Disease Applications

Through selective targeting of mTORC1 activation, Navitor’s therapeutics have the potential to modulate either the catabolic or anabolic responses that are mediated by this signaling pathway. This broad functionality presents unique opportunities for the development of novel product candidates that address a range of age-related diseases as well as several genetic and rare diseases that are linked to the dysregulation of mTORC1 activation.

Navitor’s drug discovery efforts have identified compounds that can inhibit excessive mTORC1 activity in conditions with hyperactive response to nutrient signaling—such as metabolic, neurodegenerative, and autoimmune diseases; and age-related immune suppression (immunosenesence)—as well as compounds that can activate mTORC1 activity in conditions with reduced or suppressed response to nutrient signaling, such as musculoskeletal diseases.

  • Metabolic Disease: Obesity and type 2 diabetes are metabolic diseases in which hyperactive mTORC1 activity is thought to be primarily driven through the excess availability of nutrients and increasing age, leading to cellular dysfunction and disease progression. This can be exemplified by the effects of hyperactivated mTORC1 on the insulin-producing cells of the pancreas (β cells), resulting in the progressive reduction of insulin secretion, thereby contributing to the pathophysiology of type 2 diabetes. Navitor’s therapeutic approach is designed to return mTORC1 activity to normal levels while maintaining mTORC2 activity, which is critical for β cell function.
  • Neurodegeneration: Alzheimer’s, Parkinson’s, and Huntington’s diseases are neurodegenerative diseases that involve abnormal protein folding, possibly due to excessive and unrestrained protein synthesis and a reduced ability to remove misfolded proteins through autophagy. Navitor’s therapeutic approach can specifically reduce protein synthesis while initiating autophagy and lysosomal biogenesis, which are considered important in regulating the production of abnormal proteins that are thought to be involved in disease initiation and/or progression.
  • Inflammatory and Autoimmune Disease: Psoriasis, rheumatoid arthritis, lupus, and multiple sclerosis are autoimmune diseases in which increased mTORC1 activity is thought to contribute to the activation of a specific subpopulation of T cells called Th1 and Th17, which have been demonstrated to create inflammation and tissue injury. By reducing the activity of mTORC1, Navitor’s therapeutics can suppress further expansion of the Th1 and Th17 populations and thereby reduce the chronic inflammatory response that is mediated by this population of specialized immune cells.
  • Immunosenescence: Pharmacologically reducing the activity of mTORC1 in elderly human subjects has been demonstrated to improve their immune response to a viral vaccine through the suppression of immunoscenesence, which increases with age. Navitor’s approach to selectively modulating the population of T cells that mediate the immune response may be a general strategy to improve the efficacy of vaccines in an increasingly aging population as well as to enhance the effectiveness of cancer immunotherapy.
  • Genetic and Rare Diseases: Lymphangioleiomyomatosis (LAM) and tuberous sclerosis are rare diseases caused by specific genetic defects in the mTORC1 activation pathway, resulting in an uncontrolled hyperactivity of this complex that leads to abnormal cell and tumor growth. Navitor’s therapeutics can restore more normal function by specifically inhibiting the central process leading to these diseases. Leigh’s syndrome and Friedrich’s ataxia are examples of rare metabolic and mitochondrial diseases in which protein synthesis and/or cell growth have gone awry and become overactive. Preclinical studies have demonstrated that reducing mTORC1 activity can have therapeutic effects. Diamond-Blackfan anemia is a rare genetic disease characterized by a reduced ability to produce red blood cells or erythrocytes that often leads to numerous abnormalities, including craniofacial malformations, limb abnormalities, cardiac defects, urogenital malformations, and cleft palate. Recent data have indicated that activating mTORC1 in red blood cell precursors with large doses of leucine can enhance the production of functional red blood cells and improve clinical outcome.
  • Musculoskeletal diseases include conditions that involve the progressive loss of skeletal muscle resulting from increasing age (sarcopenia), or after prolonged physical immobilization following orthopedic surgery or prolonged bed rest due to disease. In both instances, protein synthesis and/or the growth and function of skeletal muscle cells is suppressed, which can be linked back to the reduced activation of mTORC1. Navitor’s therapeutics may restore and/or maintain muscle growth and function to enhance recovery from injury and disease as well as restore and/or maintain reduced muscle function due to aging.
Navitor is focused on two areas for drug development:
  • Age-Related Diseases: Modulating signaling via mTORC1 for age-related disease processes that are mediated by nutrient availability.
  • Genetic and Rare Diseases: Selectively targeting mTORC1 activation driven by specific genetic mutations not involved in nutrient sensing pathways that result in, for example, rare diseases caused by hyperactivation of mTORC1.