Parents united to find a cure

Research Projects – United Kingdom

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Intrathecal Enzyme Replacement Therapy Sanfilippo A

Shire Human Genetics
Dr. Simon Jones
Dr. Frits Wijberg

A Phase I/II Safety, Tolerability, Ascending Dose and Dose Frequency Study of Recombinant Human Heparan N-Sulfatase (rhHNS) Intrathecal Administration Via an Intrathecal Drug Delivery Device in Patients With Sanfilippo Syndrome Type A (MPS IIIA)

Shire Human Genetic Therapies (Shire HGT) is developing a sulfamidase enzyme replacement therapy (ERT)rhHNS for patients with MPS IIIA. rhHNS is being administered into the cerebrospinal fluid (CSF) via a surgically implanted intrathecal drug delivery device (IDDD).

This study is a multicenter, multiple-dose, dose escalation study designed to evaluate the safety, tolerability, and clinical activity of up to 3 dose levels (2 doses [10 and 45mg] monthly and 1 dose [45mg] every other week for 6 months) of rhHNS administered via an IDDD in patients with Sanfilippo syndrome Type A ages greater than or equal to 3 years of age.

The phase I/II clinical trial is planning to enroll 15 patients, beginning June 2010. The study is expected to be completed March 2012, and the duration of the study for each patient is nine months.

The Phase I / II clinical study is being conducted at two sites:

  • Emma Children’s Hospital, Academic Medical Center in The Netherlands by Dr. Frits Wijberg
  • St. Mary’s Hospital in Manchester, UK under the direction of Drs. Simon Jones and Ed Wraith.

Additional information about the clinical trial can be obtained at www.clinicaltrials.gov (Identifier: NCT01155778) or by contacting Tiffany Crump 484-595-8257, tcrump@shire.com This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Daryll Heron +44 1256 894572, dheron@shire.com.

Research Projects – Spain

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Sanfilippo C: TBA
University of Barcelona. Department of Genetic
Dr. Daniel Grinberg dgrinberg@ub.edu
Dr. Lluïsa Vilageliu lvilageliu@ub.edu

Gene Therapy Type A
University of Barcelona
Dr. Fatima Bosch fatima.bosch@uab.es

This week in the meeting of The Committee for Orphan Medicinal Products (COMP), has been presented to the European Medicines Agency (EMEA) the drug “Adeno-associated virus vector serotype 9 expressing human sulfamidase for treatment of mucopolysaccharidosis type IIIA (Sanfilippo A syndrome), D. Esteve Labs, S.A. – EMA/OD/171/10)

Research Projects – Poland

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Substrate Reduction Therapy Sanfilippo A,B,C,D (Genistein Derivatives)
University of Gdansk Department of Molecular Biology
Dr. Grzegorz Wegrzyn wegrzyn@biotech.ug.gda.pl

Dr. Wegrzyn has tested many synthetic, artificial derivatives of genistein. Based on his evaluation there are a few that are promising (ability to inhibit GAG synthesis, low cytotoxicity and high potential to cross the blood-brain-barrier). Until now, we have performed only experiments on cell cultures, thus, the next step should be tests on mice. The promissing molecules are about 50% more active than genistein, are 2-3 times less toxic than genistein (though genistein is still fine in these tests), and have several times higher LogP index (calculated theoretically on the basis of chemical formulas) suggesting their more efficient crossing the blood brain barrier. We are now negotiating with a company which is interested in patenting these molecules.

Research Projects – Italy

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Substrate Reduction Therapy Sanfilippo A,B,C,D
Medical School, University of Naples Federico II
Dr. Giancarlo Parenti parenti@unina.it
Dr. Paola Di Natale dinatale@dbbm.unina.it

Development of inhibitor of GAG synthesis. Dr. Parenti and Dr. Natale have developed a compound that is an efficient inhibitor of GAG synthesis, thus reducing the amount of heparin sulfate the body produces.

Research Projects – France and Netherlands

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Gene Therapy Sanfilippo B
AMT & Institut Pasteur
Jean-Michel Heard jmheard@pasteur.fr

Amsterdam Molecular Therapeutics (Euronext: AMT), a leader in human gene therapy, announced that it has entered into an agreement with Institut Pasteur, Paris, France, and a group of French research institutes (together the “Consortium”) to support clinical development of a novel gene therapy to treat Sanfilippo B.

