Alzheimer's disease (AD) is a progressive multifactorial disease affecting more than 50 million people worldwide and is the most common dementia of late-life. To date, no interventions have demonstrated substantial therapeutic efficacy to prevent, delay or treat AD. Current thinking in the field embraces the complexity of AD pathophysiology, which has enabled a more diverse therapeutic pipeline targeting multiple aspects of the disease. The neurosteroid allopregnanolone (Allo) is under development as a regenerative therapeutic for AD. Allo is an innovative, regenerative, systems biology activator that promotes regeneration and repair while activating mechanisms that reduce the burden of AD pathology. Based on extensive preclinical discovery andIND-enabling translational research, a Phase 1 clinical trial was completed and established safety for Alloadministered intravenously using a regenerative treatment regimen. To advance therapeutic development of Alloas a regenerative therapeutic, the project proposed herein addresses two critical barriers to clinical translatability: 1) Feasibility of chronic long-term administration of Allo in an aged population with AD and 2) Route of administration optimization to promote patient compliance. To address these challenges, we propose to develop a novel Allo formulation to enable an intranasal route of administration. A transmucosal formulation of Alloadvances clinical use in an aged AD population while also addressing first-pass metabolism constraints that limitoral bioavailability of Allo. Aims of the SBIR entitled Novel Intranasal Formulations of Allopregnanolone, a Regenerative Therapeutic for AD are: Aim 1: Develop Allo formulations for IN delivery in collaboration with MedPharm; Aim 2: Establish pharmacokinetics of Allo-IN formulations in brain, olfactory bulb and plasma after administration to a rat. To achieve these aims, experts in formulation (MedPharm) will develop a solution or a suspension of Allo for IN delivery. To achieve this objective, MedPharm will: 1. Perform pre-formulation, proof of concept formulation development and stability assessments of Allo formulations and assess achievable concentrations of Allo to develop up to 5 solution or suspension formulation nasal sprays. 2. Conduct in vitroreconstituted nasal epithelial (RNE) permeation testing using primary human nasal epithelial cells which exhibitmucus production, ciliary activity, tight junctions, and barrier function. The 3 most promising formulations will advance to Aim 2 for pharmacokinetic analysis in a rat model. In vivo analyses will be conducted in both female and males to investigate potential sex differences in pharmacokinetics of intranasal absorption. This research is responsive to PAS-19-316 to "conduct research leading to the development of innovative products and/or services that may advance progress in preventing and treating AD and AD-related dementias (ADRD)" and"address recommendations and milestones for AD/ADRD research from the National Alzheimer's Act."
Public Health Relevance Statement: Project Narrative Alzheimer's disease (AD) is a neurodegenerative disease that causes loss of brain tissue and function. Aninnovative approach to treating AD is to promote regeneration of brain tissue to restore neural structure and cognitive function. We will develop an intranasal formulation of the safe regenerative therapeutic allopregnanolone (Allo) to increase ease of delivery, patient compliance and delivery directly to the brain or via the olfactory pathway.
