Formulations and methods for treating dementia and alzheimer's disease

Abstract

Applicants have discovered differential expression and activity of various miRNAs in neurodegenerative diseases. These miRNAs can serve as therapeutic targets for prevention and treatment of neurodegenerative diseases. Accordingly, embodiments of the invention include formulations and methods for treating neurodegenerative diseases such as dementia and Alzheimer's disease. The formulations and methods can include five microRNAs and two small molecule therapeutics. In aspects, the miRNAs are MIR-145-3p, let-7c-3p, MIR-383-5p, MIR-548aj-3p and MIR-548x-3p. In aspects, the small molecule therapeutics are GATC-49, fucosterol and fucoidan. In aspects, the compounds work synergistically with one another.

Description

FORMULATIONS AND METHODS FOR TREATING DEMENTIA AND ALZHEIMER’S DISEASERELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Application No. 63 / 567,221 filed on March 19, 2024, the contents of which are incorporated herein by reference.FIELD OF THE INVENTION

[0002] The invention relates to therapeutics, and more specifically, to formulations and methods to treat neurodegenerative disorders such as dementia and Alzheimer’s disease.BACKGROUND

[0003] Dementia can be defined as a decline in cognitive abilities that impacts a person's ability to perform everyday activities. This typically involves problems with memory, thinking, and behavior. Aside from memory impairment and a disruption in thought patterns, the most common symptoms include emotional problems, difficulties with language, and decreased motivation. The symptoms may be described as occurring in a continuum over several stages. Dementia ultimately has a significant effect on the individual, caregivers, and on social relationships in general. A diagnosis of dementia requires the observation of a change from a person's usual mental functioning and a greater cognitive decline than what is caused by normal aging.

[0004] Several diseases and injuries to the brain such as a stroke can give rise to dementia, most commonly, Alzheimer's disease. The Diagnostic and Statistical Manual of Mental Disorders describes dementia as either a mild or major neurocognitive disorder with varying degrees of severity and many causative subtypes. The International Classification of Diseases also classes dementia as a neurocognitive disorder (NCD) with many forms or subclasses. Dementia is listed as an acquired brainsyndrome, marked by a decline in cognitive function, and is distinguished from neurodevelopmental disorders. Dementia is also described as a spectrum of disorders with causative subtypes of dementia based on a known disorder, such as Parkinson's disease, for Parkinson's disease dementia; Huntington's disease, for Huntington's disease dementia; vascular disease, for vascular dementia; HIV infection, causing HIV dementia; frontotemporal lobar degeneration for frontotemporal dementia; or Lewy body disease for dementia with Lewy bodies and prion diseases. Subtypes of neurodegenerative dementias may also be based on the underlying pathology of misfolded proteins such as synucleinopathies, and tauopathies. More than one type of dementia existing together is known as mixed dementia.

[0005] Diagnosis of dementia is usually based on history of the illness and cognitive testing with imaging. Blood tests can rule out other possible causes and determine the dementia subtype. The greatest risk factor for developing dementia is aging, however dementia is not a normal part of aging. Several risk factors for dementia, such as smoking and obesity, are preventable by lifestyle changes.

[0006] Alzheimer's disease is the most common form of dementia. Prevalence studies indicated that in 2000 there were about 25 million persons with Alzheimer's disease worldwide and this number is expected to increase to 114 million by 2050. Onset usually occurs in those over age 65. Clinical signs include progressive cognitive loss and other associated neurobehavioral disabilities together with a declining capability of performing the activities of daily living.

[0007] The basic cause of sporadic Alzheimer's disease is not known, probably because the disease is heterogeneous and involves age-related changes together with a complex interaction of genetic and environmental risk factors. The pathophysiology of Alzheimer's disease is thought to relate to the putative deleterious effects of the two misfolded and aggregated proteins, extracellular beta amyloid and intracellular tau. Presumably, as a consequence of the selective neurodegenerative process, the synthesis of the neurotransmitter acetylcholine declines. This reduction undoubtedly interferes with normal synaptic transmission in brain. Drugs that act to correct theacetylcholine deficiency thus constitute the mainstay of current therapy.

[0008] Current treatments for dementia and AD are, however, generally considered ineffective. Acetylcholinesterase inhibitors (e.g., donepezil) can be prescribed to treat patients with mild to moderate disease states. Memantine, an NMDA receptor antagonist, can be administered to patients with more severe AD but the benefit is typically minimal. The prognosis of patients is generally bleak as the diseases become severe over time. Current treatments are generally focused on symptoms by, for example, improving mental function, controlling behavior and slowing progress of the disease.

[0009] Conventional treatments for neurodegenerative diseases such as dementia and AD are limited. Moreover, such treatments are generally considered ineffective. Accordingly, there is a need for more effective therapies for neurological disorders. Embodiments of the invention include molecules for treating neurodegenerative diseases such as dementia and Alzheimer’s disease (AD).SUMMARY OF THE INVENTION

[0010] The inventions described and claimed herein have many attributes and embodiments including those set forth or described or referenced in this brief summary. The inventions described and claimed herein are not limited to, or by, the features or embodiments identified in this summary, which is included for purposes of illustration only and not restriction.

[0011] MicroRNAs (miRNAs) are small, regulatory RNAs, that regulate gene expression by repressing translation and / or break down mRNAs of their downstream target genes. miRNAs typically modulate gene expression (e.g., increase or decrease translation) by promoting cleavage of target mRNAs or by blocking translation of the cellular transcript. miRNAs are processed from primary transcripts known as pri-miRNA to short stem-loop structures called precursor (pre)-miRNA and finally to functional, mature miRNA. Mature miRNA molecules are partially complementary to one or moremessenger RNA molecules, and their primary function is to down-regulate gene expression. Mis-regulation of miRNAs in the central nervous system can contribute to neurodegenerative disorders. Applicants have discovered differential expression levels of various miRNAs in neurodegenerative diseases. These miRNAs can serve as therapeutic targets for prevention and treatment of neurodegenerative disorders.

[0012] Accordingly, Applicants present therapeutic formulations and methods against particular targets to treat such neurodegenerative disorders such as dementia and Alzheimer’s disease (AD). One embodiment is a composition for preventing or treating a neurodegenerative disorder. In aspects, the neurodegenerative disorder is dementia, frontotemporal dementia, non-specific dementia, Alzheimer-type dementia or Alzheimer’s disease (AD).

[0013] Embodiments also include the formulations and methods for promoting longevity, for anti-aging and for the treating, preventing or improving the prognosis of neurodegenerative diseases (e.g., AD and dementia).

[0014] Embodiments also include formulations and methods for treating neurodegenerative disorders (e.g., dementia and AD) using pharmaceutical compositions that include specific miRNAs. In aspects, the miRNAs include (a) MIR- 145-3p, (b) let-7c-3p, (c) MIR-383-5p, (d) MIR-548aj-3p and (e) MIR-548x-3p.

[0015] In aspects, the miRNAs are administered using a lipid-based delivery (e.g., liposomes). In aspects, the miRNAs are administered in a Bound Nucleic Acid (BNA) formation, for example, an RNA-DNA hybrid, RNA-RNA hybrid, miRNA-siRNA or IncRNA etc.

[0016] In embodiments, the miRNAs are non-coding and act as repressors on one or more sites. In aspects, the miRNAs are packaged into nanoparticles (e.g., exosome or liposomes) for administration. In aspects, the miRNAs are conjugated (e.g., with locked nucleic acids (LNAs), 5'-(E)-vinylphosphonate modification or pyrimidine methylation) for administration.

[0017] In aspects, the miRNAs are modified to improve one or more of activity, bioavailability, solubility, stability, etc. In aspects, the miRNA nucleic acids are modified miRNAs, for example, an miRNA nucleic acid including one or more sequence modifications, modified nucleotides, and / or a 5'-end and / or 3'-end modification. The use of agomirs, mimics or mimetics are also contemplated.

[0018] In embodiments, the formulations described herein are useful to reduce signs / symptoms of a neurodegenerative disease. In aspects the formulations can treat neurodegenerative diseases of the CNS, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and the prototypic neuroinflam matory disease multiple sclerosis (MS).

[0019] In embodiments, the miRNA agent is an isolated miRNA selected from the group consisting of MIR-145-3p, let-7c-3p, MIR-383-5p, MIR-548aj-3p and MIR-548x- 3p. In aspects, the miRNA agent is an isolated miRNA that is 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of a miRNA listed above. In aspects, the miRNA agent is a seed sequence of a miRNA listed above.

[0020] Another embodiment is a formulation that includes microRNAs and small molecule therapeutics. In aspects, the microRNAs include (a) MIR-145-3p, (b) let-7c- 3p, (c) MIR-383-5p, (d) MIR-548aj-3p and (e) MIR-548x-3p. In aspects, the small molecule therapeutics include (a) GATC-49, (b) fucosterol and (c) fucoidan. In aspects, one or more of the compounds work synergistically with one another to treat a neurodegenerative disease.

[0021] Additional embodiments include methods for treating, preventing or reducing the risk of a neurodegenerative disease associated with aberrant expression of one or more miRNAs. The method can include administering a composition that includes an oligonucleotide that down-regulates the over-expression of at least one miRNA. The oligonucleotide can be a) complementary to a nucleotide sequence or b) hybridize to a nucleotide sequence. In aspects, the composition includes one or more small moleculetherapeutics (i.e., GATC-49, fucosterol and / or fucoidan).

[0022] In aspects, encapsulation and drug delivery modalities can be used such as synthetic or natural exosomes, lipid bilayers, liposomal and alginate formulation or other synthetic or natural polymer encapsulation techniques. In aspects, the miRNAs and / or small molecules described herein are administered by sublingual, acid-stable capsules, and / or transdermal methods.

[0023] In aspects, the formulation includes about 0.5 to 5 wt.% of each of each of the above compounds for either oral administration or injection.

[0024] Another embodiment is a method of reducing amyloid plaques by administering a therapeutically effective amount of a formulation described herein. Another embodiment is a method of reducing levels of intracellular tau by administering a therapeutically effective amount of a formulation described herein. Another embodiment is a method improving neuroplasticity by administering a therapeutically effective amount of a formulation described herein.

[0025] In still another aspect, the present specification provides a use of the pharmaceutical composition including the same in the preparation of drugs for the prevention or treatment of a neurodegenerative disease.

[0026] Embodiments also include compound GATC-49, a salt or an analog thereof:

[0027] Additional embodiments include a method of treating an ailment using compound GATC-49 or an analog thereof. In aspects, the ailment is a neurological disease or a neurodegenerative disorder.

[0028] Other features and advantages of aspects of the present invention willbecome apparent from the following more detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of aspects of the invention.BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The accompanying drawings illustrate aspects of the present invention. In such drawings:

[0030] FIG. 1 is a flowchart that depicts a method and compounds for treating a neurodegenerative disease.Definitions

[0031] Reference in this specification to "one embodiment / aspect" or "an embodiment / aspect" means that a particular feature, structure, or characteristic described in connection with the embodiment / aspect is included in at least one embodiment / aspect of the disclosure. The use of the phrase "in one embodiment / aspect" or "in another embodiment / aspect" in various places in the specification are not necessarily all referring to the same embodiment / aspect, nor are separate or alternative embodiments / aspects mutually exclusive of other embodiments / aspects. Moreover, various features are described which may be exhibited by some embodiments / aspects and not by others. Similarly, various requirements are described which may be requirements for some embodiments / aspects but not other embodiments / aspects. Embodiment and aspect can be in certain instances be used interchangeably.

[0032] The terms used in this specification generally have their ordinary meanings in the art, within the context of the disclosure, and in the specific context where each term is used. Certain terms that are used to describe the disclosure are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the disclosure. It will be appreciated that the same thing can be said in more than one way.

