Research & GrantsThe key to turning hope into action is tirelessly supporting and accelerating scientific research and projects that move us closer to treatments or a cure for Sanfilippo Syndrome. At any given moment, there are 5-10 projects in need of funding. New ideas to investigate, promising research that needs to be taken to the next step, or a clinical trial ready to start. Your support helps these projects happen as swiftly as possible in a race against time.
Funded ScientiFIC Grants
Thanks to your support, Cure Sanfilippo Foundation funds scientific research exploring multiple avenues for a treatment/cure to Sanfilippo Syndrome. Each is chosen because of its promise for moving forward with the possibility of treating children in clinical trials. At this stage, we can’t be sure of what therapeutic treatments will work best (or work at all), which is why we support many different options that each have promising potential. We prioritize those that are proving viable, and need additional funding to continue moving these forward to bring to children.
Re-Purposing FDA-Approved Inflammation Drug for Sanfilippo
Cure Sanfilippo Foundation is sponsoring an “Open-label Study of Anakinra in MPS III” clinical trial in collaboration with The Lundquist Institute (formerly LABiomed), and Sobi (Swedish Oprhan Biovitrium AB).
This study is an open-label, single-arm, no placebo or control group trial of the IL-1 antagonist drug Kineret. The goal of the study is to determine if a number of disease symptoms can be improved by treatment with Kineret, thereby improving patients’ quality of life.
This drug is already FDA approved for several indications, one of which is a pediatric disorder. Testing an existing drug for a new disease, as in this trial, is called “drug repositioning” or “drug repurposing.”
Pre-clinical research has shown that reducing inflammation can impact symptoms of the disease. However, unlike steriods which are often used to combat inflammation, Kineret does not carry the same side effects of long-term steriod use.
Study DescriptionInflammation has been connected with disease pathogenesis in the MPS disorders. Therapies aimed at decreasing inflammation are currently being studied in many MPS disorders and showing benefits.
IL-1 is a cytokine molecule involved in the inflammatory cascade. Research into the animal model of MPS III has identified IL-1 as a major target for addressing inflammation in the body and brain of affected animals. Blocking the ability to respond to IL-1 has shown benefits in the progression of brain disease and behavior in MPS III animals. (Read more about this research at https://www.embopress.org/doi/
This study will be assessing for beneficial changes in a number of disease related symptoms. Some of these include, but are not limited to, improved behavior, sleep, stooling, communication, mood, and mobility; as well as decreased seizure frequency, disordered movement, and fatigue as they may apply to each individual.
Administration of Kineret does not impact the primary disease enzyme deficiency of Sanfilippo syndrome. However, due to the cascade of detrimental effects from the primary disease, evidence would suggest that addressing this target in the inflammatory cascade could help slow or improve some of the secondary disease effects.
This study is open for any Type of Sanfilippo (A, B, C, D).
Study Contact InformationIn December 2019, the trial was listed as “Enrolling” on ClinicalTrials.gov.
Study contact: Adolfo Morales, The Lundquist Institute, 310-357-9023, email@example.com.
Cure Sanfilippo Co-Funds Research Into Treating Behavioral Symptoms of MPS III
TIGEM (Telethon Institute of Genetics and Medicine) is an international research institute dedicated to the discovery of the mechanisms underlying rare genetic diseases and the development of innovative therapies.
Cure Sanfilippo Funds CRISPR Gene Editing of Neural Stem Cells
Dr. Iacovino’s, Assistant Professor of Pediatrics at LA Biomed/Harbor UCLA, research career has focused on the use of stem cells in multiple disorders, MPS diseases, and blood coagulation. Her ongoing work in parallel to this research grant will further develop the iPSC approach to MPSIIIB in her lab. Dr. Iacovino commented: “We believe that this project will provide initial data essential for the development of a Neural Stem Cell therapy to treat Sanfilippo syndromes”.
The application of NSCs in neurodegenerative disorders such as Sanfilippo syndrome is particularly exciting because they could address both the underlying enzyme deficiency of Sanfilippo syndrome while also secreting special substances that help support and promote healthy brain tissue. This fascinating process transforms patients’ own skin cells back into the most basic stem cells in the human body. These newly formed primitive stem cells are then directed in the lab to become stem cells specialized to the brain (neural stem cells). Neural stem cells (NSCs) are the cells that give rise to neurons and supporting cells(glia) of the central nervous system. NSCs also supply the brain with factors
like brain derived neurotrophic factor to keep it healthy. CRISPR gene modification of the NSCs will then allow the cells to produce enough MPSIIIA enzyme to supply what is missing in the brain.
