abnormalities in the mice at eight months of age. It is important to state that genistein will not cure MPS III - only reduce the production of heperan sulfate, which cannot be broken down and stored in the cells. This action delays the progression, slows down the disease. There is already a lot of Phase I data out there, so it should be relatively quick to get it into trial. Manchester is planning a Phase II & III clinical trial - double blinded placebo. Although some families have used genestein and have anecdotal evidence of efficacy, many Doctors and researchers would like to see a proper clinical trial for genistein to determine proper dosage and effectiveness. Substrate Optimization Therapy, Zacharon’s Unique Approach (from Zacharon Pharmaceuticals' website). Zacharon is developing small molecule glycan inhibitors for the treatment of MPS and other lysosomal storage diseases. Zacharon’s therapeutic strategy is unique relative to historical attempts to develop small molecule therapies for these disorders. These historical attempts have sometimes targeted multiple glycan classes with the goal of reducing the amount of glycans produced (i.e., substrate reduction therapy). [Zacharon’s] approach is different and is designed to selectively modify the glycans to render them more readily degraded despite the presence of specific enzyme deficiencies, without altering their normal biologic function or reducing the overall amount that is produced. This strategy, termed “substrate optimization therapy”, has the potential to provide clinical efficacy without the toxicity associated with historical approaches. Importantly, this strategy also creates the potential to address the neurological symptoms and / or improve efficacy in combination with enzyme replacement therapies. (To download a copy of the poster presentation related to Zacharon’s MPS therapeutic program, please visit their publications page.) Heperan sulfate is a long polymer carbohydrate molecule widely expressed throughout the body. This glycan’s function is as a modulator, or rheostat of cell communication and cell signaling. It is the main substance stored for MPS I, II & III. Where enzyme-targeted therapies for these genetically distinct LSDs all have different enzyme replacement therapies, going after HS could be an effective way to treat across genetic types (see our notes on this here). Know your mutation. Out of roughly 21,000 genes, an individual
has 5-8 that are mutated, genes that the body was never able to repair and were passed down for generations. In order to better
treat the root cause of the disease it is important to understand the different variations of gene mutation. What kinds
of gene mutations are possible? (Genetics Home Reference.) The DNA sequence of a gene can be altered
in a number of ways. Gene mutations have varying effects on health, depending on where they occur and whether they alter the
function of essential proteins. The types of mutations include: Missense, nonsense, splice site, insertion, deletion,
duplication, frameshift, repeat expansion. Some mutations may allow for some residual enzyme production while other types
of mutations may lend themselves to certain therapies targeted for that mutation. As far as we know, there are only two labs in the U.S. that
can identify mutations for Sanfilippo Syndrome Type C. One of those is with Dr. Timothy Wood at the Greenwood Genetic Center; the other is with Dr. Jerry Thompson at the University of Alabama. Or you might discover a researcher who will find your child's specific mutation for free in
the name of research. Chaperone Therapy is designed to enhance innate enzyme activity by restoring the shape of misfolded lysosomal enzymes, so that the enzymes can subsequently leave the endoplasmic reticulum and do their job - to degrade the substrate. The website for Amicus Therapeutics helps illustrate how this novel therapy works. Some missense mutations and small in-frame deletions may lead to a misfolded protein without significantly affecting the active site. Chaperone therapy has shown promise in cell culture and animal models for a number of lysosomal disorders including Gaucher, Fabry, Pompe, MPS I, and Tay-Sachs disease (Enns, Huhn, Neurosurg Focus 2008). Transplants. Bone Marrow, Hematopoietic Stem Cell Transplantation (HSCT), Umbilical Cord Blood Transfer (CBT) are used for many LSDs that have significant CNS involvement and have shown variable therapeutic efficacy. Donor cells with normal enzyme activity repopulate the bone marrow, which allows for some cross-correction of neighboring cells lacking the normal enzyme. Although this treatment has worked for some LSDs, other disorders - including MPS II and MPS III - have showed continued progression of the disease. New Born Screening. Emerging therapeutic options require early diagnosis. Update April 2011: Mayo Clinic and Zacharon partner to develop newborn screening tests. Download the Zacharon-Mayo press release here. (PDF)
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Jonah's Just Begun - Foundation to Cure Sanfilippo, Inc.