[0033] Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein. Nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and is not intended to further limit the scope and meaning of the disclosure or of any exemplified term. Likewise, the disclosure is not limited to various embodiments given in this specification.

[0034] The term “longevity” generally refers to the length of a person's life (i.e. , life expectancy). Reflections on longevity have usually gone beyond acknowledging the basic shortness of human life and have included thinking about methods to extend life. Longevity may refer to especially long-lived members of a population, whereas life expectancy is defined statistically as the average number of years remaining at a given age. For example, a population's life expectancy at birth is the same as the average age at death for all people born in the same year (in the case of cohorts).

[0035] The term “bioavailability” refers to the fraction of an administered dose of unchanged drug that reaches the systemic circulation. For example, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases due to incomplete absorption and first-pass metabolism. Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration. In an embodiment, the bioavailability of an agent is increased by converting it to a prodrug.

[0036] The term “half maximal effective concentration” or “ECso” refers to a measure of the concentration of a drug, antibody or toxicant which induces a biological response halfway between the baseline and maximum after a specified exposure time. More simply, ECso can be defined as the concentration required to obtain a 50% [...] effect and may be also written as [A]so. It is commonly used as a measure of a drug's potency and is expressed in molar units (M).

[0037] The term “active agent” or “active ingredient” refers to a substance, compound, or molecule, which is biologically active or otherwise, induces a biological or physiological effect on a subject to which it is administered to. In other words, “active agent” or “active ingredient” refers to a component or components of a composition to which the whole or part of the effect of the composition is attributed. An active agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. An active agent can be a secondary agent, or in other words, the component(s) of a composition to which an additional part and / or other effect of the composition is attributed.

[0038] A “formulation” or a “pharmaceutical composition” can include the combination of an active agent, such as a therapeutic peptide, with a carrier, inert or active, in a sterile composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.

[0039] The term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.

[0040] The term “generally recognized as safe” or “GRAS” refers to a United States Food and Drug Administration (FDA) designation that a chemical or substance added to food is considered safe by experts under the conditions of its intended use. An ingredient with a GRAS designation is exempted from the usual Federal Food, Drug, and Cosmetic Act (FFDCA) food additive tolerance requirements.

[0041] The term “analog” or “chemical analog” refers to a compound having a structure similar to that of another compound, but differing from it in respect to a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced with other atoms, groups, or substructures.

[0042] The term “neurological disorder” broadly refers to a disorder of the nervous system. Neurological disorders can affect the brain as well as the nerves foundthroughout the human body and the spinal cord. Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms. Neurological disorders include, for example, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain-Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headaches, encephalitis and myasthenia gravis.

[0043] The term “neurodegenerative disease” refers to a disease caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. They encompass a wide range of conditions that result from progressive damage to cells and nervous system connections that are essential for mobility, coordination, strength, sensation, and cognition. Examples include: Alzheimer's disease and other memory disorders, ataxia, Huntington's disease, Parkinson's disease, motor neuron disease, multiple system atrophy, progressive supranuclear palsy, frontotemporal lobar degeneration, frontotemporal dementia; primary progressive aphasia; PNFA: progressive non-fluent aphasia; FTLD-U frontotemporal lobar degeneration with ubiquitin positive inclusions; AD: Alzheimer's Disease; MCI: mild cognitive impairment PD: Parkinson's Disease; DLB: dementia with Lewy bodies and lewy body disease

[0044] The term “post-traumatic stress disorder” or “PTSD” refers to a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, violence, etc. Symptoms can include disturbing thoughts, feelings, or dreams related to the events, mental or physical distress to trauma-related cues, attempts to avoid trauma-related cues, alterations in the way a person thinks and feels, and an increase in the fight-or-flight response. PTSD causes biochemical changes in the brain and body that differ from other psychiatricdisorders such as major depression.

[0045] The term “5-HT2A receptor” refers to a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor but has several intracellular locations. 5- HT is short for 5-hydroxy-tryptamine or serotonin. This is the main excitatory receptor subtype among the GPCRs for serotonin, although 5-HT2A may also have an inhibitory effect on certain areas such as the visual cortex and the orbitofrontal cortex.

[0046] The term “5-HT2A receptor agonist” refers to a substance that initiates a physiological response when combined with the 5-HT2A receptor. Activation of the 5- HT2A receptor is necessary for the effects of the "classic" psychedelics like LSD, psilocin and mescaline, which act as full or partial agonists at this receptor, and represent the three main classes of 5-HT2A agonists, the ergolines, tryptamines and phenethylamines, respectively. A very large family of derivatives from these three classes has been developed, and their structure-activity relationships have been extensively researched. Agonists acting at 5-HT2A receptors located on the apical dendrites of pyramidal cells within regions of the prefrontal cortex are believed to mediate hallucinogenic activity.

[0047] The term “5HTe receptor” refers to a subtype of 5HT receptor that binds the endogenous neurotransmitter serotonin ("5-HT" = 5-hydroxytryptamine, also known as serotonin). It is a G protein-coupled receptor (GPCR) that is coupled to Gs and mediates excitatory neurotransmission. HTR6 denotes the human gene encoding for the receptor.

[0048] The term “5-HTe receptor agonist” refers to a substance that initiates a physiological response when combined with the 5-HTe receptor.

[0049] The term “Alzheimer’s disease” or “AD” refers to a neurodegenerative disease that usually starts slowly and progressively worsens as it proliferates. Alzheimer’s disease is estimated to be the cause of 60-70% dementia cases, ‘dementia’ referring to an umbrella term that comprises cognitive disorders that impair memory, thinking, behavior and negatively affect a person’s ability to perform everyday activities.Specifically referring to Alzheimer’s disease, the most common symptom that leads to prognosis is a patient’s difficulty in remembering recent events.

[0050] As Alzheimer’s disease progresses, symptoms can include problems with language, disorientation (including a loss of sense-of-direction), mood swings, loss of motivation, self-neglect and further behavioral issues. Another unfortunate downside of Alzheimer’s disease is that patients who are afflicted with the disease tend to withdraw from family and society as their condition worsens.

[0051] It is believed that there are several environmental and genetic risk factors associated with the development of Alzheimer’s disease. Other risk factors may include a history of head injury, clinical depression and high blood pressure. Alzheimer’s disease and its progression is largely believed to be associated with amyloid plaques, neurofibrillary tangles and weakening neuronal connections in the brain.

[0052] The term “alcohol dependency” refers to a chronic medical condition that typically includes a current or past history of excessive drinking, a strong craving for alcohol, continued use despite repeated problems with drinking and an inability to control alcohol consumption.

[0053] The term “multiple sclerosis” or “MS” refers to an inflammatory demyelinating disease of the central nervous system (CNS) which involves a complex interaction between immune system and neural cells.

[0054] The term “transcriptional regulation” refers to the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Transcription factors are proteins that bind to specific DNA sequences in order to regulate the expression of a given gene.

[0055] Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of neural networks in the brain to change through growth and reorganization. These changes range from individual neuron pathways making new connections, to systematic adjustments like cortical remapping. Examples of neuroplasticity include circuit and network changes that result from learning a new ability, environmental influences, practice, and psychological stress. Activity-dependent plasticity can have significant implications for healthy development, learning, memory and recovery from brain damage.

[0056] The term “Neuroprotectin D1” or “NPD1” refers to a stereoselective bioactive product of DHA that exerts neuroprotection in models of experimental stroke by downregulating brain ischemia reperfusion (BIR)-induced leukocyte infiltration, proinflammatory signaling and infarct size. Further, NPD1 inhibits cytokine-mediated cyclooxygenase-2 (COX-2) expression. Moreover, neurotrophins are NPD1 -synthesis agonists, and NPD1 content is decreased in the CA1 region of the hippocampus of Alzheimer’s patients. Overall, NPD1 promotes brain cell survival via the induction of antiapoptotic and neuroprotective gene-expression programs that suppress Ap42 production and its neurotoxicity. Thus, NPD1 elicits potent cell-protective, antiinflammatory, pro-survival repair signaling.

[0057] As used herein, the term "prevention" means all of the actions by which the occurrence of the disease is restrained or retarded.

[0058] The term “treating” or “treatment” refers to one or more of (1 ) inhibiting the disease (i.e. , arresting further development of the pathology and / or symptomatology); and (2) ameliorating the disease (i.e., reversing the pathology and / or symptomatology) such as decreasing the severity of disease.

[0059] The term “prophylactic treatment” refers to any of: halting the onset, reducing the risk of development, reducing the incidence, delaying the onset, reducing the development, as well as increasing the time to onset of symptoms of a particulardisorder.

[0060] The term “prognosis” refers to the forecast or likely outcome of a disease. As used herein, it refers to the probable outcome of a neurodegenerative disease (e.g., AD or TBI) including whether the disease will respond to treatment or mitigation efforts and / or the likelihood that the disease will progress. The stage of AD can be considered in determining a prognosis of a subject.

[0061] The therapeutic agents in the pharmaceutical compositions can be formulated in a "therapeutically effective amount" or a "prophylactical ly effective amount." A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount may vary depending on the condition to be treated, the severity and course of the condition, the mode of administration, whether the agent is administered for preventive or therapeutic purposes, the bioavailability of the particular agent(s), the ability of the therapeutic small molecule to elicit a desired response in the individual, previous therapy, the age, weight and sex of the patient, the patient's clinical history and response to the agent, the type of the therapeutic small molecule used, discretion of the attending physician, etc. A therapeutically effective amount is also one in which any toxic or detrimental effects is outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result.

[0062] The term “dementia” generally refers to a range of conditions, diseases and disorders that affect the brain’s ability to think, remember and function normally.

[0063] The term “mild cognitive impairment” or “MCI” generally refers to the stage between the expected decline in memory and thinking that happens with age and the more serious decline of dementia. MCI may include problems with memory, language or judgment.

[0064] The term “Alzheimer’s disease” or “AD” generally refers to a neurodegenerative brain disorder that slowly destroys a person’s memory and thinking skills over time.

[0065] The term “preclinical Alzheimer’s disease” generally refers to the earliest stage of Alzheimer’s disease in which amyloid beta plaques form in the brain but do not present any outward and noticeable symptoms in the afflicted.

[0066] The term “early-stage Alzheimer’s disease” generally refers to individuals of any age who are experiencing mild symptoms of Alzheimer’s disease such as memory loss, misplacing items, forgetting familiar places and the names of familiar people.

[0067] The term “middle-stage Alzheimer’s disease” or “Moderate-stage Alzheimer’s disease” or “Moderate Alzheimer’s disease” generally refers to a greater decline in a person’s cognitive and functional abilities as compared to early-stage Alzheimer’s disease. Symptoms such as memory loss, difficulty in problem solving, and changes in personality become more pronounced and prevalent.

[0068] The term “late-stage Alzheimer’s disease” generally refers to severe dementia caused by Alzheimer’s disease. Those afflicted lose the ability to communicate coherently and experience a decline in physical abilities. Those with latestage Alzheimer’s disease require daily assistance with personal care and display a complete loss of short- and long-term memory.

[0069] The term “amyloid plaque” generally refers to sticky clumps of misfolded proteins that clog up the spaces in between brain cells.

[0070] The term “Lewy body” generally refers to a distinctive neuronal inclusion that is found in the substantia nigra and other specific brain regions in those who suffer from Parkinson’s disease and other disorders and diseases of dementia. Lewy bodies are abnormal aggregations of protein that develop inside nerve cells affected by Parkinson’sdisease and dementia diseases such as AD and Lewy body dementia. Lewy bodies appear as spherical masses in the cytoplasm that displace other cell components.