“Using a patient’s own cells and modifying them as needed, drastically reduces concerns about the body having a reaction to the cells, therefore allowing the regenerative cells to remain in the brain and provide benefit indefinitely. This would be an incredible achievement and benefit to the children suffering from MPSIII.”, says Dr. Cara O’Neill, Chief Scientific Officer at Cure Sanfilippo Foundation.
Link to Michelina Iacovino PhD: https://labiomed.org/michelina-iacovino-phd
Link to article on MPSIIIB iPSCs: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076361/
Cure Sanfilippo Foundation Funds New Stem Cell Research
As the Director of the UC Davis Stem Cell Program and Institute for Regenerative Cures, Dr. Nolta brings a wealth of experience and expertise to this project. Prior research conducted by her team has focused on the use of stem cell therapies for Huntington’s Disease, 20+ years of work on lysosomal storage diseases, and involvement in prior clinical trials.
Dr. Nolta commented, “We are very grateful to the Cure Sanfilippo Foundation and excited to work with Neuralstem to develop a gene-modified neural stem cell therapy for MPSIIIA. The data for retention of the Neuralstem product is compelling and gives us hope that an impact could potentially be made on this heartbreaking disease.”
Neuralstem is a clinical stage biopharmaceutical company developing treatment for neurologic diseases via small molecule and stem cell therapies. Our joint collaboration will enable the gene modification of Neuralstem’s proprietary neural stem cell line and testing of these cells in the immunodeficient MPSIIIA mouse model which was created in the Nolta lab as a part of Cure Sanfilippo Foundation’s previous support.
Neural stem cells (NSCs) are the cells that give rise to neurons and supporting cells(glia) of the central nervous system. The application of NSCs in neurodegenerative disorders such as Sanfilippo syndrome is particularly exciting. Gene modified (to express large amounts of the
deficient enzyme) neural stem cells could address the primary disease mechanism. However, NSCs are special in that they also offer the possibility to restore and support healthy brain tissue in patients.
“The opportunity to address multiple critical needs in this disease with one therapy would be an amazing thing for the children. Since we do not yet have newborn screening or an approved therapy for Sanfilippo syndrome, 99% of those diagnosed are already symptomatic and
experience ongoing brain damage. The ability to positively impact disease progression even after a child is symptomatic is of key importance to families today,” says Dr. Cara O’Neill, Chief
Scientific Officer at Cure Sanfilippo Foundation.
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Cure Sanfilippo Foundation is a 501(c)(3) not-for-profit organization dedicated to advocating for and funding research directed towards a cure and treatment options for patients with Sanfilippo Syndrome. Sanfilippo Syndrome, also called MPS III, is an inherited disease of
metabolism that means the body cannot properly break down long chains of sugar molecules called mucopolysaccharides or glycosaminoglycans (i.e., GAGs). A genetic defect passed on
from each parent results in missing or poorly functioning enzymes needed for cells to work normally. Without these enzymes, cells are unable to break down and recycle cellular waste.
Over time, this waste builds up causing cells to act abnormally and then to die. Children with this genetic disease face a progressively debilitating and rapid decline in physical and intellectual abilities, leading to an early death.
For more information on the Cure Sanfilippo Foundation and Sanfilippo Syndrome, please visit www.CureSFF.org. Contact Cure Sanfilippo Foundation at firstname.lastname@example.org.
Funding Development of Nematode & Fly Disease Models and Screening Compounds
Cure Sanfilippo Announces Support for Autophagy Research
Dr. Selleck’s prior research specialized in neurodevelopment, proteoglycan genetics and biochemistry. His neurodevelopment work has investigated the genetic basis of autism spectrum disorder and gene-environment interactions. Preliminary work with the Multiple Sulfatase Deficiency (MSD) fruit fly model has shown autophagy suppression, prompting Dr. Selleck to translate that finding to the mouse model in another MPS disorder.
Autophagy is a process by which cells engulf and dispose of misfolded proteins and damaged mitochondria that occur during normal metabolism and even more so in disease states. Research has shown that in Sanfilippo syndrome, as well as many other neurodegenerative diseases, there is an impairment in the body’s ability to carry out the autophagy process. This causes other parts of the cell to function poorly and eventually leads to cell death.