Project Terms: AD dementia; Alzheimer Type Dementia; Alzheimer disease dementia; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimers Dementia; Primary Senile Degenerative Dementia; primary degenerative dementia; senile dementia of the Alzheimer type; Alzheimer's Disease; Biological Availability; Bioavailability; Physiologic Availability; Brain; Brain Nervous System; Encephalon; Cells; Cell Body; Clinical Trials; Diagnosis; Disease; Disorder; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; intravenous administration; Epithelial Cells; Exhibits; Female; Fragile X Syndrome; Escalante syndrome; Fragile X; Martin-Bell Syndrome; Martin-Bell-Renpenning syndrome; Renpenning syndrome 2; X-linked mental deficiency-megalotestes syndrome; X-linked mental retardation with fragile X syndrome; X-linked mental retardation-fragile site 1 syndrome; autism-fragile X (AFRAX) syndrome; fra(X) syndrome; fra(X)(28) syndrome; fra(X)(q27) syndrome; fra(X)(q27-28) syndrome; fragile X-mental retardation syndrome; fragile Xq syndrome; fragile site mental retardation 1; macro-orchidism-marker X (MOMX) syndrome; macro-orchidism-marker X syndrome; mar(X) syndrome; marker X syndrome; mental retardation-macroorchidism syndrome; Genes; Goals; Hippocampus; Ammon Horn; Cornu Ammonis; hippocampal; Human; Modern Man; In Vitro; Intravenous infusion procedures; IV Infusion; intravenous infusion; Liver; hepatic body system; hepatic organ system; Magnetic Resonance Imaging; MR Imaging; MR Tomography; MRI; MRIs; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; Zeugmatography; male; men; Metabolism; Intermediary Metabolism; Metabolic Processes; Mucous Membrane; Mucosa; Mucosal Tissue; Mucous body substance; Mucus; mucous; Persons; Nose; Nasal; Nasal Passages Nose; Respiratory System, Nose, Nasal Passages; olfactory bulb; Olfactory Pathways; Olfactory system; olfactory circuitry; olfactory circuits; Legal patent; Patents; Peer Review; Drug Kinetics; Pharmacokinetics; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Production; Wistar Rats; Rattus; Common Rat Strains; Rat; Rats Mammals; Recommendation; Natural regeneration; Regeneration; regenerate; Research; Safety; Suspensions; Suspension substance; Syndrome; Testing; Thinking; thoughts; Time; Treatment Protocols; Treatment Regimen; Treatment Schedule; Tremor; Drug Delivery; Drug Delivery Systems; improved; Chronic; Clinical; Penetration; repair; repaired; Phase; Occluding Junctions; Zonula Occludens; Tight Junctions; Funding; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Collaborations; Therapeutic; Allopregnanolone; Life; cognitive function; Oral; Route; brain tissue; Dementia; Amentia; Severity of illness; disease severity; Neurodegenerative Disorders; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; Services; Infusion procedures; Infusion; infusions; slow potential; Nasal Epithelium; neural; Structure; novel; white matter; substantia alba; Bypass; neurosteroids; neuroactive steroids; Modeling; Intervention; Intervention Strategies; interventional strategy; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; preventing; prevent; Patient Compliance; patient adherence; patient cooperation; therapy compliance; therapy cooperation; treatment compliance; compliance behavior; Address; Systems Biology; Data; Reproducibility; in vivo; Clinical Data; Cognitive; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Translational Research; Translational Science; translation research; translational investigation; Development; developmental; Placebo Control; placebo controlled; open label; open label study; pre-clinical; preclinical; intervention efficacy; therapeutic efficacy; therapy efficacy; Treatment Efficacy; Outcome; Population; aged; Coupled; innovate; innovative; innovation; self-renew; self-renewal; cognitive recovery; reconstitute; reconstitution; commercialization; aged population; population aging; aging population; regeneration based therapy; regeneration therapy; regenerative therapeutics; regenerative therapy; therapeutic agent development; therapeutic development; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; new treatment approach; new treatment strategy; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; novel therapeutic intervention; primary outcome; regenerative; AD pathology; Alzheimer's pathology; Alzheimer's disease pathology; Formulation; in-home care; demented; clinically translatable; clinical translation; clinical development; AD related dementia; ADRD; Alzheimer's and related dementias; Alzheimer's disease and related dementia; Alzheimer's disease and related disorders; Alzheimer's disease or a related dementia; Alzheimer's disease or a related disorder; Alzheimer's disease or related dementia; Alzheimer's disease related dementia; Differences between sexes; Differs between sexes; Sexual differences; sex-dependent differences; sex-related differences; sex-specific differences; Sex Differences; Alzheimer's therapeutic; Alzheimer's disease therapeutic; Alzheimer's patient; patient living with Alzheimer's disease; patient suffering from Alzheimer's disease; patient with Alzheimer's; patient with Alzheimer's disease; Alzheimer's disease patient; regenerative treatment; Regenerative capacity; regeneration ability; regeneration capacity; absorption; Oral Drug Administration; intraoral drug delivery; Oral Administration; Affect; ages; Age; advanced age; elders; geriatric; late life; later life; older adult; older person; senior citizen; Elderly; Aging