[0071] The term “neuronal autophagy,” “autophagy” or “type II programmed cell death” is characterized by the accumulation of autophagic vacuoles during cell death, along with toxic components such as proteins or damaged organelles. Excessive autophagy may lead to self-destruction and cell death. Autophagosomes have been identified in affected neurons of patients with AD, HD, and PD. Many stimuli also induce autophagy, including nutrient starvation, mitochondrial toxins, hypoxia, and oxidative stress.

[0072] The term “retrograde degeneration” refers to degeneration of the proximal neuronal cell body that can result from axonal injury or transection and may be associated with various pathological changes in the cell body, including apoptosis and chromatolysis of the neuronal perikaryon. The association of neuronal apoptosis with axonal damage suggests that inflammation-induced axotomy may produce retrograde (secondary) death of neuronal cell bodies via apoptosis.

[0073] The term “Wallerian degeneration” refers to proximal damage to the neuron or axon that can result in anterograde degeneration of the distal axon, termed Wallerian degeneration. Wallerian degeneration is a cascade of events that includes granular degeneration of the axonal cytoskeleton, accumulation of activated macrophages and microglia, and local changes in the immune environment. Evidence that Wallerian degeneration occurs in MS is seen in a histopathological study demonstrating inflammatory cervicomedullary junction lesion with distal axonal atrophy in the absence of demyelination, as well as in MRI studies.

[0074] The term “demyelination” refers to loss of myelin with relative preservation of the axon. The relationship between the oligodendrocyte and axon is complex, with the provision of mutual support through trophic factors that can be disrupted in demyelinating diseases. In addition to protecting the axon from immune-mediated damage, myelin integrity protects the integrity of the developing axon. Myelin- associated glycoprotein and proteol ipid protein deliver essential myelin-derived trophicsignals to axons. Mice lacking proteolipid protein developed axonal swellings and degeneration, suggesting that local oligodendroglial support is critical for axon survival.

[0075] The term “astrogliopathy” refers to dysfunction of astrocytes. Aging-related tau astrogliopathy (ARTAG) describes the pathological accumulation of abnormally phosphorylated tau protein in astrocytes that is found in AD, frontal temporal lobe dementias, and corticobasal degeneration. Neuromyelitis optica (NMO) presents with optic neuritis and myelitis and can mimic MS. NMO is associated with the presence of aquaporin-4 (AQP4) antibodies, which target astrocyte water channels. Pathologically NMO is characterized by extensive loss of immunoreactivity for the astrocytic proteins AQP4 and glial fibrillary acidic protein (GFAP), perivascular deposition of immunoglobulins, and activation of complement even within lesions with relative preservation of myelin.

[0076] The term “nanoparticle” refers to a particle of matter, generally between about 1 and 100 nanometers (nm) in diameter. As used herein, a nanoparticle can refer to a liposome, virus, viral vector or other viral particle.

[0077] The term “liposome” refers to a spherical vesicle having at least one lipid bilayer (i.e. an aqueous solution core surrounded by a hydrophobic membrane). Liposomes can be prepared by disrupting biological membranes (such as by sonication). Liposomes are formed when phospholipids and their derivatives are dispersed in water. Upon dispersion in water the phospholipids form closed vesicles called “liposomes,” which are characterized by lipid bilayers encapsulating an aqueous core. Various liposomes have been used as carriers for entrapped therapeutic agents, such as drugs, enzymes and genetic sequences for use in medical science, in pharmaceutical science and in biochemistry. Specific uses include delivery of nutrients and pharmaceutical drugs, such as lipid nanoparticles in mRNA vaccines and DNA vaccines. Liposomes can be modified by the incorporation of polyethylene glycol or other hydrophilic polymers (e.g., a PEG liposome where one or more of the constituent lipids is modified by attachment of PEG). Liposomes can also be modified to target particular cell types by incorporating targeting factors (e.g., “targeting ligands”) forparticular cell types. Examples include asialoglycoprotein, folate, transferrin, antibodies, etc.

[0078] The term “exosome” refers to a membrane-bound extracellular vesicles that are produced in the endosomal compartment of most eukaryotic cells. In multicellular organisms, exosomes and other EVs are found in biological fluids including saliva, blood, urine and cerebrospinal fluid. Exosomes are similar to liposomes in terms of consisting of bilayered phospholipids, but the biogenesis of exosomes ensures their biocompatibility and low toxicity. It also significantly complicates pharmaceutical development, production and safety profiling (immunogenicity, and potential biological impurities).

[0079] The term “miRNA” or “micro RNA,” “miRNA biomarkers,” or “MicroRNAs” refers to small, single-stranded, non-coding RNA molecules generally about 16 - 27 nucleotides in length. miRNAs base-pair to complementary sequences in mRNA molecules, then silence said mRNA molecules by one or more of the following processes: (a) cleavage of the mRNA strand into two pieces, (b) destabilization of the mRNA by shortening its poly(A) tail, or (c) reducing translation of the mRNA into proteins. In cells of humans and other animals, miRNAs primarily act by destabilizing the mRNA. miRNAs resemble the small interfering RNAs (siRNAs) of the RNA interference (RNAi) pathway, except miRNAs derive from regions of RNA transcripts that fold back on themselves to form short hairpins, whereas siRNAs derive from longer regions of double-stranded RNA. The human genome may encode over 1900 miRNAs. However, only about 500 human miRNAs represent bona fide miRNAs in the manually curated miRNA gene database MirGeneDB. Mature miRNA originates from the 5' arm or the 3' arm of the precursor product and is denoted with a -5p or -3p suffix, respectively.

[0080] miRNA sequences are publicly available. For example, miRBase (mirbase.org) includes a searchable database of annotated miRNA sequences. miRNA sequences are also available through other databases known to those in the art,including the National Center for Biotechnology Information (ncbi.nlm nih.gov). One can also identify targets for specific miRNAs utilizing public databases and algorithms, for example at MicroCosm Targets (ebi.ac.uk / enright-srv / microcosm / htdocs / targets / ), TargetScan (targetscan.org), and PicTar (pictar.mdc-berlin.de). Based on miRNA sequences from one organism (e.g., a mouse), one in the art can utilize the available databases to determine a corresponding miRNA from another organism (e.g., a human).

[0081] The nomenclature used herein will be understood by those in the art. MicroRNAs are named using the “mir” prefix and a unique identifying number (e.g., miR- 1 , miR-2, . . . miR-89, etc.). The genes that encode the miRNA are also named using the same three-letter prefix, with capitalization, hyphenation, and italics according to the conventions of the organism (for example, mir-1 in C. elegans and Drosophila, MIR156 in Arabidopsis and rice). The identifying numbers are assigned sequentially, with identical miRNAs having the same number, regardless of organism.

[0082] The term “miRNA mimic” or “mimetic” refers to miRNA that has the same sequence as the native or wild type miRNA, but has a modified backbone, a modified base, and / or a 5' or 3' end modification. In some examples an miRNA mimetic is may less susceptible to degradation or nuclease activity. In aspects, an miRNA mimic is an miRNA with at least one sequence modification and having 75% or higher sequence identity to a native or wild type miRNA and that also binds to the same mRNA(s) with similar affinity as the wild type or native miRNA. The disclosed miRNAs may also be both an miRNA mimetic and an miRNA mimic, for example, an miRNA with at least one sequence modification (e.g., 75% or higher sequence identity) to a wild type miRNA, and also having a modified backbone, base, and / or end modification.

[0083] The term “seed sequence” refers to a 6 - 8 nucleotide (nt) long substring within the first 8 nt at the 5'-end of the miRNA (i.e. , seed sequence) that is an important determinant of target specificity.

[0084] The term “agomir” refers to a synthetic oligonucleotide or oligonucleotide mimetic that functionally mimics a miRNA. An agomir can be an oligonucleotide withthe same or similar nucleic acid sequence to a miRNA or a portion of a miRNA. In certain embodiments, the agomir has 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleotide differences from the miRNA that it mimics. Further, agomirs can have the same length, a longer length or a shorter length than the miRNA that it mimics.

[0085] The term “messenger RNA” or “mRNA” refers to a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene and is read by a ribosome in the process of synthesizing a protein. As used herein, mRNA can also include “miRNA” and small interfering RNAs (siRNAs).

[0086] The term “composition” or “pharmaceutical composition” refers to a product with the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from such combinations of the specified ingredients in the specified amounts and one or more pharmaceutically acceptable carriers therefor.

[0087] The term “pharmaceutically acceptable carrier” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0088] The term "administration" refers to the introduction of an amount of a predetermined substance into a patient by a certain suitable method. The composition disclosed herein may be administered via any of the common routes, as long as it is able to reach a desired tissue, for example, but is not limited to, inhaling, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrapulmonary, or intrarectal administration.

[0089] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are to be understood as approximations inaccordance with common practice in the art. When used herein, the term “about” may connote variation (+) or (-) 1 %, 5% or 10% of the stated amount, as appropriate given the context. It is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0090] Many known and useful compounds and the like can be found in Remington’s Pharmaceutical Sciences (13thEd), Mack Publishing Company, Easton, PA — a standard reference for various types of administration. As used herein, the term “formulation(s)” means a combination of at least one active ingredient with one or more other ingredient, also commonly referred to as excipients, which may be independently active or inactive. The term “formulation” may or may not refer to a pharmaceutically acceptable composition for administration to humans or animals and may include compositions that are useful intermediates for storage or research purposes.

[0091] Other technical terms used herein have their ordinary meaning in the art that they are used, as exemplified by a variety of technical dictionaries. The particular values and configurations discussed in these non-limiting examples can be varied and are cited merely to illustrate at least one embodiment and are not intended to limit the scope thereof.DETAILED DESCRIPTION

[0092] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the subject technology as claimed. Additional features and advantages of the subject technology are set forth in the description below, and in part will be apparent from the description, or may be learned by practice of the subject technology. The advantages of the subject technology will be realized and attained by the structure particularly pointed out in the written description and claims hereof.Dementia

[0093] Dementia refers to a group of symptoms affecting memory, thinking and social abilities. It generally involves memory loss but symptoms include cognitive and psychological changes which gradually get worse as the disease progresses. Alzheimer's disease is the most common cause of dementia in older adults, but there are other causes of dementia. The pathophysiology of dementia is broadly characterized by the aggregation of misfolded proteins (e.g., amyloid-[3 plaques and neurofibrillary tangles in Alzheimer's disease) and cerebrovascular disease.Alzheimer’s disease

[0094] Alzheimer’s disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens as it proliferates. Alzheimer’s disease is estimated to be the cause of 60 - 70% of dementia cases. The most common symptom that leads to prognosis is difficulty remembering recent events. As Alzheimer’s disease progresses, symptoms can include problems with language, disorientation, mood swings, loss of motivation, self-neglect and further behavioral issues. Another unfortunate downside of Alzheimer’s disease is that patients who are afflicted with the disease tend to withdraw from family and society as their condition worsens.

[0095] It is believed that there are several environmental and genetic risk factors associated with the development of Alzheimer’s disease. Other risk factors may include a history of head injury, clinical depression and high blood pressure. Alzheimer’s disease and its progression is largely believed to be associated with amyloid plaques, neurofibrillary tangles and weakening neuronal connections in the brain.MicroRNA

[0096] MicroRNAs (miRNAs) belong to a class of small non-coding RNAs that are involved in development and diseases. miRNAs control gene expression by targeting mRNAs based on sequence complementarity. In addition to the dissection of their relevance for cellular processes, miRNAs also show great potential for diagnostic and therapeutic applications.