“Our focus is to provide both the scientific underpinnings and means of rescuing neuronal loss in children with MPS disorders. We hope these findings and methods will also translate to other neurodegenerative diseases.” Scott Selleck, MD, PhD.
This project will specifically look at the effects of activating autophagy in the brains of MPSIIIA mice, either directly, or by inhibiting Tor, a master regulator and suppressor of autophagy. Since mTOR is a universal pathway that is not disease specific, findings here would be translatable across MPS conditions and neurodegenerative disorders. This pathway will be studied both through genetic modification and the use of an FDA approved class of drugs known to block mTOR activity. This drug is currently used to treat children with tuberous sclerosis complex and has been shown to reduce seizure frequency and severity.
“Dr. Selleck’s work will provide further insight into a possible way to impact the neurodegenerative process in Sanfilippo syndrome, beyond replacing the primary enzyme deficiency. Developing complementary strategies, such as this, to improve the life of children with this devastating disease is a critical need,” said Dr. Cara O’Neill, Scientific Director at Cure Sanfilippo Foundation.
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Cure Sanfilippo Foundation is a 501(c)(3) not-for-profit organization dedicated to advocating for and funding research directed towards a cure and treatment options for patients with Sanfilippo Syndrome. Sanfilippo Syndrome, also called MPS III, is an inherited disease of metabolism that means the body cannot properly break down long chains of sugar molecules called mucopolysaccharides or glycosaminoglycans (i.e., GAGs). A genetic defect passed on from each parent results in missing or poorly functioning enzymes needed for cells to work normally. Without these enzymes, cells are unable to break down and recycle cellular waste. Over time, this waste builds up causing cells to act abnormally and then to die. Children with this genetic disease face a progressively debilitating and rapid decline in physical and intellectual abilities, leading to an early death.
For more information on the Cure Sanfilippo Foundation and Sanfilippo Syndrome, please visit www.CureSFF.org. Contact Cure Sanfilippo Foundation at email@example.com.
Re-positioning of FDA-Approved Compounds in MPS III Cell Models
Awardee: Diego Medina, PhD- Telethon Institute of Genetics and Medicine (TIGEM)- Italy
Start Date: June 2018
UPDATE: October 2019
In October 2019, TIGEM presented preliminary results of this study at the Conference of Telethon Fundamental Associations in Italy. Read more.
New Therapeutic Approach to Treat Central Nervous System in Sanfilippo
Target Amyloid Aggregation as a New Therapeutic Approach to Treat the Central Nervous System in Sanfilippo SyndromeCure Sanfilippo Foundation has awarded funds to the Telethon Institute of Genetics and Medicine (TIGEM) in Italy to study the effect of a new drug compound on the buildup of toxic proteins in the brains of those affected by Sanfilippo Syndrome.
Project lead Alessandro Fraldi specializes in the study of neurodegeneration in lysosomal storage diseases (LSDs) and novel treatment approaches. Under his lead, the Fraldi team aims to build upon their preliminary data supporting the effects of a novel drug compound in reducing the effects of harmful accumulated proteins in the brain of Sanfilippo animals. The drug functions by a different mechanism of action than previously tried in other neurodegenerative diseases characterized by protein aggregation.
“We are pleased to support this new approach to addressing a key feature of neurodegeneration. The many biochemical similarities among neurodegenerative conditions like Alzheimer’s Disease, Parkinson’s Disease and Sanfilippo Syndrome are striking. Research aimed at these common features offers the opportunity to find ways to improve the lives of loved ones with these devastating conditions”, said Dr. Cara O’Neill, Scientific Director of Cure Sanfilippo Foundation.
Initial proof of concept work has been conducted using the MPSIIIA mouse model. Inclusions of aggregated proteins was shown to be a general feature of MPSIIIA brain disease in which such aggregation progressively builds up as neurodegeneration is seen. Preliminary data indicates that the drug is able to clear protein aggregation, thus reducing inflammation and oxidative stress.
In this project, a large efficacy study will be performed testing the drug’s effects on toxic protein clearance, inflammation, nerve signaling, and behavior in MPSIIIA mice. Dr. Fraldi has also assembled a team of collaborators to further evaluate these findings in the other subtypes of Sanfilippo syndrome (MPSIIIB-D).
