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Batten Disease Research Past Grants
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2011 Jon Cooper, PhD, Institute of Psychiatry, King's College London Taylor’s Tale awarded $5,000 to the Pediatric Storage Disorders Laboratory, located at King’s College London, in support of its infantile NCL mouse colony. The lab is led by Jon Cooper, PhD, an internationally known expert on neuronal ceroid lipofuscinosis (NCL), or Batten disease. Dr. Cooper is a highly regarded researcher within the Batten disease community and beyond. He maintains his own research projects and performs much of the pathology for numerous other researchers. He worked at Stanford University in Palo Alto, CA prior to joining the team at King’s College London and is a strong connector between the American and European research communities. Taylor’s Tale has previously supported Dr. Cooper’s work through a grant to perform the pathology studies for research led by Sandra Hofmann, MD, PhD, of the University of Texas Southwestern Medical Center at Dallas. Sandra Hofmann, MD, PhD, University of Texas Southwestern For the fifth consecutive year, Taylor's Tale awarded a grant to Sandra Hofmann, MD, PhD, of the University of Texas Southwestern. This project involves the development of biomarkers needed to track the effectiveness of therapies for infantile Batten disease (INCL). INCL is caused by the lack or severe deficiency of the PPT1 enzyme, and enzyme activity measurement is necessary to evaluate treatment methods. Taylor's Tale co-funded this project with the Batten Disease Support & Research Association (BDSRA). The total amount of the grant is $100,626. 2010 Sandra Hofmann, MD, PhD, University of Texas Southwestern For the fourth consecutive year, Taylor's Tale awarded a grant to Sandra Hofmann, MD, PhD, of the University of Texas Southwestern. In 2010-11, Dr. Hofmann will collaborate with Jon Cooper, PhD, of Kings College London, who will perform the pathology studies. The work done by Dr. Hofmann over the past several years has yielded promising results. The goal of the project is to develop enzyme replacement therapy for infantile NCL, a form of Batten disease. During the course of this project, Dr. Hofmann has successfully produced PPT1, the enzyme that children with infantile Batten disease lack, and has also shown it to have characteristics that make it ideal for mass production. More recently, she has conducted mouse studies using the PPT1 enzyme, work that has also made significant progress. Dr. Hofmann is currently addressing methods of delivering the enzyme across the blood brain barrier, a common problem in the treatment of brain-based diseases such as Batten disease. She is attempting to fuse the enzyme with various peptide (protein) combinations in order to chaperone the enzyme into the brain. Taylor's Tale has contributed more than $200,000 to this ongoing project since July 2007. 2009 Sandra Hofmann, MD, PhD, University of Texas Southwestern From July 2007-2009, Dr. Hofmann biopanned the PPT1 enzyme in sufficient quantities and determined a way to cross the blood brain barrier. If successful, Dr. Hofmann's work will eliminate the need to inject the enzyme directly into the brain and will correct the disorder. With a third year of funding, Dr. Hofmann plans to begin preclinical work with mice. This grant was made possible by Taylor's Tale in partnership with the Hayden's Batten Disease Foundation, Inc. and the Batten Disease Support and Research Association (BDSRA) North American and Australian chapters. Shannon L. Macauley, PhD, Washington University School of Medicine INCL is a neurodegenerative disease that affects the central nervous system during infancy or childhood. The PPT1-/- mouse, an INCL model, mimics the disease. The first pathological change seen in the PPT1-/- brain is astrocyte activation (e.g. GFAP upregulation) in the thalamus and cerebellum. These sites act as a predictor for future sites of neurodegeneration. Dr. Macauley's team hypothesizes that preventing GFAP upregulation - a sign of activated astrocytes - will alter the disease course. Preliminary data suggests that reactive astrocytes play a major role in modulating a neuroimmune response in the central nervous systems of PPT1-/- mice. She proposes a three-prong approach to curing INCL, including a bone marrow transplant, gene therapy and medication therapy using Cystagon. This grant was made possible by Taylor's Tale in partnership with the Hayden's Batten Disease Foundation, Inc. and the Batten Disease Support and Research Association (BDSRA) North American and Australian chapters. Anil Mukherjee, PhD, National Institutes of Health (NIH) Dr. Mukherjee is a senior investigator in the Section on Developmental Genetics/NIH. His study will include two phases using a drug called Ataluren (formerly PTC124). Initial in vitro experiments will use cell lines of Infantile INCL (INCL) patients. The follow-up “proof of principle” will be performed in INCL mice. Ataluren is the first investigational drug designed to enable the formation of a functioning protein in patients with genetic disorders due to a nonsense mutation. A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. Ataluren is currently being investigated for use in patients with nonsense mutation Duchenne muscular dystrophy and nonsense mutation cystic fibrosis. How does it work? In healthy individuals, ribosomes translate