[0097] Disclosed herein are miRNAs that can be utilized to treat or inhibit aneurodegenerative disease. To identify miRNAs of potential regulatory, biologic, and / or therapeutic importance, Applicant employed an integrated approach that combined structural and functional genomic analyses. The Applicant compared analysis of expression of miRNAs and inversely correlated mRNAs from a validation data set. Integration of data and a functional screen of an miRNA library uncovered five miRNAs of particular relevance: MIR-145-3p, let-7 c-3p, MIR-383-5p, MIR-548aj-3p and MIR- 548x-3p.

[0098] Embodiments include methods for prevention and treatment of neurological disorders (e.g., dementia and AD) using pharmaceutical compositions that include specific miRNAs. In aspects, the miRNAs include one or more of (a) MIR-145-3p, (b) let-7 c-3p, (c) MIR-383-5p, (d) MIR-548aj-3p and (e) MIR-548x-3p. In aspects, the miRNAs are administered using a lipid-based delivery (e.g., liposomes). In embodiments, the miRNAs are non-coding and act as repressors on one or more sites.

[0099] In contrast to small interfering RNA (siRNA), miRNA-targeted therapy can influence not just a single gene, but entire cellular pathways or processes. It is possible to supplement down regulated or non-functional miRNAs by synthetic oligonucleotides, as well as alleviating effects caused by overexpression of malignant miRNAs through artificial antagonists, either oligonucleotides or small molecules. Thus, in aspects, the miRNAs are non-coding and act as repressors on one or more sites. hsa-mir-145-3p

[0100] MIR145 is a microRNA that has been found to be involved in various biological processes and diseases. Recent studies have shown that (human) hsa-miR- 145-3p is involved in two processes which are pivotal for the treatment of Alzheimer’s including (a) the epigenetic pattern age regression in neurons and astrocytes and (b) the reduction in both speed and volume of production of beta amyloid protein. hsa-let-7c-3p5, 6, 7

[0101] Two major biological roles have been elucidated for the let-7 miRNA: as an essential regulator of terminal differentiation, and as a fundamental tumor suppressor.This non-coding RNA which reduces expression of Interleukin 8 (IL-8) via the CDH11- TGF[3 pathway. In Alzheimer’s IL-8 is involved upstream of Tau phosphorylation and neurofilament tangle (NFT) formation. Increased cerebrospinal fluid (CSF) levels of IL-8 are correlated with the amyloid A[3-42 / A[3-40 ratio, MMSE[WL1 ], Tau and pTau181. In aspects, one or more of hsa-let-7c-3p5, hsa-let-7c-3p6 and hsa-let-7c-3p7 is administered. hsa-mir-3833p and 5p

[0102] Down-regulated expression of anti-tumor miR-383 has been found in many kinds of cancer. MiR-383 family members can directly target the 3'-untranslated region (3'-UTR) of the mRNA of some pro-tumor genes to attenuate several cancer-related processes, including cell proliferation, invasion, migration, angiogenesis, immunosuppression, epithelial-mesenchymal transition, glycolysis, chemoresistance, and the development of cancer stem cells, whilst promoting apoptosis. These two miRNAs (3p and 5p2) are involved in reducing overall necroptosis of neurons in Alzheimer’s disease. In aspects, one or more of hsa-mir-383 and hsa-mir-383 5p is administered. hsa-mir-548aj-3p

[0103] Recent studies demonstrate that mir-548aj-3p Improves overall functional survivability of Neurons. hsa-mir-548x-3p

[0104] Recent studies demonstrate that mir-548x-3p Improves overall functional survivability of Neurons.Small molecule therapeutics

[0105] Embodiments of the invention relate to the fields of addiction and mental health. Particular embodiments include compounds and methods for treating mental health ailments and / or addictions. Specifically, aspects of the invention include novel compounds that are selective HT2A and HTe receptor agonists. The compounds werevalidated in silico and screened for targeting, ADME (i.e., absorption, distribution, metabolism and excretion) and toxicity.

[0106] The 5-HT2A receptor is a widely expressed Gq-coupled protein receptor (GCPR) that triggers a range of intracellular pathways. Central nervous system (CNS) expression of the 5-HT2A receptor is most extensive in the cortex, hippocampus, basal ganglia, and forebrain. Because these areas of the CNS are primarily involved with cognitive function and social interactions, 5-HT2A is implicated in the pathology of several cognitive and learning disorders including schizophrenia, obsessive-compulsive disorder (OCD) and depression. The highest density of 5-HT2A receptors is found in levels 1 , 4, and 5a of the cortex, with medial expression levels in the olfactory bulb, brainstem, and dorsal horn of the spinal cord. 5-HT2A is also expressed by a range of CNS cells, including pyramidal neurons and glia, and has several intracellular locations.

[0107] The 5-HTe receptor is a G-protein-l inked receptor, and is expressed primarily in the striatum, olfactory tubercle, frontal and entorhinal cortex, nucleus accumbens, hippocampus and molecular layer of the cerebellum. Pharmacological blockade of 5- HT6receptor had been shown to produce promnesic or antiamnesic effects (or both) in a number of memory tasks, and emergent evidence indicates that its agonists also seem facilitate memory in diverse memory tasks; the reasons for apparent paradox of promnesic and / or anti amnesic effects of 5-HTe receptor agonists and antagonists are unclear. The development of potent and selective 5-HTe receptor antagonists has been crucial in the clarification of the role of 5-HTe receptor role on memory; in addition, the findings that 5-HTe receptor agonists can improve memory are providing new insights.

[0108] Applicants have discovered that agonists of 5-HT2A receptor and 5-HTe receptor can be used therapeutically to treat neurodegenerative diseases. Accordingly, embodiments include selective HT2A and HTe agonists that can be used therapeutically. In aspects, the compounds are capable of crossing the blood brain barrier to reach a target tissue.

[0109] Further validation of the compounds indicated the need for brain-availablethiamine as a co-factor in fentanyl addiction treatment. Applicants evaluated target molecules for activity that would be selective HT2A and HT6A agonists along with coadministration of the pro-drug sulbutiamine.

[0110] Accordingly, one embodiment is a formulation that includes small molecule therapeutics to treat a neurodegenerative disease. In aspects, the small molecule therapeutics include (a) GATC-49, (b) fucosterol and (c) fucoidan. One embodiment is a formulation that includes microRNAs and small molecule therapeutics. In aspects, the microRNAs include (a) MIR-145-3p, (b) let-7 c-3p, (c) MIR-383-5p, (d) MIR-548aj-3p and (e) MIR-548x-3p and the small molecule therapeutics include (a) GATC-49, (b) fucosterol and (c) fucoidan.GATC-49

[0111] In aspects, the formulations and methods described herein include a compound of GATC-49, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.GATC-49Recent studies demonstrate that this small molecule compound functions to improve plasticity and dendritic arborization in the brain via selective modulation of 5ht2R and 5ht6R.Fucosterol

[0112] In aspects, the formulations and methods described herein include fucosterol, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof. This small molecule can inhibit the aggregation of betaamyloid proteins. Its lUPAC name is (3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17- [(Z,2R)-5-propan-2-ylhept-5-en-2-yl]-2,3,4,7,8,9, 11 , 12, 14, 15, 16, 17-dodecahydro-1 H- cyclopenta[a]phenanthren-3-olFucosterol has been recognized as an antioxidant and a hepatoprotective agent.Fucoidan

[0113] In aspects, the formulations and methods described herein include fucoidan, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.Recent studies have demonstrated that fucoidan can inhibit the clustering of microglial cells induced by A[34. Its IIIPAC name is [(2S,3S,4S,5S,6R)-4-hydroxy-5-methoxy-2,6- dimethyloxan-3-yl] hydrogen sulfate.

[0114] Accordingly, embodiments include methods of treating an ailment such as a neurodegenerative disease that includes administering microRNAs and small moleculetherapeutics. FIG. 1 is a flowchart that depicts neurodegenerative disorders, related disorders and compounds that can be administered to reduce / alleviate the disorders. Other neurodegenerative disorders include, for example, dementia, frontotemporal dementia, non-specific dementia, Alzheimer-type dementia or Alzheimer’s disease (AD). The miRNA therapeutics can be administered using liposomes. Further, the liposome surface can be loaded with different substances, such as polyethylene glycol (extending their systemic half-life) or molecular recognition moieties like aptamers for specific binding to targeted cells.

[0115] A compound of a given Formula (e.g., the “compound of Formula GATC-49”) is intended to encompass the compounds of the disclosure, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, hydrates, polymorphs, and prodrugs of such compounds. Additionally, the compounds of the disclosure may possess one or more asymmetric centers and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of a given Formula depends upon the number of asymmetric centers present (there are 2n stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound by conventional means. The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present invention, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated.Methods of Treatment

[0116] Embodiments include formulations and methods to treat neurodegenerative diseases such as dementia and Alzheimer’s disease (AD). In aspects, the treatment improves neural function, increases neuroplasticity, improves a prognosis and / or improves signs / symptoms of neurodegeneration.

[0117] The compounds described herein can be administered in various forms, depending on the disorder to be treated and the age, condition, and body weight of the patient, as is well known in the art. For example, where the compositions are to be administered orally, they may be formulated as tablets, capsules, granules, powders, or syrups; or for parenteral administration, they may be formulated as injections (intravenous, intramuscular, or subcutaneous), drop infusion preparations, or suppositories. Any suitable route or mode of administration can be employed for providing the patient with a therapeutically or prophylactically effective dose of the therapeutic peptide. Exemplary routes or modes of administration include parenteral (e.g., intravenous, intraarterial, intramuscular, subcutaneous, intratumoral), oral, topical (nasal, transdermal, intradermal or intraocular), mucosal (e.g., nasal, sublingual, buccal, rectal, vaginal), inhalation, intralymphatic, intraspinal, intracranial, intraperitoneal, intratracheal, intravesical, intrathecal, enteral, intrapulmonary, intralymphatic, intracavital, intraorbital, intracapsular and transurethral, as well as local delivery by catheter or stent.

[0118] The methods described herein can be used to treat numerous disorders related to neurodegeneration including post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain-Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headaches, encephalitis and myasthenia gravis.

[0119] A pharmaceutical formulation in accordance with the present disclosure can be formulated in any pharmaceutically acceptable carrier(s) or excipient(s). Pharmaceutical compositions can include suitable solid or gel phase carriers or excipients. Exemplary carriers or excipients include calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Exemplary pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. In many cases it will be preferable to includeisotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically acceptable carriers can further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the therapeutic agents.

[0120] The therapeutic compounds can be incorporated into a pharmaceutical composition suitable for parenteral administration. Suitable buffers include, for example, sodium succinate, sodium citrate, sodium phosphate or potassium phosphate. Sodium chloride can be used to modify the toxicity of the solution at a concentration of 0 - 300 mM (optimally 150 mM for a liquid dosage form). Cryoprotectants can be included for a lyophilized dosage form, principally 0 - 10% sucrose (optimally 0.5 - 1.0%). Other suitable cryoprotectants include trehalose and lactose. Bulking agents can be included for a lyophilized dosage form, principally 1 - 10% mannitol (optimally 2 - 4%).Stabilizers can be used in both liquid and lyophilized dosage forms, principally 1 - 50 mM L-Methionine (optimally 5 - 10 mM). Other suitable bulking agents include glycine, arginine, can be included as 0 - 0.05%> polysorbate-80 (optimally 0.005 - 0.0 1 %). Additional surfactants include but are not limited to polysorbate 20 and BRU surfactants.

[0121] Therapeutic preparations can be lyophilized and stored as sterile powders, preferably under vacuum, and then reconstituted in bacteriostatic water (containing, for example, benzyl alcohol preservative) or in sterile water prior to injection.Pharmaceutical compositions can be formulated for parenteral administration by injection e.g., by bolus injection or continuous infusion.