Start Date: April 2018
Creating a Zebrafish Model of Sanfilippo Syndrome Type A
Cure Sanfilippo Foundation and Sanfilippo Children’s Foundation (Australia) are delighted to announce we have collaborated again. This joint grant funding is to the Australian Regenerative Institute at Monash University in Melbourne to create a zebrafish model of Sanfilippo. The project, led by zebrafish disease modelling expert Dr. Jan Kaslin and team, aims to produce a new tool to be used in the fight against Sanfilippo!
Dr. Cara O’Neill, Scientific Director of Cure Sanfilippo Foundation said: “We’re pleased to support Dr. Kaslin’s work which will create a new experimental model for the study of Sanfilippo. Unique aspects of the zebrafish model offer the potential to accelerate the rate of drug discovery for children who are in dire need.”
“We’re excited to be funding this project that could open up new avenues for Sanfilippo research around the world, providing a new tool for understanding this devastating condition and developing much-needed new therapies,” said Megan Donnell, Executive Director of the Sanfilippo Children’s Foundation.
Zebrafish are a useful research tool because they allow quick and precise understanding of the mechanisms of disease and can be used in the search for drugs. Zebrafish have already been used to help unlock a number of biological processes behind diseases such as muscular dystrophy. Zebrafish are transparent so the cellular processes inside their bodies can be watched in real-time under a microscope.
Start Date: February 2018
Mesenchymal Stem Cells for Sanfilippo Syndrome
Engineering Mesenchymal Stem Cells (MSCS) to Produce Sulfamidase for Intrathecal Treatment of Sanfilippo Syndrome
Awardee: Jan Nolta, PhD, Director of UC Davis Stem Cell Program, University of California Davis, Institute for Regenerative Cures
Start Date: August 2017
New Therapy for Six Mucopolysaccharidoses
Cure Sanfilippo Foundation is co-funding this project in Collaboration with Sanfilippo Children’s Foundation (Australia).
Project Summary: Substrate reduction therapy by targeting the N-deacetylase/N-sulfotransferase (NDST) isozymes, NDST1, represents a promising approach to developing a therapy for multiple MPS disorders including MPS I, MPS II, MPS IIIA, MPS IIIC, MPS IIID, MPS IIIE. One of the advantages of such small molecule therapy is the likely ability of the molecules to pass through the blood-brain barrier and thus treating the disease in the brain. It provides a potential strategy to enhance effectiveness of emerging therapies, i.e. enzyme replacement and gene delivery approaches, and it offers treatments for almost all disease sub-types.
This study aims to decrease the synthesis of glycosoaminoglycans (GAGs) by targeting NDST1, a key enzyme in the pathway leading to modifications of heparan sulfate. This project will screen a library of 6,000 compounds to identify drugs that reduce NDST1 activity by two independent approaches; via repression of NDST1 gene expression or via direct inhibition of NDST1 enzyme activity
Repurposing of approved drugs will be prioritized in this research for faster transition of drug candidates into clinical studies. The hospital’s CRISPR approach enables testing drug effects on the full regulatory circuity of the endogenous target gene and is expected to identify compounds that act via a wider range of pathways and thereby extending this therapeutic modality to larger set of patients independent of their age. Drugs showing signs of efficacy will be designated as lead substrate reduction compounds for further in vivo animal studies.
Start Date: March 2017
Neural And Mesenchymal Stem Cell-Mediated Gene Therapy for Sanfilippo Syndrome Type B
Cure Sanfilippo Foundation is co-funding this gene therapy-approach project with Sanfilippo Children’s Foundation (Australia).
Project Summary: Current therapy for Sanfilippo Syndrome (MPS III) is aimed at restoring functional enzyme or reducing heparan sulfate storage, but does not address restoration of the damage done prior to therapy. Regeneration of damaged central nervous system and prevention or reversal of immune activation by neural stem cells (NSC) and mesenchymal stem cells (MSC) may be necessary in the treatment of MPSIIIB.
This study will evaluate the effect of transplanting NSC and MSC on immune system modulation and regenerative repair. Using lentiviralvector gene-modified stem cells to over express N-acetylglucosaminidase (NAGLU), the study will evaluate the response and therapeutic benefit of each cell type on MPSIIIB mice and controls.
This strategy uses a cell-based, gene-therapy approach to address two priority areas:
- Halt disease progression (Enzyme replacement, gene therapy, cell therapy to stop progression) and
- Repair Damage (Repair and reverse cell damage).
Research Strategy for Pre-Existing AAV Antibodies
Project Summary: As the field moves forward with AAV9-gene therapy approaches for clinical applications, a critical challenge is the presence of pre-existing antibodies against AAV9. Many AAV serotypes infect humans, including AAV9. As a result of infection, pre-existing antibodies to AAV are common in humans.
