U01NS116752

Immunomodulation Approaches to Improve Safety and Efficacy of Gene Therapy Treatment in Friedrich's Ataxia - Project Summary / Abstract

Friedreich's Ataxia (FA) is the most common form of hereditary ataxia, affecting approximately 1 in every 50,000 people in the US. FA is an autosomal recessive condition caused by the inheritance of GAA trinucleotide repeat expansions in the Frataxin (FXN) gene, which results in reduced levels of FXN in mitochondria. Clinical manifestations appear between the ages of 8 and 16 as a multisystem disorder, primarily affecting the cardiac and nervous systems. FA is steadily progressive and is characterized by diminished quality of life (QOL) and premature death, usually caused by ventricular arrhythmia. Unfortunately, there is currently no effective treatment available.

Gene replacement using recombinant adeno-associated viral vectors (RAAV) carrying the human FXN gene has shown promise as a therapeutic strategy for FA, as demonstrated by our group and others. Our group has conducted toxicology and biodistribution studies in support of the first-in-human gene therapy study for the treatment of FA. The Investigational New Drug (IND) application will be submitted in the second quarter of 2020, and we expect to enroll the first patient immediately after approval. However, a critical unresolved challenge for the success of gene therapy is the host immune response to the vector capsid. Administration of RAAV vectors carrying a transgene elicits cellular and adaptive immune responses against the vector capsid. Exaggerated immune responses can lead to safety concerns, impact the longevity of expression, and contribute to the loss of the therapeutic effect.

Additionally, preclinical data from our lab and others suggest that prior natural exposure to adeno-associated virus (AAV) (pre-existing immunity) can lead to severe infusion reactions and diminished therapeutic efficacy with subsequent AAV exposure. Therefore, current AAV-mediated gene therapy trials must consider a single exposure to the therapeutic vector at a dose below the toxic level and exclude subjects with pre-existing AAV immunity. Our hypothesis is that a more effective dose could be achieved safely by incremental dosing of AAV with multiple lower AAV doses over time. Our extensive preclinical and clinical data demonstrate that B-cell depletion with rituximab and sirolimus in association with AAV delivery prevents the formation of antibodies and confirms our hypothesis. However, prolonged use of rituximab has been associated with rare but devastating adverse events.

In this U01 application, we propose to improve the overall efficacy and safety of the planned FA gene therapy program by identifying an optimal immunomodulation regimen to prevent immune responses against the AAV capsid. This will allow for safe repeated administration of AAV (Aim 1) and therapeutic AAV administration in subjects with pre-existing immunity (Aim 2). We anticipate that the proposed studies will have a major impact on the application of gene therapy approaches not only for FA but for a wide array of neuromuscular genetic disorders.

University Of Florida

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Florida United States

State-Wide

NINDS CREATE Bio Optimization Track for Biologics (U01) (PAR-17-456)

Amendment Since initial award the End Date has been extended from 04/30/26 to 08/31/26 and the total obligations have increased 293% from $792,500 to $3,114,054.