[0122] The therapeutic compounds can be administered as a preventive measure (i.e. , to avoid an ailment) at one time or multiple times. Alternatively, the therapeutic small molecule is suitably administered to the patient at one time or over a series of treatments and may be administered to the patient at any time from diagnosis onwards. The therapeutic small molecule may be administered as the sole treatment or in conjunction with other drugs or therapies useful in treating the condition in question.

[0123] Certain embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the present invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0124] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.Delivery Vehicles

[0125] Therapeutics that utilize miRNA can require efforts to promote stability and / or delivery of miRNA to the target site. To arrive at a target site they must be resistant to nuclease degradation in the extracellular space. To resolve this problem, chemical modifications of oligonucleotides can be designed to enhance delivery efficiency. Presently, there are ten FDA-approved oligonucleotide drugs, most of which are chemically modified. These drugs are mostly delivered locally or to the liver. The nucleic acid backbone, ribose sugar moiety and nucleobase itself can all be chemically modified to enhance delivery using locked nucleic acids (LNAs), 5' -(E)- vinylphosphonate modification and pyrimidine methylation. Cobomarsen is an oligonucleotide with chemical modification (partially LNA, full PS backbone) that doesnot require an additional delivery system. However, chemical modification of miRNA inhibitors cannot target specific tumour sites in vivo. Hence, covalent conjugation of specific moieties to miRNAs, mimetics or inhibitors promotes the uptake of oligonucleotide drugs to specific tissues. The moieties vary, including peptides, antibodies, aptamers and sugars. For example, N-acetylgalactosamine (GalNAc)- conjugated miR-122 was developed to treat hepatitis C virus infection of the liver (Miravirsen, Roche, Switzerland). GalNAc specifically binds to the Asialoglycoprotein receptor on the cell surface of hepatocytes. The interaction between GalNAc and the Asialoglycoprotein receptor leads to the endocytosis of GalNAc-conjugated oligonucleotide drugs. Asialoglycoprotein receptor is highly expressed on hepatocytes, so GalNAc-conjugated oligonucleotides can be specifically taken up by hepatocytes. It should be noted that chemical modification might prevent miRNA mimetic recognition and loading into Argonaute and RISC.

[0126] In addition to the conjugation of various moieties, miRNAs, miRNA mimetics or inhibitors can also be packaged into nanoparticles to increase uptake efficiency. Advances in nanotechnology and material science present versatile solutions for oligonucleotide drug delivery. The most commonly used nanotechnology for nucleic acid drugs is lipid formulations. MRX34 is a double-stranded miR-34 mimetic in liposome nanoparticles. Pharmacodynamic data indicated that MRX34 suppressed miR-34 targets in the white blood cells of enrolled patients.

[0127] Among those, lipid-based delivery is a popular approach. The classical approach consists of a mixture of lipids with cationic head groups and helper lipids, including some with polyethylene glycol chains for masking of the surface charge. Polyanionic nucleic acids are electrostatically complexed to the cationic lipid, yielding lipoplexes. A high degree of optimization of those formulations, both in terms of structures and multi-component compositions, has been achieved, and loading capacity and delivery efficiency have been increased to considerably lower the dose necessary for functional effects. However, they still suffer from inherent toxicity, which is, like uptake and re-release efficiency, closely linked to the cationic surface charge.Examples of the in vivo use of lipoplexes include the delivery of miR-133b and miR-29b with a mixture of DOTMA, cholesterol and a PEG lipid, pre-miR-107 with DDAB, cholesterol and PEG lipids, and the use of solid lipid nanoparticles consisting of DDAB, cholesterol and other components for delivery of miR-34a.Polymers

[0128] The cationic polymer polyethylene imine (PEI) is the most widely used polymeric delivery system for plasmid DNA and siRNA. Efficient packaging and a net cationic charge ensure adequate shielding and sufficient interaction with anionic polysaccharides on cell membranes. PEI is thought to increase endosomal escape by the proton sponge effect, an influx of hydrogen ions into acidic endosomes, resulting in swelling and disruption of the intracellular vesicles. Thus, PEI has quickly been adopted for delivery of miRNA mimics.

[0129] PEI can also be used as carrier system for targeted delivery by attaching specific ligands to the polymer. For an miRNA application, the rabies peptide RVG was attached to PEI for transport to and across the blood-brain barrier. In mice, fluorescently tagged miR-124a was found in higher accumulation in the brain compared to underivatized PEI. However, no functional effects were reported, and mannitol was necessary for sufficient blood-brain barrier permeabilization, which limits the therapeutic utility.

[0130] Poly(lactic-co-glycolic acid) (PLGA) is a polymer that has been utilized for antisense and siRNA delivery. PLGA needs to be coated or functionalized for efficient oligonucleotide delivery, but affords long-term dissociation from the carrier for a prolonged effect. While no studies with miRNA mimics delivered with PLGA have been reported, oligonucleotides for antagonizing miRNAs have been successfully delivered to tumours. Coating with cationic peptides nona-arginine or penetratin afforded passive tumour accumulation of an antisense peptide nucleic acid targeted at miR-155 in lymphoma in vivo.

[0131] The use of targeted silica nanoparticles for miRNA delivery resulted inreduction of neuroblastoma growth. The oligonucleotide cargo is noncovalently entrapped in the silica matrix, and dissociates upon hydrolysis of the matrix. Since this anorganic carrier will not be taken up into cells on its own, a receptor-targeting ligand is necessary to achieve intracellular delivery. Grafting an antibody against the cell surface antigen disialoganglioside GD2 afforded successful delivery of miR-34a into neuroblastoma cells in a murine xenograft model.Conjugates

[0132] Conjugation of lipids or receptor-binding molecules directly to the nucleic acid is a promising way to increase cellular uptake of siRNA, and has also been explored for miRNA applications. By attaching cholesterol to the 3'-end of the passenger strand, an accumulation in liver tissue can be achieved. The restriction to liver targeting and the high doses needed for sufficient delivery limit the use of cholesterol- and similar conjugates to scientific rather than therapeutic applications.

[0133] The asialoglycoprotein receptor ligand N-acetylgalactosamine (GalNAc) has been intensively used for targeting siRNA and antisense oligonucleotides to hepatocytes

[0012] , with several agents already advanced to clinical evaluation. For achieving hepatocyte delivery of an anti-miR-122, a covalent conjugate with GalNAc has been developed. The respective compound RG-101 , developed for treatment of HCV infections, has recently begun testing in human volunteers

[0156] , In preclinical animal models, RG-101 showed efficient reduction of viral titers, and a good safety profile.Exosomes and Bacteriophages

[0134] Circulating miRNAs are found in body fluids (plasma, saliva, etc.) and are exchanged between cells despite the abundance of nucleases throughout the body. Natural shielding of endogenous miRNAs is afforded through extracellular vesicles, called exosomes. They are small membrane vesicles (up to 100 nm), and are produced by many cell types, including epithelial, dendritic, and immune cells. Lately, exosomes have been used to encapsule and deliver synthetic or endogenously expressed siRNAs and miRNAs in vivo. The oligonucleotide cargo can be introduced by transfection ofcorresponding plasmid into exosome-producing cells, or synthetic oligonucleotides can be inferred through electroporation of the mature exosomes. For miRNA delivery, transfection of exosome-producing HEK293 cells with synthetic let-7 was employed to produce miRNA containing exosomes. A peptide binding to the EGF-receptor was introduced by means of a peptide-encoding plasmid. Exosomes distribute preferentially to the reticuloendothelial system (RES), and thus the spleen and liver, but are also found in other organs. Targeting can be achieved through specific ligands, which can be expressed through genetic engineering methodology. Using the RVG peptide, siRNA-containing exosomes were even shown to cross the blood-brain barrier. Targeting and biodistribution of exosomes is also dependent on the cell type they are isolated from. Exosomes are similar to liposomes in terms of consisting of bilayered phospholipids, but the biogenesis of exosomes ensures their biocompatibility and low toxicity. It also significantly complicates pharmaceutical development, production and safety profiling (immunogenicity, and potential biological impurities).

[0135] Bacteriophages have been used to develop virus-like particles for oligonucleotide and drug delivery. The MS2 bacteriophage was modified to produce particles with covalent linkage to pre-m iR-146a. After grafting the HIV-TAT peptide to the particles, the system induced a two-fold higher expression of m iR-146a in vivo. A similar approach used RNA from bacteriophage Phi29 for packaging miRNAs targeted at coxsackievirus B3. Conjugation of folic acid was used for folate-specific cellular uptake to result in reduction of viral replication in an in vitro model. Similar to exosomes, concerns of immune responses triggered by virus-like particles need to be addressed before further development of bacteriophage-derived particles into clinical evaluation.Administration

[0136] The formulations described herein can be suitably administered to the patient at one time or over a series of treatments and may be administered to the patient at any time from diagnosis onwards. Alternatively, it can be administered as a preventive measure (i.e. to avoid infection). The solution can be administered as thesole treatment or in conjunction with other drugs or therapies useful in treating the condition in question.

[0137] As a general proposition, a therapeutically effective amount or prophylactical ly effective amount of therapeutic agents in the pharmaceutical compositions will be each administered in a range from about 1 ng / kg body weight to about 100 mg / kg body weight whether by one or more administrations. In a particular embodiment, each therapeutic small molecule is administered in the range of from about 1 ng / kg body weight to about 10 mg / kg body weight, about 1 ng / kg body weight to about 1 mg / kg body weight, about 1 ng / kg body weight to about 100 g / kg body weight, about 1 ng / kg body weight to about 10 g / kg body weight, about 1 ng / kg body weight / day to about 1 g / kg body weight, about 1 ng / kg body weight to about 100 ng / kg body weight, about 1 ng / kg body weight to about 10 ng / kg body weight, about 10 ng / kg body weight to about 100 mg / kg body weight, about 10 ng / kg body weight to about 10 mg / kg body weight, about 10 ng / kg body weight to about 1 mg / kg body weight, about 10 ng / kg body weight / to about 100 g / kg body weight, about 10 ng / kg body weight to about 10 mg / kg body weight, about 10 ng / kg body weight to about 1 mg / kg body weight, 10 ng / kg body weight to about 100 ng / kg body weight / , about 100 ng / kg body weight to about 100 mg / kg body weight, about 100 ng / kg body weight to about 10 mg / kg body weight, about 100 ng / kg body weight to about 1 mg / kg body weight, about 100 ng / kg body weight to about 100 mg / kg body weight, about 100 ng / kg body weight to about 10 mg / kg body weight, about 100 ng / kg body weight to about 1 mg / kg body weight, about 1 mg / kg body weight to about 100 mg / kg body weight, about 1 mg / kg body weight to about 10 mg / kg body weight / day, about 1 mg / kg body weight to about 1 mg / kg body weight, about 1 mg / kg body weight to about 100 mg / kg body weight, about 1 mg / kg body weight to about 10 mg / kg body weight, about 10 mg / kg body weight to about 100 mg / kg body weight, about 10 mg / kg body weight to about 10 mg / kg body weight, about 10 mg / kg body weight to about 1 mg / kg body weight / day, about 10 mg / kg body weight to about 100 mg / kg body weight, about 100 mg / kg body weight / day to about 100 mg / kg body weight, about 100 mg / kg body weight / day to about 10 mg / kg body weight, about 100 mg / kg body weight / day to about 1 mg / kg body weight, about 1 mg / kg body weight to about 100 mg / kg body weight, about 1 mg / kg body weight to about 10 mg / kg body weight, about10 mg / kg body weight to about 100 mg / kg body weight / day.