In the setting of gene therapy, individuals with pre-existing AAV9 antibodies would not be eligible for treatment using AAV9 vectors due to diminished efficacy.
There are currently no effective approaches available which deplete pre-existing antibodies enough to allow for effective gene transfer in antibody positive patients.
Small-scale preliminary experiments in Dr Fu’s lab have shown the potential of appropriate immuno-supporessive regimens in overcoming the pre-existing Abs.
The goal of this study is to identify immuno-suppressive regimens that can effectively overcome pre-existing AAV Abs, in order to be able to treat all individuals who have the target diseases, as well as those who have received AAV9 gene therapy treatment and may need vector re-administration later.
Start Date: March 2017
Re-Purposing of FDA-Approved Drugs for LSD
Re-Purposing of FDA-Approved Drugs for the Treatment of LYSOSOMAL STORAGE DISEASES (LSD)
Project is funded by Cure Sanfilippo Foundation
Project Summary: The study aims to identify FDA-approved compounds that activate the clearance of pathologic lysosomal accumulation in MSD cellular models independently of the missing enzyme in each particular disease.
Relevant cell-based, high-content (HC) screening assays have been developed, targeting common features of most MPS diseases, such as expansion and aggregation of lysosomal compartment and lysosomal degradation impairment.
These assays will be used to screen a FDA collection of 1,280 compounds that are marketed drugs. Thus, the hits derived from the HCS, once validated in secondary assays, could in principle be immediately tested in patients to allow repositioning of known drugs as correctors of MPS.
Repositioning of FDA-approved drugs may reduce the clinical translation time of the findings.
Dates: March 2017 – March 2018
UPDATE: October 2019
In October 2019, TIGEM presented preliminary results of this study at the Conference of Telethon Fundamental Associations in Italy. Read more.
Research Extension: Intranasal Delivery of Sulfamidase
Start Date: Janaury 2017
Synaptic Dysfunction in Sanfilippo Type C
Project Summary: The study’s major objective is to understand the pathophysiological mechanism underlying cognitive decline and behavioral abnormalities in the genetic metabolic disease Mucopolysaccharidosis type III (MPS III, Sanfilippo disease) and to develop new strategies for its therapy.
The hypothesis is that early decline in CNS functions in MPS III is caused not by neuronal death, but rather by breakdown in neurotransmission due to synaptic defects.
Confirmation of this hypothesis, which will be tested by studying synaptic function in gene-targeted mouse model of MPS IIIC, would mean that MPS III patients could benefit from therapeutic approaches based on restoration of the synaptic function to a point sufficient to reverse disease symptoms.
Date: January to December 2016
Testing Compounds on MPS III Fibroblasts
Project Summary: Results of two previously-published studies in which MPS IIIA fibroblasts were treated with calcium channel blockers showed partial rescue of enzyme activity.
This study further evaluates the suitability of this drug class as chaperones in MPS III. It will investigate the action of L-type Ca2+ channel blocker and potential chaperone, diltiazem, on the residual level of the enzyme activity in skin fibroblasts from the MPSIIIA, MPSIIIC, and MPSIIID patients affected with missense mutations.
Also investigated was the possibility that diltiazem could be synergistic with the known MPSIIIC chaperone, glucosamine, the two substances were co-administered to cells.
Start Date: May 2015
Update February 2017: Study did not indicate rescue of enzyme activity in the presence of diltiazem or diltiazem/glucosamine combination in MPSIIIA cells. MPSIIIC cells did not show increased enzyme activity with diltiazem but did have an increase in activity with glucosamine.
Intranasal Delivery of Sulfamidase for Sanfilippo
Project Summary: This study focuses on the development of a novel way to perform enzyme replacement therapy and its application to MPS IIIA. In this method, the missing enzyme is produced in cells, purified and then attached to a small chemical entity that acts as a carrier. Previous work has shown that cells derived from MPS IIIA patients take up conjugated enzyme and that intravenous injection of modified enzyme reduces storage of glycosaminoglycans (GAGs) in a mouse model of MPS IIIA (Sgsh-/- ). Unexpectedly, intranasal administration of modified enzyme demonstrated high levels of delivery to the brain and reduction of pathological GAGs in a short-term experiment.
The purpose of this study is to optimize the transfer of enzyme into the central nervous system in the MPS IIIA mouse. The results will provide the pre-clinical information needed to proceed towards a novel treatment of the disease in humans.
