Methods of treating peripheral nervous system myelination conditions

Abstract

Provided herein are methods of treating a subject having a peripheral nervous system (PNS) myelination condition, comprising administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a polypeptide having cholesterol efflux activity, wherein the polypeptide is selected from CS6253 and variants thereof. The PNS myelination condition can be a condition characterized by PMP22 dysfunction in the PNS, a PNS myelination disorder resulting from abnormal ABCA1 regulated cholesterol transport disorder, a demyelinating condition resulting from Schwann cell dysfunction and a non-hereditary PNS myelination condition.

Description

Methods of Treating Peripheral Nervous System Myelination ConditionsSTATEMENT AS TO FEDERALLY SPONSORED RESEARCH

[0001] None.REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of the filing date of U. S. provisional application 63 / 712,033, filed October 25, 2024, the entirety of which is incorporated by reference.THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT

[0003] None.SEQUENCE LISTING

[0004] None.BACKGROUND

[0005] Peripheral neuropathies can occur alone or as a complication of other conditions. They can significantly impact the quality of life, with symptoms ranging from severe pain to paralysis. Hereditary neuropathies are often more severe compared to idiopathic neuropathies and can cause extreme weakening and wasting of skeletal muscles, gait abnormalities, loss of tendon reflexes, numbness, and respiratory dysfunction. There are no approved drug therapies for hereditary neuropathies, and supportive treatment is limited to physical therapy and surgical interventions to correct musculoskeletal deformities - any or all of which significantly impact quality of life and reduce life expectancy. Besides the mobility issues associated with neuromuscular deficits, patients may suffer from respiratory dysfunction, significantly impacting the quality of life, and reducing life expectancy. One characteristic of neuropathy is the breakdown or dysfunction of the neuronal and / or glial cell membranes and organelle membranes, e.g., membranes.

[0006] A critical component for maintaining specialized membrane structures and the function and integrity of membrane domains, including lipid rafts, is cholesterol. Lipid rafts are cholesterol-enriched microdomains involved in signaling and linkage of the cytoskeleton with the plasma membrane. Simons et al., 2002, J. Clin. Invest. 110(5): 597-603. Cholesterol homeostasis within each cell balances intracellular synthesis, transport and extracellular uptake. Abnormal intracellular accumulation of cholesterol, or cholesterol deficiency, has been linked to numerous disorders, including Alzheimer’s and Tangier’s disease. Tangier’s disease (TD), a low cholesterol condition, is believed to be due to mutations in the ATP-binding cassette subfamily A transporter (ABCA1). Mercan et al., 2018, J Peripher Nerv Syst. 23:88-98. Patients with TDdevelop enlarged orange-yellow tonsils and often present with peripheral neuropathy. ABCA1, one of the most studied members of the ABCA family of sterol transporters, has a major role in regulating cholesterol efflux and cholesterol and phospholipid content of the plasma membrane. Jacabo-Albavera et al., 2021, Int J Mol Sci. 22. Recent studies also implicate ABCA1 in the redistribution of cholesterol between membrane microdomains and in modulating the solubility of cholesterol in the membrane. Plummer etal., 2021, Annu Rev Physiol. 83:153181. ABCA1 is studied widely because of its interaction with apoE, the strongest genetic risk factor in Alzheimer’s disease, and the major lipid carrier protein within the nervous system. Sun et al., 2023, Cell Mol Neurobiol: 1-22. ABCA1 is believed to be the rate limiting step in high density lipoprotein assembly by mediated cholesterol and phospholipid efflux from cells to apoA-1 at the cell surface, which in turn combine to form pre-p-HDL. Yokoyama, Curr. Opin. Lipidol. 16: 269-279, 2005; Neufeld etal., J. Biol. Chem. 279: 15571-15578, 2004. In the PNS, ApoE is upregulated during peripheral nerve regeneration, and when applied exogenously as a mimetic peptide, stimulates axonal regeneration and remyelination. Li et al., 2010, J Pharmacol Exp Ther. 334:106115.

[0007] One specialized structure maintained by cholesterol is myelin. Myelin is the multilayered plasma membrane extension of oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS). Myelin has a high lipid (70-85%) and relatively low protein (15-30%) content, compared with other biological membrane components. Myelin insulates axons and supports the rapid conduction of electrical impulses. The enriched presence of lipids such as cholesterol convey to myelin low capacitance and high resistance which are vital properties for this function. While the lipid composition of CNS and PNS myelin are qualitatively similar, they each contain unique proteins, including tetraspans (4 membrane-spanning domains) such as proteolipid protein (PLP) of oligodendrocytes and peripheral myelin protein 22 (PMP22) in Schwann cells. Both PLP and PMP22, along with myelin-associated glycoprotein (MAG), myelin protein zero (P0 or MPZ), and plasmolipin, harbor conserved Cholesterol Recognition Amino acid Consensus (CRAC) sequence(s), signifying the importance of protein-lipid interaction and cholesterol stabilization in myelin. Zhou et al., 2020, Glia, 68:2300-2315. Zhou etal., 2019, J Neurosci. 39:5404-5418. Hence it would seem that distinct protein components may be involved in the transport of lipoproteins in CNS v. PNS myelination.

[0008] The importance of cholesterol in peripheral myelination has only recently come to light. While cholesterol distribution and transport were generally understood to be important to peripheral nerve health, the specific molecular pathways which control it were not. Clinical studies indicate that abnormal expression of peripheral myelin protein 22 (PMP22) may account for nearly 70% of hereditary demyelinating neuropathies. DiVincenzo et al., 2014, Mol Genet Genomic Med. 2:522-529. PMP22 causes disease by gene duplication, deletion, andmutations, signifying that correct levels of this 22 kDa glycoprotein are critical for peripheral nerve health. Autosomal inherited type 1A (CMT1A) is associated with PMP22 duplication and CMT1E is associated single point mutations resulting in dysfunctional PMP22. PMP22 haploinsufficiency caused Hereditary Neuropathy with Pressure Palsy (HNPP) -- an underdiagnosed, episodic, recurrent demyelinating neuropathy. