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Project Number: 1R43NS087730-01 Contact PI / Project Leader: MENDELSOHN, ANDREW R
Title: TUNABLE FRATAXIN REPLACEMENT THERAPY Awardee Organization: PANORAMA RESEARCH, INC.
Description
Abstract Text:
DESCRIPTION (provided by applicant): Friedrich's ataxia (FA) is a devastating inherited degenerative disease that afflicts children and young adults resulting in early death. It is caused by homozygous recessive mutations in the frataxin (FXN) gene, which m encodes a protein important in the assembly of iron-sulfur clusters in mitochondria. We propose to develop a therapy for FA that uses recombinant adeno-associated viral (AAV) vectors to deliver the FXN gene for tunable, long-term expression in the peripheral nervous system (PNS) and heart. To this end, we have developed an inducible AAV gene transfer system for regulated expression of FXN in target tissues. Oral administration of a small molecule drug can modulate the levels and duration of FXN expression from our third generation vectors. We hypothesize that increased levels of human frataxin containing the native mitochondrial targeting sequence will repair dysfunctional mitochondria and reduce target cell apoptosis. Since ectopic frataxin will be expressed locally in neural cells, the blood brain barrier (BBB) will not limit frataxin access to affected neurons, a potential problem with protein-based approaches. AAV-delivered FXN solves the BBB problem of systemic protein therapy and represents a novel and potentially practical approach to the treatment of FA. In Phase I, we will construct the vectors and test their constitutive and inducible expression in vitro and in the hearts and PNS of recipient mice. Meaningful augmentation of mitochondrial bioenergetic profiles is expected. Phase II will focus on expanded proof-of-concept studies in animal models. Given the remarkable recent progress in using AAV therapeutically-there are over 50 clinical trials using AAV as delivery vehicles, including safe delivery of transgenes to the heart-we are optimistic that our regulated AAV expression system for delivery of FXN to the brains and hearts of patients will provide a novel restorative therapy for this devastating neurodegenerative and cardiomyopathic disease. Because expression from AAV vectors is expected to be stable over long periods of time, our approach represents a potential critical step on the road to a cure for FA.
Public Health Relevance Statement:
PUBLIC HEALTH RELEVANCE: Friedrich's ataxia (FA) is a fatal inherited disorder that results when a patient has two defective copies of the frataxin (FXN) gene. We will use a novel, tunable genetic approach to restore normal levels of frataxin in the cardiac and nervous tissues of FA patients.
NIH Spending Category:
Genetics; Neurosciences
Project Terms:
adeno-associated viral vector; Affect; Animal Model; Apoptosis; assay development; Ataxia; base; Bioenergetics; Blood - brain barrier anatomy; Brain; Cardiac; Cardiac Myocytes; Cells; Cessation of life; Child; Clinical Trials; Degenerative Disorder; Disease; Drug Kinetics; efficacy evaluation; frataxin; Functional disorder; Gene Transfer; Generations; Genes; Genetic; Genetic Transcription; Goals; Heart; Human; In Vitro; in vivo; Inborn Genetic Diseases; Inherited; Iron; Mitochondria; mitochondrial dysfunction; Morbidity - disease rate; mortality; Mus; Mutation; Nerve Degeneration; Nerve Tissue; Neurons; novel; Oral Administration; Organ; Patients; Peripheral Nervous System; Pharmaceutical Preparations; Pharmacodynamics; Phase; phase 2 study; Plasmids; Play; pre-clinical; Preparation; Proteins; public health relevance; Recombinants; repaired; Replacement Therapy; Rodent; Role; satisfaction; small molecule; Spinal Ganglia; Sulfur; System; Testing; Time; Tissues; Toxic effect; Toxicology; Transgenes; vector; Viral; Viral Genes; Virus; Work; young adult
Contact PI Information: Program Official Information: Other PI Information:  
Name: MENDELSOHN, ANDREW R
Email: Unavailable
Title: DIRECTOR OF MOELCULAR BIOLOGY 		Name: FERTIG, STEPHANIE
Email: Click to view PO email address 		Not Applicable  
Organization: Department / Educational Institution Type: Congressional District:
Name: PANORAMA RESEARCH, INC.
City: SUNNYVALE Country: UNITED STATES (US) 		Unavailable
Unavailable 		State Code: CA
District: 17
Other Information:    
FOA: PA-13-234
Study Section: Special Emphasis Panel (ZRG1-ETTN-M (11)B)
Fiscal Year: 2014 Award Notice Date: 25-APR-2014 		DUNS Number: 556962439
Project Start Date: 1-MAY-2014
Budget Start Date: 1-MAY-2014 		CFDA Code: 853
Project End Date: 30-APR-2016
Budget End Date: 30-APR-2016
Administering Institutes or Centers:
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Project Funding Information for 2014:
Total Funding: $218,589
Publications
Year Funding IC FY Total Cost by IC
2014 NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE $218,589
Categorical Spending by IC: Click here for more information on NIH Categorical Spending
Genetics; Neurosciences;
NIH Categorical Spending:
Funding IC FY Total Cost by IC NIH Spending Category
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE $218,589 Neurosciences; Genetics;

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