Dates: October 2015 – September 2016
Update – April 2017: An improved enzyme assay has been created to more reliably evaluate the activity levels in organs, earliest safe age of administration in animal model has been established, long term dosing study is underway. Manuscript has been submitted for publication on GNeo carrier conjugation with enzyme (MPSI and early MPSIIIA work).
Mesenchymal Stem Cells to Produce Sulfamidase for Intrathecal Delivery
Project Summary: This study aims to evaluate the use of non-embryonic mesenchymal stem cells (MSCs) for delivery of sulfamidase, the deficient enzyme in MPSIIIA, into the spinal fluid compartment.
MSCs will be gene modified to overexpress a normal copy of the SGSH gene (the MPSIIIA gene) and compared to unmodified MSCs.
In order to administer human MSCs to the mouse model, an immunodeficient strain of the MPSIIIA mouse model will be created.
Once complete, this new mouse model will be available for the scientific community at large.
The approach to use human MSCs to deliver enzyme, offers the possibility to deliver enzyme in a steady and physiologic fashion in the brain.
In addition, MSC-based delivery could avoid issues of pre-existing neutralizing antibodies that are inherent in AAV based gene therapies.
Due to the relative immune privilege of MSCs, they could be re-dosed with less concern of antibody development.
MSCs also inherently secrete neuroprotective and neurotrophic factors which could be beneficial in this neurodegenerative disease.
Update April 2017: MSCs have been gene-modified. Characterization of their enzyme expression is underway. An immunodeficient MPSIIIA mouse model is being cross bred and expanded for adequate study numbers after which animal dosing will begin.
Start Date: December 2015
Support for AAV9 Gene Therapy for MPS IIIA and MPS IIIB
Project Summary: Funding support of staff to enable necessary clinical trial preparatory steps to move forward. The positions are 1) Genetics Clinical Research Fellow (1 year), and 2) Program Manager (2 years).
The duties of these positions include, but not limited to: analysis of the data from the natural history study; drafting of manuscripts related to it; participation in aspects of preparing for gene transfer trials; and analysis and presentation of the data derived from them, participation in the development and filing of regulatory documents, development of standard operating procedures and source documents, management of interactions with contracted services (such as the hospital’s clinical research services and outside monitoring contract researchers organizations), and interactions with the Institutional Review Board, FDA submission of IND and other needed paperwork, additional program coordination, finalizing publication of natural history study data.
Dates: June 2015 – May 2017
March 2017: MPSIIIA gene therapy clinical trial is underway. Safety has been established in the low dose cohort (3 patients) to date. Data presented at the World Symposium in February 2017 noted a 67% decrease in spinal fluid heparan sulfate (the toxic storage material) levels, lowered urine heparan sulfate levels and continued reduced liver and spleen sizes. High dose cohort patient dosing is proceeding. The IND has been approved for commencement of MPSIIIB gene therapy trial.
Curing Sanfilippo is our ultimate goal, but your support also allows us to play a critical roll in influencing the road that leads there. The path from identifying symptoms to diagnosis to evaluating treatments needs to be as direct as possible and filled with accurate and patient-centric information for families, scientists, physicians, and regulators.
The following are projects led or supported by the Foundation that promote valuable, disease-specific and patient-preference information about Sanfilippo Syndrome, benefiting the scientific and medical communities as well as caregivers.
Why and how to achieve novel outcomes in neurodegenerative gene therapy trials
Picking outcome measures for neurodegenerative gene therapy trials in rare disease is difficult. The conditions often have a lot of heterogeneity, relatively small sample sizes, and rarely disease-specific outcome measures. That is why “outside the box” thinking is necessary, and Cure Sanfilippo Foundation Chief Science Officer Cara O’Neill, MD FAAP, shared how novel outcomes could be used to expand and improve evaluation of gene therapy trials for neurodegenerative diseases at the Lysogene/Sarepta satellite symposium during SSIEM 2019 last week in Rotterdam, Netherlands.
Most of the measures used in childhood neurodegenerative conditions are drawn from more general measures based on normal neurodevelopment and behavior patterns, rather than hallmarks of particular disease. So rare diseases are always being compared to “Normal.” But is that a fair comparison knowing that these patients have had chronic ongoing brain injury to the immature developing brain?
“We have to do a better job of matching endpoints with the patient’s needs across the spectrum of any given disease,” urged O’Neill.
