May 2016 – A prospective one-year natural history study of mucopolysaccharidosis
types IIIA and IIIB: Implications for clinical trial design ~
Here is the abstract of the study. Several of us parent foundations funded this study for the gene therapy so we could have a natural history to share with possible trial start ups that we chose to do. In the past each drug company was doing their own Natural History Study and not willing to share the information. Rarely were any the children going thru these studies chosen for a treatment. Now we own rights to the study to use at anytime. If you wish to view the full article you can contact one of us via email and we will gladly send you the pdf.
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Abeona Therapeutics, Inc. is developing gene therapy based potential cures for the deadly childhood diseases Sanfilippo (SF) Syndrome Type A and Type B. In SF disease, the predominant symptoms occur due to improper cell function within the central nervous system (CNS), which result in cognitive decline, motor dysfunction, and eventual death. Our two lead products, ABX-A and ABX-B, uniquely deliver the therapeutic product to the CNS with the aim of reversing the effects of the genetic errors that cause the disease. ABX-A and ABX-B induce cells in the CNS and digestive tract to produce the missing enzymes and help repair damage caused to the cells.
Safety studies conducted in large animal models have demonstrated that delivery of ABX-A and ABX-B are well tolerated with minimal side effects. Importantly, efficacy studies in animals with Sanfilippo syndrome have demonstrated unprecedented therapeutic benefit months after treatment. A single dose of ABX-A or ABX-B significantly restored normal cell and organ function and increased the lifespan of animals with SF over 100% a year after treatment compared to untreated control animals. Similarly, animals treated with ABX-A and ABX-B demonstrated significant corrections of cognitive defects that remained months after drug administration. These results are consistent with studies from several laboratories suggesting ABX-A and ABX-B treatment could potentially benefit patients with for Sanfilippo Syndrome Type A and B, respectively.
Abeona, in partnership with Nationwide Children’s Hospital (Columbus, OH), has met with the FDA and is planning to initiate clinical studies of ABX-A and ABX-B in patients with Sanfilippo Syndrome Type A and B set to begin in 2014.
Substrate Optimization Therapy Sanfilippo A,B,C and MPSI and II
Dr. Brett Crawford
Dr. Lluïsa Vilageliu email@example.com
Gene Therapy Type A
University of Barcelona
Robin M Jackman RMJackman@zacharon.com
Zacharon is developing a novel small molecule therapy which selectively modulates the biosynthesis of the GAGs which accumulate in patients with MPS I, II, and III A,B and C. Due to this selective modification, the deficient enzyme is no longer required for GAG degradation thus reducing lysosomal accumulation. Zacharon has completed important preclinical development activities including the demonstration of proof of concept using MPS animal models including reduction in GAG accumulation in the brain. In March of 2011, Zacharon formed a partnership with Pfizer Inc.’s Orphan and Genetic Disease Unit to complete preclinical development and successfully advance this program through clinical trials and subsequent commercialization. The successful completion of these activities is designed to enable the first small molecule therapy capable of addressing neurological decline and other needs of patients with MPS I, II, and III A,B and C.
Lysosomal Enhancement Therapy Sanfilippo A,B,C,D and many lysosomal diseases
Texas Children’s Hospital
Marco Sardiello firstname.lastname@example.org
This project is based on our recent discovery of a gene network that controls cellular clearance by regulating lysosomal biogenesis and function (Sardiello et al. Science 2009). Lysosomes are ubiquitous intracellular organelles dedicated to the degradation and recycling of the byproducts of cellular metabolism. We have discovered that human cells have a genetic program that controls the activity of lysosomes through the modulation of master gene TFEB, which encodes a transcription factor that directly binds to promoters of lysosomal genes and coordinately activates their transcription. By acting on TFEB, we can induce the cell to make more lysosomes, hence increasing its degradation capacity.
Sanfilippo syndrome and other neurodegenerative diseases are caused by the intracellular accumulation of undegraded, toxic molecules. We postulate that the increase of cellular degradation capacity as a result of the activation of lysosomal master gene TFEB will result in the clearing of toxic molecules. Preliminary data obtained in cells from other neurodegenerative diseases (Batten disease, Huntington’s disease) showed that the enhancement of lysosomal function via TFEB over expression results in the efficient clearance of the toxic molecules that accumulate in these diseases (lipofuscins and mutated huntingtin, respectively). Moreover, cell lines stably over expressing TFEB showed enhanced ability to degrade glycosaminoglycans (Sardiello et al. 2009), the substrate that accumulates in Sanfilippo syndrome. Therefore, this clearing effect appears to be independent from the biochemical nature of accumulated substances and from the specific site of their accumulation (lysosome for glycosaminoglycans and lipofuscins, cytoplasmic for expanded hungtintin protein). This is likely due to the fact that the lysosome is implicated in autophagy, which clears portions of the cytoplasm, and TFEB is also able to promote autophagy by activating the transcription of several autophagy genes.