[0138] In other embodiments, the compounds described herein are each administered in the range of about 10 ng to about 100 ng per individual administration, about 10 ng to about 1 g per individual administration, about 10 ng to about 10 g per individual administration, about 10 ng to about 100 mg per individual administration, about 10 ng to about 1 mg per individual administration, about 10 ng to about 10 mg per individual administration, about 10 ng to about 100 mg per individual administration, about 10 ng to about 1000 mg per injection, about 10 ng to about 10,000 mg per individual administration, about 100 ng to about 1 mg per individual administration, about 100 ng to about 10 mg per individual administration, about 100 ng to about 100 mg per individual administration, about 100 ng to about 1 mg per individual administration, about 100 ng to about 10 mg per individual administration, about 100 ng to about 100 mg per individual administration, about 100 ng to about 1000 mg per injection, about 100 ng to about 10,000 mg per individual administration, about 1 mg to about 10 mg per individual administration, about 1 mg to about 100 mg per individual administration, about 1 mg to about 1 mg per individual administration, about 1 mg to about 10 mg per individual administration, about 1 mg to about 100 mg per individual administration, about 1 mg to about 1000 mg per injection, about 1 mg to about 10,000 mg per individual administration, about 10 mg to about 100 mg per individual administration, about 10 mg to about 1 mg per individual administration, about 10 mg to about 10 mg per individual administration, about 10 mg to about 100 mg per individual administration, about 10 mg to about 1000 mg per injection, about 10 mg to about 10,000 mg per individual administration, about 100 mg to about 1 mg per individual administration, about 100 mg to about 10 mg per individual administration, about 100 mg to about 100 mg per individual administration, about 100 mg to about 1000 mg per injection, about 100 mg to about 10,000 mg per individual administration, about 1 mg to about 10 mg per individual administration, about 1 mg to about 100 mg per individual administration, about 1 mg to about 1000 mg per injection, about 1 mg to about 10,000 mg per individual administration, about 10 mg to about 100 mg per individual administration, about 10 mg to about 1000 mg per injection, about 10 mg to about 10,000 mg per individual administration, about 100 mg to about 1000 mg per injection,about 100 mg to about 10,000 mg per individual administration and about 1000 mg to about 10,000 mg per individual administration. The therapeutic small molecule may be administered daily, every 2, 3, 4, 5, 6, 7 or 10 days, or every 1 , 2, 3 or 4 weeks.

[0139] In other particular embodiments, the amount of the compounds described herein can each be administered at a dose of about 0.0006 mg, 0.001 mg, 0.003 mg, 0.006 mg, 0.01 mg, 0.03 mg, 0.06 mg, 0.1 mg, 0.3 mg, 0.6 mg, 1 mg, 3 mg, 6 mg, 10 mg, 30 mg, 60 mg, 100 mg, 300 mg, 600 mg, 1000 mg, 2000 mg, 5000 mg or 10,000 mg. As expected, the dosage will be dependent on the condition, size, age and condition of the patient.

[0140] Alternatively, the formulations described herein can include equal amounts of each compound. In aspects, the total amount administered for a therapeutic effect is 250 mg / day to 500 mg / day. In other embodiments, the total (combined) amount of the compounds described herein is administered at a dose of about 0.0006 mg, 0.001 mg, 0.003 mg, 0.006 mg, 0.01 mg, 0.03 mg, 0.06 mg, 0.1 mg, 0.3 mg, 0.6 mg, 1 mg, 3 mg, 6 mg, 10 mg, 30 mg, 60 mg, 100 mg, 300 mg, 600 mg, 1000 mg, 2000 mg, 5000 mg or 10,000 mg.

[0141] In other aspects of this embodiment, a pharmaceutical composition compound disclosed herein reduces signs / symptoms of an ailment such as a neurological disorder by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In yet other aspects of this embodiment, a pharmaceutical composition disclosed herein reduces signs / symptoms of an ailment such as a neurological disorder from, e.g., about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% toabout 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0142] A pharmaceutical composition disclosed herein is in an amount sufficient to allow customary administration to an individual. In aspects of this embodiment, a pharmaceutical composition disclosed herein can be, e.g., at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a pharmaceutical composition. In other aspects of this embodiment, a pharmaceutical composition disclosed herein may be, e.g., at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 ,000 mg, at least 1 ,100 mg, at least 1 ,200 mg, at least 1 ,300 mg, at least 1 ,400 mg, or at least 1 ,500 mg of a pharmaceutical composition. In yet other aspects of this embodiment, a pharmaceutical composition disclosed herein may be in the range of, e.g., about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1 ,000 mg, about 850 mg to about 1 ,200 mg, or about 1 ,000 mg to about 1 ,500 mg. In still other aspects of this embodiment, a pharmaceutical composition disclosed herein may be in the range of, e.g., about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1 ,000 mg, about 10 mg to about 1 ,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1 ,000 mg, about 50 mg to about 1 ,500 mg, about 100 mg to about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1 ,000 mg, about 100 mg to about 1 ,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1 ,000 mg, about 200 mg to about 1 ,500 mg, about 5 mg to about 1 ,500 mg, about 5 mg to about 1 ,000 mg, or about 5 mg to about250 mg.

[0143] A pharmaceutical composition disclosed herein can include a solvent, emulsion or other diluent in an amount sufficient to dissolve a pharmaceutical composition disclosed herein. In other aspects of this embodiment, a pharmaceutical composition disclosed herein may comprise a solvent, emulsion or a diluent in an amount of, e.g., less than about 90% (v / v), less than about 80% (v / v), less than about 70% (v / v), less than about 65% (v / v), less than about 60% (v / v), less than about 55% (v / v), less than about 50% (v / v), less than about 45% (v / v), less than about 40% (v / v), less than about 35% (v / v), less than about 30% (v / v), less than about 25% (v / v), less than about 20% (v / v), less than about 15% (v / v), less than about 10% (v / v), less than about 5% (v / v), or less than about 1 % (v / v). In other aspects of this embodiment, a pharmaceutical composition disclosed herein may comprise a solvent, emulsion or other diluent in an amount in a range of, e.g., about 1 % (v / v) to 90% (v / v), about 1 % (v / v) to 70% (v / v), about 1 % (v / v) to 60% (v / v), about 1 % (v / v) to 50% (v / v), about 1 % (v / v) to40% (v / v), about 1 % (v / v) to 30% (v / v), about 1 % (v / v) to 20% (v / v), about 1 % (v / v) to10% (v / v), about 2% (v / v) to 50% (v / v), about 2% (v / v) to 40% (v / v), about 2% (v / v) to30% (v / v), about 2% (v / v) to 20% (v / v), about 2% (v / v) to 10% (v / v), about 4% (v / v) to50% (v / v), about 4% (v / v) to 40% (v / v), about 4% (v / v) to 30% (v / v), about 4% (v / v) to20% (v / v), about 4% (v / v) to 10% (v / v), about 6% (v / v) to 50% (v / v), about 6% (v / v) to40% (v / v), about 6% (v / v) to 30% (v / v), about 6% (v / v) to 20% (v / v), about 6% (v / v) to10% (v / v), about 8% (v / v) to 50% (v / v), about 8% (v / v) to 40% (v / v), about 8% (v / v) to30% (v / v), about 8% (v / v) to 20% (v / v), about 8% (v / v) to 15% (v / v), or about 8% (v / v) to 12% (v / v).

[0144] The final concentration of a pharmaceutical composition disclosed herein in a pharmaceutical composition disclosed herein can be of any concentration desired. In an aspect of this embodiment, the final concentration of a pharmaceutical composition in a pharmaceutical composition may be a therapeutically effective amount. In other aspects of this embodiment, the final concentration of a pharmaceutical composition in a pharmaceutical composition may be, e.g., at least 0.00001 mg / mL, at least 0.0001 mg / mL, at least 0.001 mg / mL, at least 0.01 mg / mL, at least 0.1 mg / mL, at least 1mg / mL, at least 10 mg / mL, at least 25 mg / mL, at least 50 mg / mL, at least 100 mg / mL, at least 200 mg / mL or at least 500 mg / mL. In other aspects of this embodiment, the final concentration of a pharmaceutical composition in a pharmaceutical composition may be in a range of, e.g., about 0.00001 mg / mL to about 3,000 mg / mL, about 0.0001 mg / mL to about 3,000 mg / mL, about 0.01 mg / mL to about 3,000 mg / mL, about 0.1 mg / mL to about 3,000 mg / mL, about 1 mg / mL to about 3,000 mg / mL, about 250 mg / mL to about 3,000 mg / mL, about 500 mg / mL to about 3,000 mg / mL, about 750 mg / mL to about 3,000 mg / mL, about 1 ,000 mg / mL to about 3,000 mg / mL, about 100 mg / mL to about 2,000 mg / mL, about 250 mg / mL to about 2,000 mg / mL, about 500 mg / mL to about 2,000 mg / mL, about 750 mg / mL to about 2,000 mg / mL, about 1 ,000 mg / mL to about 2,000 mg / mL, about 100 mg / mL to about 1 ,500 mg / mL, about 250 mg / mL to about 1 ,500 mg / mL, about 500 mg / mL to about 1 ,500 mg / mL, about 750 mg / mL to about 1 ,500 mg / mL, about 1 ,000 mg / mL to about 1 ,500 mg / mL, about 100 mg / mL to about 1 ,200 mg / mL, about 250 mg / mL to about 1 ,200 mg / mL, about 500 mg / mL to about 1 ,200 mg / mL, about 750 mg / mL to about 1 ,200 mg / mL, about 1 ,000 mg / mL to about 1 ,200 mg / mL, about 100 mg / mL to about 1 ,000 mg / mL, about 250 mg / mL to about 1 ,000 mg / mL, about 500 mg / mL to about 1 ,000 mg / mL, about 750 mg / mL to about 1 ,000 mg / mL, about 100 mg / mL to about 750 mg / mL, about 250 mg / mL to about 750 mg / mL, about 500 mg / mL to about 750 mg / mL, about 100 mg / mL to about 500 mg / mL, about 250 mg / mL to about 500 mg / mL, about 0.00001 mg / mL to about 0.0001 mg / mL, about 0.00001 mg / mL to about 0.001 mg / mL, about 0.00001 mg / mL to about 0.01 mg / mL, about 0.00001 mg / mL to about 0.1 mg / mL, about 0.00001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 0.01 mg / mL, about 0.001 mg / mL to about 0.1 mg / mL, about 0.001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 10 mg / mL, or about 0.001 mg / mL to about 100 mg / mL.

[0145] Aspects of the present specification disclose, in part, treating an individual who is susceptible to an ailment (e.g., a neurological disorder) or suffering from an ailment. As used herein, the term "treating," refers to reducing or eliminating the signs / symptoms of the ailment; or lowering or depleting signs / symptoms. For example, the term "treating" can mean reducing a symptom of a condition characterized by an ailment, by, e.g., at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, atleast 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 95%, or at least 100%. Those of skill in the art will know the appropriate symptoms or indicators associated with a specific type of ailment and will know how to determine if an individual is a candidate for treatment as disclosed herein.