the informational code in the mRNA into protein until arriving at a normal stop signal in the mRNA, at which point the ribosome appropriately stops translation and a functioning protein results. Nonsense mutations, however, create a premature stop signal in the mRNA. This premature stop signal causes the ribosome to halt translation before a functioning protein id generates, creating a shortened, nonfunctioning protein. The resulting disease is determined by which protein cannot be expressed in its entirely and is no longer functional (ie., the dystrophir protein in Duchenne or the CFTR protein in cystic fibrosis). Ataluren is designed to allow the ribosome to ignore the premature stop signal and continue translation of the mRNA, resulting in the formation of a functioning protein. Ataluren does not cause the ribosomes to read through the normal stop signal. Taken orally, Ataluren has the potential to address the underlying cause of the disease by overriding the premature stop signal, enabling the synthesis of a functioning protein. Ataluren does not alter the patient’s genetic code or introduce genetic materials into the body. The NIH Office of Rare Diseases estimates that rare diseases affect 25 million people in the US and that the majority of these people have genetic disorders. In more than 2,400 genetic disorders, a nonsense mutation causes the disease in an average of 5 to 15% of the patients. Besides nonsense mutation Duchenne muscular dystrophy and nonsense mutation cystic fibrosis, these genetic disorders include a range of serious diseases across multiple therapeutic areas, including spinal muscular atrophy, hemophilia, lysosomal storage disorders (such as NCL) and some forms of cancer. Ataluren has demonstrated proof of concept in Phase 2a clinical trials of nonsense mutation pediatric patients with Duchenne muscular dystrophy and nonsense mutation pediatric and adult patients with cystic fibrosis. The drug has been generally well tolerated. Adverse events have been largely consistent with background symptoms and have usually been mild. No concerning adverse findings have been identified based on physical examinations, vital sign measurements, ECGS or lab studies. This grant was made possible by Taylor's Tale in partnership with the Hayden's Batten Disease Foundation, Inc. and the Batten Disease Support and Research Association (BDSRA) North American and Australian chapters. 2008 Sandra Hofmann, MD, PhD, University of Texas Southwestern Taylor's Tale originally funded Dr. Hofmann's work in July 2007 with a gift of $50,000. During the first year of the project, she showed that PPT1, the missing enzyme associated with Infantile NCL, can be produced in the laboratory setting. During the second year of the project, she produced a sufficient amount of the enzyme for testing and developed a means of delivering it in such a way that it could cross over the blood brain barrier. The blood brain barrier is the reason that conventional methods of delivering a therapy for Batten disease and other brain-based diseases fails. David Pearce, PhD, University of Rochester Neuronal ceroid lipofuscinosis (NCL), or Batten disease, is an inherited disease caused by certain defective genes. A gene is like a string of beads, and for the gene to be correct, all of the beads must be on the string and in the proper sequence. Anything else – such as missing beads, extra beads or out-of-order beads – will result in a defective gene. Genes are instructions for making enzymes or proteins that are read from start to finish. One type of gene defect, called a "stop codon," is an incorrectly placed bead that creates a stop sign. In the case of Infantile NCL, this stop sign prevents the completion of the instructions and thus the production of the PPT1 enzyme, which is essential for breaking down fatty substances in the body's tissues. The buildup of these substances over time causes the manifestations of the disease, including blindness, seizures and cognitive and motor impairment. A particular compound has shown the potential to "read through" the stop sign that causes cystic fibrosis. Dr. Pearce believes there is a chance this effect could also be applied to stop codon defects that cause Infantile NCL. If successful, PPT1 enzyme activity would be increased, perhaps enough to overcome the effects of the disease. Children like Taylor could survive long-term simply by taking a pill. During the project period, Dr. Pearce tested several compounds for their ability to increase PPT1 enzyme activity in cell cultures. 2007 Sandra Hofmann, MD, PhD, University of Texas Southwestern The first Taylor's Tale grant was awarded to support Dr. Hofmann's efforts to develop a viable method of enzyme replacement therapy for children with Infantile NCL (INCL). Dr. Hofmann is well-known for her work in the field; her lab discovered PPT1, the enzyme that is lacking or severely deficient in INCL patients. One of the largest roadblocks in the search for a cure, as with other brain-based diseases, is the blood brain barrier. Dr. Hofmann's work focuses on finding a way to cross the blood brain barrier and effectively deliver the missing enzyme. Dr. Hofmann made great progress over the first year, and as a result, Taylor's Tale awarded an additional $55,000 to extend its support through July 2009. |
Thanks to the generosity of our donors, Taylor's Tale is able to award grants to support promising Batten disease research projects.