The key is meeting the patient needs, not the clinician’s needs or fulfilling assumptions that have been made in the past about patients’ need.
“We must get as close as we can to discerning what is going to make their life better, for however long that is.”
Sharing early data from the Foundation’s MPS III Caregiver Preference Study, O’Neill noted that the more than 160 Sanfilippo caregivers across 14 different countries listed pain, communication, mobility and hyperactivity among their treatment priorities. Additionally, what caregivers prioritize changes along the course of the disease.
O’Neill detailed how the Foundation has partnered with Aparito, Casimir Trials, and Lysogene to conduct an exploratory study of novel outcomes for MPS IIIA running in parallel to AAV10-SGSH intracranial gene therapy trial. The study uses frequent video capture by caregivers to monitors specific disease hallmarks and priorities identified by the Caregiver Preference Study in the child’s familiar environment to capture the child’s best ability.
The patient-reported outcome videos study has allowed detection of subtle, but meaningful, incremental changes and appears feasible for longer term monitoring of real-world functioning and patient status, reported O’Neill.
Insights to Help Clinicians Understand Caregiver Burden with Sanfilippo
A group of international clinical advisors with expertise in the care of pediatric patients with Sanfilippo and lysosomal storage disorders met to begin filling this void of understanding and create best-practice guidance for clinicians. Cure Sanfilippo Foundation Chief Science Officer Cara O’Neill, MD FAAP, was among the advisors. As a mother of a child with Sanfilippo, Cara brought first-hand caregiver perspective to the collaboration in addition to scientific and medical expertise.
The group reviewed key aspects of caregiver burden associated with Sanfilippo B by identifying and quantifying the nature and impact of the disease on patients and caregivers. They co-authored recommendations based on findings from qualitative and quantitative research, which were recently published in the Orphanet Journal of Rare Diseases.
The article’s authors report that:
“Providing care for patients with Sanfilippo B impinges on all aspects of family life, evolving as the patient ages and the disease progresses. Important factors contributing toward caregiver burden include sleep disturbances, impulsive and hyperactive behavior, and communication difficulties.
Caregiver burden remained high throughout the life of the patient and, coupled with the physical burden of daily care, had a cumulative impact that generated significant psychological stress.”
Additionally, the authors call for changing the narrative associated with Sanfilippo:
“The panel agreed that the perceived aggressive behavior of the child may be better described as ‘physical impulsiveness’ and is often misunderstood by the general public. Importantly, the lack of intentionality of the child’s behavior is recognized and shared by parents and panel members.
Parents may seek to protect their child from public scrutiny and avoid situations that many engender criticism of their parenting skills.”
Read the complete article from the Orphanet Journal on Rare Diseases.
Helping the research, clinical, and regulatory communities understand the perspectives of caregivers for Sanfilippo children is a priority for Cure Sanfilippo. The fastest path to a cure is when researchers, clinicians, regulators, and patient advocates collaborate and align. Another way to the Foundation is working to amplify the caregiver voice and project it into the industry space is with its Caregiver Preference Study. Learn more about this initiative.
Speeding Diagnosis of Rare Diseases By Empowering Pediatricians
First-Ever Collaboration: Pilot Program Giving Pediatricians Direct Access to Geneticists so Rare Diseases Are Diagnosed Accurately and Early
Families need faster, accurate diagnosis so they can access clinical trial opportunities as soon as possible. A key to this happening is bridging the gap in pediatricians’ access to genetics information, especially regarding rare diseases. To help bridge this gap, Cure Sanfilippo Foundation has partnered to pilot the Genetics Access in Primary Pediatrics (GAAP) project, linking Greenwood Genetic Center’s (GCC) clinical geneticists and genetic counselors to pediatricians through the Faces2Genes app.
Face2Gene analyzes patient photographs using machine learning and computer algorithms to help make challenging diagnoses. Through the GAPP pilot project, the Face2Gene improves patient wait times and allows a pediatrician to identify patients through a list of genetic “triggers” or features that may indicate a need for further genetic evaluation.
If the patient’s family elects to be a part of the GAPP pilot project, the pediatrician uploads facial photos and other clinical information to Face2Gene where it can be securely shared with GGC clinicians for review. The geneticist can suggest appropriate referrals or genetic testing that can be initiated by the pediatrician in advance of the genetics appointment. Urgent referrals can be prioritized, and when the patient does come in for their genetics consultation, initial test results have already been completed, saving valuable time.