[0146] In aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces signs / symptoms of an ailment, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 100%. In other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces signs / symptoms of an ailment by, e.g., at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 95% or at most 100%. In yet other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces signs / symptoms of an ailment by, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0147] In yet other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein generally is in the range of about 0.001 mg / kg to about 100 mg / kg and administered, for example, every 3, 5, 7, 10 or 14 days. In aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein may be, e.g., at least 0.001 mg / kg, at least 0.01 mg / kg, at least 0.1 mg / kg, at least 1 .0 mg / kg, at least 5.0 mg / kg, at least 10 mg / kg, at least 15 mg / kg, atleast 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 45 mg / kg, or at least 50 mg / kg and administered, for example, every 3, 5, 7, 10 or 14 days. In other aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein may be in the range of, e.g., about 0.001 mg / kg to about 10 mg / kg, about 0.001 mg / kg / day to about 15 mg / kg, about 0.001 mg / kg to about 20 mg / kg, about 0.001 mg / kg to about 25 mg / kg, about 0.001 mg / kg to about 30 mg / kg, about 0.001 mg / kg to about 35 mg / kg, about 0.001 mg / kg to about 40 mg / kg, about 0.001 mg / kg to about 45 mg / kg, about 0.001 mg / kg to about 50 mg / kg, about 0.001 mg / kg to about 75 mg / kg, or about 0.001 mg / kg to about 100 mg / kg and administered, for example, every 3, 5, 7, 10 or 14 days. In yet other aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein may be in the range of, e.g., about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 15 mg / kg, about 0.01 mg / kg to about 20 mg / kg, about 0.01 mg / kg to about 25 mg / kg, about 0.01 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 35 mg / kg, about 0.01 mg / kg to about 40 mg / kg, about 0.01 mg / kg to about 45 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.01 mg / kg to about 75 mg / kg, or about 0.01 mg / kg to about 100 mg / kg and administered, for example, every 3, 5, 7, 10 or 14 days. In still other aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein may be in the range of, e.g., about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 35 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.1 mg / kg to about 45 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 75 mg / kg, or about 0.1 mg / kg to about 100 mg / kg and administered, for example, every 3, 5, 7, 10 or 14 days.

[0148] Dosing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art. For example, treatment of an ailment or addiction infection can comprise a one-time administration of an effective dose of a pharmaceutical composition disclosed herein. Alternatively, treatment of an ailment or addiction may include multiple administrations of an effective dose of a pharmaceutical composition carried out over a range of time periods, such as, e.g., once daily, twice daily, trice daily, once every few days, or once weekly. The timing of administration canvary from individual to individual, depending upon such factors as the severity of an individual's symptoms. For example, an effective dose of a pharmaceutical composition disclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer requires therapy. A person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a pharmaceutical composition disclosed herein that is administered can be adjusted accordingly.

[0149] In a further embodiment, the therapeutic compounds described herein have half-lives of 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, one month, two months, three months, four months or more.

[0150] In an embodiment, the period of administration of the formulations described herein therapeutic is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0151] In aspects of this embodiment, a therapeutically effective amount of a therapeutic disclosed herein reduces the signs / symptoms of an ailment such as a neurological disorder by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 100%. In other aspects of this embodiment, a therapeuticallyeffective amount of a therapeutic disclosed herein reduces the signs / symptoms of an ailment such as a neurological disorder by, e.g., at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 95% or at most 100%. In yet other aspects of this embodiment, a therapeutically effective amount of a therapeutic disclosed herein reduces the signs / symptoms of an ailment such as a neurological disorder, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0152] In an embodiment, treatment with a formulation described herein decreases the severity of a neurological disorder, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0153] In an embodiment, treatment with a formulation described herein decreases the signs / symptoms of a neurodegenerative disease, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0154] In an embodiment, treatment with a formulation described herein decreases CNS inflammation in a patient, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0155] In one embodiment, the dose of the compositions are administered daily, semi-weekly, weekly, bi-weekly, or monthly. The period of treatment may be for a week, two weeks, a month, two months, four months, six months, eight months, a year, or longer. The initial dose may be larger than a sustaining dose. In one embodiment, the dose (of each compound) ranges from a weekly dose of at least 0.01 mg / kg, at least 0.25 mg / kg, at least 0.3 mg / kg, at least 0.5 mg / kg, at least 0.75 mg / kg, at least 1 mg / kg, at least 2 mg / kg, at least 3 mg / kg, at least 4 mg / kg, at least 5 mg / kg, at least 6 mg / kg, at least 7 mg / kg, at least 8 mg / kg, at least 9 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, or at least 30 mg / kg In one embodiment, a weekly dose may be at most 1 .5 mg / kg, at most 2 mg / kg, at most 2.5 mg / kg, at most 3 mg / kg, at most 4 mg / kg, at most 5 mg / kg, at most 6 mg / kg, at most 7 mg / kg, at most 8 mg / kg, at most 9 mg / kg, at most 10 mg / kg, at most 15 mg / kg, at most 20 mg / kg, at most 25 mg / kg, or at most 30 mg / kg. In a particular aspect, the weekly dose may range from 5 mg / kg to 20 mg / kg. In an alternative aspect, the weekly dose may range from 10 mg / kg to 15 mg / kg.EXAMPLES

[0156] The following non-limiting examples are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments now contemplated. These examples are intended to be a mere subset of all possible contexts in which the components of the formulation may be combined. Thus, these examples should not be construed to limit any of the embodiments described in thepresent specification, including those pertaining to the type and amounts of components of the formulation and / or methods and uses thereofExample 1 Formulation and Method for Treating Alzheimer's Disease

[0157] In this example, a patient complains of symptoms characteristic of Alzheimer's disease (AD) including problems with language, disorientation, mood swings, loss of motivation and self-neglect. The treating physician diagnoses the patient with early to mid-onset AD. To prevent progression of the disease, the patient is administered in the formulations described below. The microRNA formulation is administered as a liposome suspension. It is administered by injection daily (0.50 mL x 5) for 30 days followed by a no-treatment observation period.

[0158] The small molecule formulation is administered orally. A dose (total of 250 mg) is taken morning and a second dose is taken in the evening (combined total of 500 mg / day).

[0159] Within six weeks, the signs / symptoms of AD diminish and the patient appears in good health. The patient resumes the treatment and is periodically monitored for changes in her condition.Table 1 - miRNA FormulationTable 2 - Small Molecule Formulation* * *

[0160] The present specification also provides a pharmaceutical composition for the administration to a subject. The pharmaceutical composition disclosed herein may further include a pharmaceutically acceptable carrier, excipient, or diluent. As used herein, the term "pharmaceutically acceptable" means that the composition is sufficient to achieve the therapeutic effects without deleterious side effects, and may be readily determined depending on the type of the diseases, the patient's age, body weight, health conditions, gender, and drug sensitivity, administration route, administration mode, administration frequency, duration of treatment, drugs used in combination or coincident with the composition disclosed herein, and other factors known in medicine.

[0161] The pharmaceutical composition herein may further include a pharmaceutically acceptable carrier. For oral administration, the carrier may include, for example, a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersing agent, a stabilizer, a suspending agent, a colorant, and a flavorant. For injectable preparations, the carrier may include a buffering agent, a preserving agent, an analgesic, a solubilizer, an isotonic agent, and a stabilizer. For preparations for topical administration, the carrier may include a base, an excipient, a lubricant, and a preserving agent.

[0162] The disclosed compositions may be formulated into a variety of dosage forms in combination with the aforementioned pharmaceutically acceptable carriers. For example, for oral administration, the pharmaceutical composition may be formulated into tablets, troches, capsules, elixirs, suspensions, syrups or wafers. For injectable preparations, the pharmaceutical composition may be formulated into an ampule as a single dosage form or a multidose container. The pharmaceutical composition may also be formulated into solutions, suspensions, tablets, pills, capsules and long-acting preparations.

[0163] On the other hand, examples of the carrier, the excipient, and the diluent suitable for the pharmaceutical formulations include, without limitation, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oils. In addition, the pharmaceutical formulations may further include fillers, anti-coagulating agents, lubricants, humectants, flavorants, and antiseptics.

[0164] Further, the pharmaceutical composition disclosed herein may have any formulation selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, liquids for internal use, emulsions, syrups, sterile aqueous solutions, non-aqueous solvents, lyophilized formulations and suppositories.

[0165] The composition may be formulated into a single dosage form suitable for the patient's body, and preferably is formulated into a preparation useful for small molecule drugs according to the typical method in the pharmaceutical field so as to be administered by an oral or parenteral route such as through skin, intravenous, intramuscular, intra-arterial, intramedullary, intramedullary, intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal, intranasal, intracolonic, topical, sublingual, vaginal, or rectal administration, but is not limited thereto.

[0166] The composition may be used by blending with a variety of pharmaceutically acceptable carriers such as physiological saline or organic solvents. In order to increase the stability or absorptivity, carbohydrates such as glucose, sucrose or dextrans, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers may be used.

[0167] The administration dose and frequency of the pharmaceutical composition disclosed herein are determined by the type of active ingredient, together with various factors such as the disease to be treated, administration route, patient's age, gender, and body weight, and disease severity.

[0168] The total effective dose of the compositions disclosed herein may be administered to a patient in a single dose or may be administered for a long period of time in multiple doses according to a fractionated treatment protocol. In the pharmaceutical composition disclosed herein, the content of active ingredient may vary depending on the disease severity. Preferably, the total daily dose of the small molecule disclosed herein may be approximately 0.0001 g to 500 mg per 1 kg of body weight of a patient. However, the effective dose of the small molecule is determined considering various factors including patient's age, body weight, health conditions, gender, disease severity, diet, and secretion rate, in addition to administration route and treatment frequency of the pharmaceutical composition. In view of this, those skilled in the art may easily determine an effective dose suitable for the particular use of the pharmaceutical composition disclosed herein. The pharmaceutical composition disclosed herein is not particularly limited to the formulation, and administration route and mode, as long as it shows suitable effects.

[0169] Moreover, the pharmaceutical composition may be administered alone or in combination or coincident with other pharmaceutical formulations showing prophylactic or therapeutic efficacy.

[0170] In various embodiments, a formulation can include, without limitation, combinations of bioactive agents (such as viruses, proteins, antibodies, peptides and the like as described herein) in the formulation. For example, a formulation as described herein can include a single bioactive agent for treatment of one or more conditions, including without limitation, disease. A formulation as described herein also can include, in an embodiment, without limitation, two or more different bioactive agents for a single or multiple conditions. Use of multiple bioactive agents in a formulation can be directed to, for example, the same or different indications. Similarly, in another embodiment, multiple bioactive agents can be used in a formulation to treat, for example, both a pathological condition and one or more side effects caused by the primary treatment. In a further embodiment, multiple bioactive agents also can be included, without limitation, in a formulation as described herein to accomplish differentmedical purposes including, for example, simultaneous treatment and monitoring of the progression of the pathological condition. In an additional embodiment, multiple, concurrent therapies such as those exemplified herein as well as other combinations well known in the art are particularly useful for patient compliance because a single formulation can be sufficient for some or all suggested treatments and / or diagnosis. Those skilled in the art will know those bioactive agents that can be admixed for a wide range of combination therapies. Similarly, in various embodiments, a formulation can be used with a small molecule drug and combinations of one or more bioactive agents together with one or more small molecule pharmaceuticals. Therefore, in various embodiments a formulation is provided containing 1 , 2, 3, 4, 5 or 6 or more different bioactive agents, as well as, for one or more bioactive agents combined with one or more small molecule pharmaceuticals.

[0171] In various embodiments, a formulation can include, one or more preservatives and / or additives known in the art. Similarly, a formulation can further be formulated, without limitation, into any of various known delivery formulations. For example, in an embodiment, a formulation can include, surfactants, adjuvant, biodegradable polymers, hydrogels, etc., such optional components, their chemical and functional characteristics are known in the art. Similarly known in the art are formulations that facilitate rapid, sustained or delayed release of the bioactive agents after administration. A formulation as described can be produced to include these or other formulation components known in the art.

[0172] The composition can therefore be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. Appropriate dosages may be ascertained through use of appropriate dose-response data. In various embodiments, the bioactive agents in formulations described herein can, without limitation, be administered to patients throughout an extended time period, such as chronic administration for a chronic condition. The composition can be a solid, asemi-solid or an aerosol and a pharmaceutical compositions is formulated as a tablet, geltab, lozenge, orally dissolved strip, capsule, syrup, oral suspension, emulsion, granule, sprinkle or pellet.