On behalf of the Consortium, Institut Pasteur will lead the development program and will also sponsor the initial Phase I/II clinical study of a gene therapy to replace an enzyme (alpha-N-acetylglucosaminidase) that is missing in brain cells of Sanfilippo B patients. This enzyme is specifically required for the degradation of heparan sulfate glycosaminoglycans (GAGs), essential carbohydrate molecules used to build tissue. The accumulation of incompletely degraded GAG molecules triggers a cascade of pathological events leading to neuronal dysfunction and death.

AMT will manufacture and supply the adeno-associated viral 5 (AAV5) gene therapy product to the Consortium. Thanks to donations collected during the French Telethon, the French Muscular Dystrophy Association (AFM), a Consortium member, will fully fund the development program through to completion of the Phase I/II clinical study, including all AMT manufacturing costs. The overall manufacturing contract entails payments to AMT of EUR1.8 million. If the Consortium successfully demonstrates proof of concept in the Phase I/II study, AMT will have an option to acquire full commercial rights for the program.

 

 

Gene Therapy Sanfilippo A

LYSOGENE

Locations:

Hôpital Bicêtre – Assistance Publique des Hôpitaux de Paris
Le Kremlin Bicêtre, France, 94275
Hôpital Necker, Assistance Publique des Hôpitaux de Paris
Paris, France, 75015

Michaël HOCQUEMILLER, PhD
Program Management
Scientific & Clinical Affairs
LYSOGENE
52 rue la Boétie 75008 PARIS

Tel : + 33 1 56 88 52 84
www.lysogene.com

Alliance Sanfilippo coordinated discussions between researchers and clinicians susceptible of being interested in developing a similar clinical trial for Sanfilippo Syndrome type IIIA. All of them expressed their desire to work together in exchanging expertise, reagents and preclinical data
Gene therapy program for intracerebral administration of an adeno-associated virus vector to replace Sulfamidase enzyme missing in Sanfilippo A patients. The program is structured in phases with synergized management of activities and partnerships:

  • Construction and validation of an adeno-associated vector with good brain tropism: a AAV vector (serotype 10) encoding human SGSH and SUMF1 cDNA for treatment of type IIIA Sanfilippo syndrome
  • Effectiveness studies carried out on mouse models
  • Vector production according to GMP (Good Manufacturing Practice) quality standards
  • Regulation toxicological studies
  • Preparation of a protocol for open,phase I/II clinical trials to assess the tolerance of intracerebral administration of this adeno-associated vector to treat type IIIA Sanfilippo syndrome
  • Management of regulatory affairs in cooperation with the competent health authorities

Study launched under the express condition that proper authorization be granted by health authorities
The phase I/II trial will be start on August 2011. 4 Children, 18 months to 6 years.

Chaperone Therapy Sanfilippo B
CNRS / UMR
Dr. Matthieu Sollogoub matthieu.sollogoub@upmc.fr

Conception and evaluation of new chemical chaperones of the N-acetyglucosaminidase in the context of the development of a treatment for Sanfilippo Syndrome (MPS III B).

This research and development project, organized by the team of Professor Matthieu Sollogoub (CNRS / UMR, Université Pierre and Marie Curie, Paris), consists of developing glycosidic inhibitors of the N-acetyglucosaminidase.

It is expected that these new molecules will be able to correct the structure and intracellular transport of certain mutated forms of the N-acetyglucosaminidase and therefore restore the ability to degrade heparan sulfate.

The Swiss Sanfilippo Foundation create a commercial company, SanOrphan, in February 2011 in order to raise more funds from venture capital in relation to the program of Dr. Sollogoub, the aim is to perform trial as soon as possible. (http://www.sanorphan.com – website under construction)

Research Projects – Canada

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Chaperone Therapy for Sanfilippo C
Ste-Justine Hospital
Dr.Alexey Pshezhetsky alexei.pchejetski@umontreal.ca

The concept of the chaperone therapy is a novel idea in which a lead molecule is nominated from a library of candidates. This molecule is small enough to breach the Blood-Brain Barrier (BBB). Once the molecule enters the body it is attracted to the enzyme and theoretically will enter the enzyme and “prop up” the folded part of its mutation. This will allow the enzyme to pass through the cell and enter the body, where it can perform its job of breaking down the substrate, also called a sugar molecule. In our case that substrate is known as Heparan Sulfate. The molecule used for the chaperone therapy doesn’t perform like an average drug. It’s the shape of the molecule that matters here. We need an exact fit to help our kids, who have specific folds in their enzyme Partial restoration of the deficient activity of N-acetyltransferase, even if modest, could help alleviate the disease symptoms or drastically slow the disease progression. Experiments using patients cells demonstrated that glucosamine could partially restore the protein folding defect and increase its activity.

