U01NS134672

Ind-enabling studies of non-immunogenic gene therapy for ultra-rare DMD patients excluded from dystrophin trials.

Duchenne muscular dystrophy (DMD) is a rare childhood onset neuromuscular disease caused by genetic deficiency of the protein dystrophin.

DMD is an incurable disease with a devastating impact on patients as a result of progressive weakness, wheelchair confinement, loss of independence/activities of daily living, and ultimately premature death from combined cardiorespiratory insufficiency.

The majority of dystrophin gene mutations worldwide are multi-exon, frameshifting deletions that eliminate expression of variable portions of the 79 exon gene into the 427 kD full length protein isoform DP427.

DP427 is a cytoskeletal protein primarily composed of three protein folding domains, the largest of which is the rodlike mid-section composed of 24 spectrin-like triple helical repeats.

DP427 is thought to transmit muscle contractile force between the outermost sarcomeres and the membrane-spanning proteins of the dystrophin-glycoprotein complex (DGC).

Recently, an ultra-rare subset of DMD patients has been found to develop T cell-mediated, treatment-emergent serious adverse events (TESAEs) following systemic gene therapy using AAV vectors encoding miniaturized, ~ 140 kD recombinant proteins derived from DP427 by internal deletion.

Our preclinical studies, as published in 2019 by Song, et al, Nature Medicine, predicted these TESAEs by virtue of our use of an informative animal model, the German Shorthaired Pointer Muscular Dystrophy (GSHPMD) in which a naturally occurring deletion eliminates peptide epitopes corresponding to the miniaturized versions of DP427.

In this study we also showed that a non-immunogenic alternative AAV vector encoding a miniaturized version of the dystrophin-related protein utrophin was protected from T cell destruction of transduced myofibers by central immunological tolerance towards this “self” protein.

In this U01 proposal, we provide a milestone-driven, comprehensive translational and clinical research program to set the stage for a safe and effective alternative for the ultra-rare subset of DMD patients excluded from dystrophin gene therapy trials.

We propose innovative, non-invasive physiological and biochemical outcome measures precisely targeted to the underlying pathophysiology of the disease, segmental myonecrosis incited by forceful muscle contraction.

The four specific aims are structured to yield the highest probability of a successful IND application as the final deliverable, while providing ample information generalizable to therapeutics development for other genetic diseases under the NINDS mission.

The proposed IND application will set the stage for a Phase 1/2A clinical trial of AAV-microutrophin gene therapy in the ultra-rare subset of DMD patients with N-terminal dystrophin deletions, with results of the trial anticipated to apply broadly to the entire DMD patient population.

Trustees Of The University Of Pennsylvania

(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]

Pennsylvania United States

State-Wide

Translational Efforts to Advance Gene-based Therapies for Ultra-Rare Neurological and Neuromuscular Disorders (U01 - Clinical Trial Optional) (PAR-22-030)

Amendment Since initial award the total obligations have increased 105% from $1,541,019 to $3,161,261.