Dr. Sardiello discovered an already FDA approved molecule that is shown to activate TFEB. Currently this molecule is being tested on Batten mice. A colony of Sanfilippo mice are being prepared for testing this compound. Mouse study will take approximately six months to complete.
Dr. Sardiello will be screening all FDA compounds with high throughput drug screening to find compounds that can reduce toxic accumulations in Sanfilippo Syndrome.
Gene Therapy Sanfilippo B
Nationwide Children’s Hospital, Columbus, Ohio
Dr. Haiyan Fu
Dr. Fu has developed an efficient gene therapy procedure to treat MPSIIIB. We have made an AAV9 vector that has the ability to cross the blood-brain-barrier. This AAV9 vector carries the gene for NAGLU, the enzyme missing in MPSIIIB patients. By a singly intravenous injection of this AAV9-NAGLU vector, we were able to restore the NAGLU enzyme activity and correct the lysosomal storage pathology throughout the brain, spinal cord and multiple somatic tissues in adult MPSIIIB mice. Most importantly, the AAV9-vector-treated mice showed significant behavioral improvement and survived to a normal lifespan. In addition, this approach is minimally invasive and the IV injection itself has minimal risk to patients. With the generous support from the Sanfilippo families and friends through Ben’s Dream – The Sanfilippo Research Foundation, the experiments of this project are still ongoing.
We believe that we are in a very good position to move our AAV9-gene-therapy approach to clinical trial. We have established a strong team with the goal of obtaining the approval from the FDA for a Phase I/II clinical trial in patients with MPS IIIB. Led by Dr. Kevin Flanigan, MD and professor of neurology, we have submitted a Pre-pre-IND package to the FDA and have a pre-pre-IND meeting scheduled with the FDA. This Pre-pre-IND interaction is for us to get advices from the FDA on specific requirements for the Pre-IND toxicology/safety testing of our approach in animals. This Pre-IND toxicology testing is absolutely required for obtaining the FDA approval for our planned MPS IIIB gene therapy clinical trial.
Additional plans and efforts have been made to prepare for moving this MPS IIIB gene therapy to a clinical trial. 1) We have submitted a translational grant application to the NIH. 2) We are planning to establish a MPS III patient registry. 3) Establish and validate the stable high yield vector producing cell line. 4) Produce clinical grade AAV9 vectors needed for the planned clinical trial, and this is required by the FDA when submitting the IND (Investigational New Drug) application. 5). Testing our AAV9-NAGLU vector in large animals considering the clinical relevance to humans.
A recent Team Sanfilippo – Pepsi grant will add support to our work involved in establishing a high yield AAV9-hNAGLU vector production system.
Gene Therapy Sanfilippo A
University of North Carolina
Dr. Doug McCarty
Because all four forms of MPS III share similar disease properties, we believe that the gene therapy approach similar to that we developed for MPS IIIB may also be feasible for other forms of MPS involving a secreted enzyme. We have therefore expanded our gene therapy program to develop efficient AAV9 vector for the treatment of MPS IIIA. This project is led by Dr. Doug McCarty and has been supported by a research grant from the Sanfilippo Children’s Research Foundation (Canada) and Team Sanfilippo Foundation.
To date, we have made multiple AAV vectors carrying the gene for human SGSH, the enzyme missing in patients with MPS IIIA. We tested these vectors in human MPS IIIA cell cultures. The preliminary data showed that these AAV-SGSH-treated MPS IIIA cells produced and secreted SGSH enzyme. In addition, we treated the MPS IIIB cells with the secreted SGSH and saw significant reduction of GAG in these cells.
We are also in the process to establish the MPS IIIA mouse colony (with the help from Dr. Steve Walkley). The MPS IIIB mice will be used to test the AAV9-SGSH vectors and select the optimal vector for potential future clinical application in MPS IIIA patients. The goal of this project is to develop a systemic AAV9-SGSH gene therapy approach for the treatment of MPS IIIA in patients.
The very recent Team Sanfilippo – Pepsi grant will support us to construct/test the AAV9-SGSH vectors, to develop high yield AAV9-SGSH vector producing plasmid, and to initiate the development of vector producing cell line inconsideration of potential clinical application.
ERT Sanfilippo B
Synageva research laboratory in Lexington, MA, has protein engineering capabilities and expertise in the rapid production of recombinant proteins for biological characterization. These capabilities allow us to engineer and manufacture proteins that are either identical to the defective protein or incorporate unique modifications to enhance the biological activity and/or therapeutic usefulness of the defective protein
Program SB-103 rhNAGLU