These results, published in the recent issue of PLoS ONE (Matthew Feldhammer, Stéphanie Durand and Alexey V. Pshezhetsky Protein Misfolding as an Underlying Molecular Defect in Mucopolysaccharidosis III Type C PLoS ONE, October 13th, 2009; http://dx.plos.org), may provide future therapeutic solutions for this devastating untreatable disease.

Recently, Pshezhetsky was awarded a grant of $650,000 from the Canadian Institute of Health.

Charities Unite To Fund Research

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Charities Unite to Fund Research into Reversing Brain Damage Caused By Sanfilippo Syndrome

New Study Will Focus on Sanfilippo Syndrome but Findings May Benefit Other Lysosomal Storage Disorders with Similar Pathways

DANA POINT, CA – January 23, 2012 – Rare Disease affects 350 million people worldwide, consisting of 7,000+ identified diseases and disorders. Currently less than 5% of all rare diseases have any type of therapy or treatment, and much of the early stage research is frequently seed-funded by parent advocates, advocacy organizations and non-profit groups.

In an important new trend in rare disease research, rare disease advocates (sometimes representing different rare diseases), collaborate, and pool their resources to fund promising early research. Led by the Team Sanfilippo Foundation, a group of worldwide charities has announced a $145,000 AUD grant to Dr. Kim Hemsley and Professor John Hopwood in Adelaide, Australia to study the fundamental disease processes involved in the pathology of MPS III Sanfilippo Syndrome.

“The ability to treat symptomatic, older patients is crucial not only for patients currently living with neurodegenerative disorders like Sanfilippo Syndrome but also for future patients that will inevitably go undiagnosed until they show symptoms,” said Kathleen Buckley, President of the Team Sanfilippo Foundation. “Given the rarity of lysosomal storage diseases, global collaboration is required to obtain critical mass in our collective battle.”

Sanfilippo Syndrome is a rare and progressive neurodegenerative disease affecting 1 in 70,000 births. It is caused by a genetic defect resulting in a dysfunction of one of four crucial enzymes. The absence of any of these missing enzymes results in an accumulation of heparan sulfate. The disease primarily affects the brain and central nervous system. Children develop normally for the first couple years of life and then suffer progressive loss of skills including the ability to talk, walk, eat and even eventually breathe. Affected children typically die as teenagers.

“Collaboration is critical and necessary for the rare disease community on all fronts and forward thinking organizations that understand this will move the needle much more quickly for their specific diseases,” Nicole Boice, Founder of the R.A.R.E Project. “The Sanfilippo community is making strides on important research that will ultimately help find treatments and cures. They are a model for other rare disease organizations to follow.”

There is hope that the current treatments in human clinical trials, enzyme replacement and gene therapy, will halt the progression of Sanfilippo Syndrome but are not expected to fully recover lost cognitive ability. While a missing enzyme and resultant build-up of waste materials are implicated as the root cause of the disease, incomplete knowledge exists as to the precise damage mechanisms at play in the pathology of the disease. Understanding these processes is important to improve the life of patients whose treatment has begun after they show symptoms. As newborns are not screened for the disease, most patients are not identified until symptoms present.

“This effort will use the latest science to study the real-time progression of the disease in a mouse model, enabling an understanding of what goes wrong and why,” added Buckley. “The ultimate goal is that this new understanding will lead to more effective treatments and a better understanding of what, if any, of the damage might be reversed.”

While this study will focus on Sanfilippo Syndrome, the findings of the study could benefit those suffering from similar lysosomal storage disorders with similar pathways such as Hunter Syndrome, Hurler Syndrome and Tay-Sachs.

For more information regarding ongoing clinical trials in Sanfilippo Syndrome, see:

Sanfilippo Syndrome Type A

Sanfilippo Syndrome Type B

Inquiries regarding this effort may be made to teamsanfilippo@gmail.com.

Funding for the project is provided by

This press release was generated in collaboration with and sponsored by the R.A.R.E Project, a 501c3 non-profit organization whose mission is to increase awareness, build a connected community and catalyze funding for early research, all in an effort to make life better for those living with rare disease. For more information, visit www.rareproject.org.

Top Vote Getter in Pepsi Grant Challenge

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Orlando Families Cause is Top Vote- Getter In Pepsi Grant Challenge

The $250,000 grant will go to an Ohio researcher who has discovered what may be a gene therapy to stop the disease. Team Sanfilippo still has additional funds to raise for the research, which has yet to be approved by the FDA, but the parents are hopeful — and grateful.

Learn more.