Learn more about the Faces2Gene project and Foundation’s collaboration.
Creation of Global Clinical Guidelines for Sanfilippo Syndrome
Cure Sanfilippo Foundation is leading the development the first-ever Global Clinical Guidelines for the management of Sanfilippo Syndrome in partnership with the Sanfilippo Children’s Foundation (Australia).
Best-practice guidelines for clinical care are critical for both patients and health care professionals in the management of rare diseases where lack of experience and knowledge about a condition often causes late diagnosis and less than optimal management of the condition. Such guidelines allow clinicians and other health-care professionals to make recommendations based on best-available evidence; improve consistency of diagnosis and clinical management across treatment centers; and enable affected families to make informed decisions regarding care and treatment.
As several promising treatments move into clinical trial, the need for Global Clinical Guidelines has become increasingly important. The international steering committee for this project includes: Dr. Simon Jones, UK (Chair); Dr. Joseph Muenzer, US; Dr. Chester Whitley, US; Dr. Nicole Muschol, Germany; Dr. Nicholas Smith, Australia; and Dr. Roberto Guigliani, Brazil.
Experts worldwide from all of the disciplines of health professionals involved in the care of children and young adults with Sanfilippo will be invited to contribute content to the clinical management guidelines.
These guidelines will be collated and validated by a wider pool of clinicians and the finalized Global Clinical Guidelines published in a peer-reviewed medical journal towards the end of 2019. Production of a family-friendly version of the guidelines is also planned.
This project is supported by a grant from Global Genes and BioMarin Pharmaceutical.
Below: The team aggregated by the Foundation to lead the project.
Update: Read the April 2019 Foundation Update for the latest on the project.
Caregiver Preference Study for Sanfilippo Syndrome
The aim of the Caregiver Preference Study is to help inform the selection and development of clinical trial endpoints to reflect desired treatment benefits across the lifespan of children with Sanfilippo Syndrome.
Our hope is that the publication of these findings further inform key stakeholders, allowing the incorporation of patient voice into the decision making regarding the drug approval process and access.
Our project design for the Caregiver Preference Study incorporates these various stakeholders including industry partners, regulatory, and parents of children with Sanfilippo Syndrome.
More than 150 caregivers recently completed the quantitative survey and are currently being analyzed. Ongoing study results will be shared via poster presentations and manuscripts, as they become available.
Outcomes and interim results from our focus groups (the qualitative portion) were shared in a Platform and Poster Presentation at the World Symposium in February 2019 and 2020, and can be found here: presentation poster from the WORLD Symposium 2019 and poster presentation from the WORLD Symposium 2020.
This important project has received grant support from BioMarin Pharmaceutical, Lysogene, Sobi, and Orchard Therapeutics.
Collaborating on facial-recognition app to diagnose Sanfilippo Syndrome
Cure Sanfilippo Foundation is collaborating with Face2Gene, a suite of digital resources for physicians from FDNA, to populate its Clinic app that uses facial recognition technology to assist in accurately and timely diagnoses of Sanfilippo Syndrome.
One way to determine if different genetic syndromes have distinctly recognizable facial features is by using sophisticated facial recognition software. This distinction could, in time, lead to an earlier diagnosis by medical professionals.
Cure Sanfilippo asked the network of Sanfilippo families that elect to operate under its umbrella to provide facial photos of their children to help create a definition of the facial features for Sanfilippo Syndrome (MPS III) and study the facial features over different ages, genders and ethnicities.
Once sufficient numbers of photos have been submitted, FDNA will run an analysis on the different groups of photos to determine whether there are distinct gestalts and how these gestalts change over time.
Update: In 2018, the information uploaded to Face2Gene was used to create a Natural History of Facial Features Observed in Sanfilippo Syndrome, Type B. The following poster presentations were displayed at the 2018 World Symposium. To download a PDF of the posters, click the image.
OUR 360-Degree Approach
Taking a 360-degree view, the Foundation funds extensive research into multiple avenues for a treatment/cure, as well as spearheads, supports, and funds initiatives that provide valuable, disease-specific and patient-preference information about Sanfilippo. This combination of approaches leads to better understanding of the disease, more effective treatments, and opportunities for earlier diagnosis.
We partner with academic institutions, bio-technology companies, and other non-profit organizations to support projects that benefit all forms of Sanfilippo (Types A, B, C, D). Our Chief Science Officer and Scientific/Physician Advisory Board steer and thoroughly vet these initiatives.