[0173] In an embodiment, for oral, rectal, vaginal, parenteral, pulmonary, sublingual and / or intranasal delivery formulations, tablets can be made by compression or molding, optionally with one or more accessory ingredients or additives. In an embodiment, compressed tablets are prepared, for example, by compressing in a suitable tableting machine, the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (for example, without limitation, povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, without limitation, sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) and / or surface-active or dispersing agent.

[0174] In an embodiment, molded tablets are made, for example, without limitation, by molding in a suitable tableting machine, a mixture of powdered compounds moistened with an inert liquid diluent. In an embodiment, the tablets may optionally be coated or scored, and may be formulated so as to provide slow or controlled release of the active ingredients, using, for example, without limitation, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. In an embodiment, tablets may optionally be provided with a coating, without limitation, such as a thin film, sugar coating, or an enteric coating to provide release in parts of the gut other than the stomach. In an embodiment, processes, equipment, and toll manufacturers for tablet and capsule making are well-known in the art.

[0175] In an embodiment, capsule formulations can utilize either hard or soft capsules, including, without limitation, gelatin capsules or vegetarian capsules such as those made out of hydroxymethylpropylcellulose (HMPC). In an embodiment, a type of capsule is a gelatin capsule. In an embodiment, capsules may be filled using a capsule filling machine such as, without limitation, those available from commercial suppliers such as Miranda International or employing capsule manufacturing techniques well- known in the industry, as described in detail in Pharmaceutical Capules, 2. sup. nd Ed.,F. Podczeck and B. Jones, 2004. In an embodiment, capsule formulations may be prepared, without limitation, using a toll manufacturing center such as the Chao Center for Industrial Pharmacy & Contract Manufacturing, located at Purdue Research Park.

[0176] Packaging and instruments for administration may be determined by a variety of considerations, such as, without limitation, the volume of material to be administered, the conditions for storage, whether skilled healthcare practitioners will administer or patient self-compliance, the dosage regime, the geopolitical environment (e.g., exposure to extreme conditions of temperature for developing nations), and other practical considerations.

[0177] Injection devices include pen injectors, auto injectors, safety syringes, injection pumps, infusion pumps, glass prefilled syringes, plastic prefilled syringes and needle free injectors syringes may be prefilled with liquid, or may be dual chambered, for example, for use with lyophilized material. An example of a syringe for such use is the Lyo-Ject™, a dual-chamber pre-filled lyosyringe available from Vetter GmbH, Ravensburg, Germany. Another example is the LyoTip which is a prefilled syringe designed to conveniently deliver lyophilized formulations available from LyoTip, Inc., Camarillo, California, U.S.A. Administration by injection may be, without limitation intravenous, intramuscular, intraperitoneal, or subcutaneous, as appropriate.Administrations by non-injection route may be, without limitation, nasal, oral, cocular, dermal, or pulmonary, as appropriate.

[0178] In certain embodiments, kits can include one or more single or multichambered syringes (e.g., liquid syringes and lyosyringes) for administering one or more formulations described herein. In various embodiments, the kit can comprise formulation components for parenteral, subcutaneous, intramuscular or IV administration, sealed in a vial under partial vacuum in a form ready for loading into a syringe and administration to a subject. In this regard, the composition can be disposed therein under partial vacuum. In all of these embodiments and others, the kits can contain one or more vials in accordance with any of the foregoing, wherein each vial contains a single unit dose for administration to a subject.

[0179] The kits can comprise lyophilates, disposed as herein, that upon reconstitution provide compositions in accordance therewith. In various embodiment the kits can contain a lyophilate and a sterile diluent for reconstituting the lyophilate.

[0180] Also described herein, are methods for treating a subject in need of therapy, comprising administering to the subject an effective amount of a formulation as described herein. The therapeutically effective amount or dose of a formulation will depend on the disease or condition of the subject and actual clinical setting.

[0181] In an embodiment, a formulation as described herein can be administered by any suitable route, specifically by parental (including subcutaneous, intramuscular, intravenous and intradermal) administration. It will also be appreciated that the preferred route will vary with the condition and age of the recipient, and the disease being treated. Methods of determining the most effective means and dosage of administration are known to those of skill in the art and will vary, without limitation, with the composition used for therapy, the purpose of the therapy, and the subject being treated. Single or multiple administrations can be carried out, without limitation, the dose level and pattern being selected by the treating physician. Suitable dosage formulations and methods of administering the agents are known in the art.

[0182] The formulations as described herein can be used in the manufacture of medicaments and for the treatment of humans and other animals by administration in accordance with conventional procedures.

[0183] Also provided herein are combinatorial methods for developing suitable virus formulations using combinations of amino acids. These methods are effective for developing stable liquid or lyophilized formulations, and particularly pharmaceutical virus formulations.

[0184] Compositions in accordance with embodiments described herein have desirable properties, such as desirable solubility, viscosity, syringeability and stability. Lyophilates in accordance with embodiments described herein have desirable properties, as well, such as desirable recovery, stability and reconstitution.

[0185] In an embodiment, the pH of the pharmaceutical formulation is at least about 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, or 9.

[0186] In an embodiment, the pH of the pharmaceutical formulation is from about 3 to about 9, about 4 to about 19, about 5 to about 9, about 6 to about 8, about 6 to about 7, about 6 to about 9, about 5 to about 6, about 5 to about 7, about 5 to about 8, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about5, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 7 to about 8, about 7 to about 9, about 7 to about 10.

[0187] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the present invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0188] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0189] Unless otherwise indicated, all numbers expressing a characteristic, item,quantity, parameter, property, term, and so forth used in the present specification and claims are to be understood as being modified in all instances by the term “about.” As used herein, the term “about” means that the characteristic, item, quantity, parameter, property, or term so qualified encompasses a range of plus or minus ten percent above and below the value of the stated characteristic, item, quantity, parameter, property, or term. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values setting forth the broad scope of the invention are approximations, the numerical ranges and values set forth in the specific examples are reported as precisely as possible. Any numerical range or value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Recitation of numerical ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate numerical value falling within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated into the present specification as if it were individually recited herein.

[0190] Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s).Embodiments of the present invention so claimed are inherently or expressly described and enabled herein.

[0191] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members disclosedherein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0192] All patents, patent publications, and other publications referenced and identified in the present specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

[0193] In closing, it is to be understood that although aspects of the present specification are highlighted by referring to specific embodiments, one skilled in the art will readily appreciate that these disclosed embodiments are only illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to a particular methodology, protocol, and / or reagent, etc., described herein. As such, various modifications or changes to or alternative configurations of the disclosed subject matter can be made in accordance with the teachings herein without departing from the spirit of the present specification. Lastly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. Accordingly, the present invention is not limited to that precisely as shown and described.

Claims

CLAIMSWhat is claimed is:1 . A formulation comprising: a) MIR-1 5-3p, b) let-7c-3p, c) MIR-383-5p, d) MIR-548aj-3p and e) MIR-548x-3p.

2. The formulation of claim 1 , further comprising one or more of GATC-49, fucosterol and fucoidan.

3. A method of treating an ailment, the method comprising administering a therapeutic amount of the formulation of claim 1 or claim 2 to a subject.

4. The method of claim 3, wherein the ailment is a neurodegenerative disorder.

5. The method of claim 4, wherein the neurodegenerative disorder is one or more of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease and dementia.

6. A method of reducing or modulating transcription of one or more proteins to treat an ailment in a subject, the method comprising administering a therapeutic amount of the formulation of claim 1 or claim 2 to the subject.

7. The method of claim 6, wherein the ailment is a neurodegenerative disorder.

8. The method of claim 7, wherein the neurodegenerative disorder is one or more of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease and dementia.

9. A method of reducing or modulating transcription of one or more proteins to treat an ailment in a subject, comprising administering a therapeutic amount of one or more microRNAs selected from: a) MIR-145-3p, b) let-7c-3p, c) MIR-383-5p, d) MIR-548aj-3p, and e) MIR-548x-3p.

10. The method of claim 9, wherein the one or microRNAs are administered as liposomes.11 . The method of claim 9, further comprising a step of inhibiting aggregation of beta amyloid proteins.

12. The method of claim 9, further comprising a step of inhibiting clustering of microglial cells.

13. The method of claim 9, further comprising a step of activating HT2A and / or HT6 receptors.

14. The method of claim 9, further comprising administerubg a therapeutic amount of one or more one small molecule therapeutics selected from GATC-49, fucosterol and fucoidan.

15. A method of preventing or treating a neurodegenerative disorder, the method comprised of steps of: a) modulating transcription of one or more proteins, b) inhibiting aggregation of beta amyloid proteins, b) inhibiting clustering of microglial cells, and / orc) activating HT?A or HTe receptors.

16. The method of claim 15, wherein the step of modulating transctiption of one more more proteins comprises administering one or more microRNAs selected from MIR-145- 3p, let-7c-3p, MIR-383-5p, MIR-548aj-3p, and MIR-548x-3p.

17. The method of claim 15, wherein the step of activating HT2A or HTe receptors comprises administering one or more therapeutics selected from GATC-49, fucosterol and fucoidan.

18. The method of claim 15, wherein the neurodegenerative disorder is one or more of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease and dementia.

19. A formulation comprising: a) MIR-145-3p, b) let-7c-3p, c) MIR-383-5p, d) MIR-548aj-3p, e) MIR-548x-3p, f) GATC-49, g) fucosterol, and h) fucoidan.

20. A method of treating an ailment, the method comprising administering a therapeutic amount of the formulation of claim 19 to a subject.21 . The method of claim 20, wherein the ailment is a neurodegenerative disorder.

22. The method of ciaim 21 , wherein the neurodegenerative disorder is one or more of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease and dementia.

23. The method of claim 20, further comprising a step of packaging one or more of MIR- 145-3p, let-7c-3p, MIR-383-5p, MIR-548aj-3p and MIR-548x-3p into nanoparticles.

24. The method of claim 23, wherein the nanoparticles are exosomes.

25. The method of claim 23, wherein the nanoparticles are liposomes.

26. A method of increasing neuroplasticity or improving neural function to treat an ailment in a subject, the method comprising administering a therapeutic amount of the formulation of claim 19 to the subject.

27. The method of claim 26, wherein the ailment is one or more of inflammation, addiction, post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain- Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headaches, encephalitis and myasthenia gravis.

28. A method of treating an ailment, the method comprising administering an effective amount of a formulation comprising: a) MIR-145-3p, b) let-7c-3p, c) MIR-383-5p, d) MIR-548aj-3p, e) MIR-548x-3p, f) GATC-49,g) fucosterol, and h) fucoidan.

29. The method of claim 28, wherein the ailment is a neurodegenerative disorder.

30. The method of claim 29, wherein the neurodegenerative disorder is one or more of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease and dementia.31 . The method of claim 28, wherein one or more of MIR-145-3p, let-7c-3p, MIR-383- 5p, MIR-548aj-3p and MIR-548x-3p are administered as nanoparticles.

32. The method of claim 31 , wherein the nanoparticles are exosomes.

33. The method of claim 31 , wherein the nanoparticles are liposomes.

34. The method of claim 28, wherein one or more of MIR-145-3p, let-7c-3p, MIR-383- 5p, MIR-548aj-3p and MIR-548x-3p are administered using a viral vector.

35. The method of claim 34, wherein the viral vector is a lentiviral vector, a herpes simplex virus (HSV) vector, an adenoviral vector or an adeno-associated viral (AAV) vector.

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