SB1NS135733

Manufacture of an intracerebroventricular enzyme replacement therapy for CLN1 Batten disease - summary. The neuronal ceroid lipofuscinoses (NCLS) are a group of incurable neurodegenerative storage disorders primarily affecting the brain and the retina of children and young adults, leading to dementia, blindness, epilepsy, and early death, with a prevalence of approximately 1.5 to nine per million population (1.3 to 7 per 100,000 live births).

The infantile onset form CLN1 disease is caused by mutations in the CLN1/PPT1 gene, which codes for the lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1) resulting in a reduction or absence of enzyme activity. CLN1 disease usually presents between 6 and 24 months of age and there are 2-3 children with this form identified each year and currently 24 known children with CLN1 in the US, 11 in Brazil and at least 10 in the UK (with likely many more undiagnosed).

There are currently no treatments available other than palliative therapies and the disease is fatal. Human recombinant PPT1 (rhPPT1) expressed in CHO cells has been previously reported to modify disease phenotypes following a single intrathecal (IT) and intravenous (IV) administration in PPT1 deficient mice (PPT1-/-). After successful completion of our Phase I SBIR in which we exceeded our milestones monthly intracerebroventricular (ICV) administration of rhPPT1 produced statistically significant treatment effects in PPT1-/- mice, such as rescue of more than 60% PPT1 enzyme activity decreased secondary enzyme levels, decreased the loss of neurons in all regions of brain and spinal cord and improved gait and rotarod results. The CLN1 ERT data clearly pointed to ICV dosing as ideal for future studies, which is also a preferred route according to physicians. Our Phase II SBIR has enabled us to 1. prepare our quality documents, 2 identify a CDMO (STC Biologics) who has manufactured our GLP quality protein for preIND toxicity studies in rat. 3. submitted a preIND request to the FDA (with the assistance of RTI International,).

We now propose in this project 1. production of GMP protein (with STC Biologics), 2. continued development of quality procedures, 3. prepare a clinical trial protocol (with assistance from CTI Clinical Trial Services, Inc.), 4 and submit an IND (with assistance from RTI). These collaborations will enable us to cost effectively and more rapidly translate this potential treatment to the clinic that can potentially save the lives of children living with this devastating disease. We have already obtained an orphan drug designation and rare pediatric disease designation from the FDA for rhPPT1 as a biological product for a “rare pediatric disease” which offers several benefits in future upon FDA approval, including marketing exclusivity for 7 years and the potential to obtain a rare pediatric disease voucher and thus provide a return on investment (current value ~$100 M).

We are engaged with CLN1 families and we are now well positioned to continue the development of this potential treatment for a devastating disease. This proposed work would bring us closer to a clinical trial. Our work on developing rhPPT1 as an ERT for CLN1 would position us well to work on further rare diseases in future and grow CPI. There is an important role to bring treatments to patients with ultra-rare diseases as illustrated by other much larger companies such as Biomarin and Ultragenyx who we aspire to emulate.

Collaborations Pharmaceuticals

(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]

Raleigh, North Carolina 276065222 United States

Single Zip Code

SBIR/STTR Commercialization Readiness Pilot (CRP) Program Technical Assistance and Late Stage Development (SB1, Clinical Trial Not Allowed) (PAR-20-129)

Amendment Since initial award the total obligations have increased 115% from $1,840,246 to $3,953,139.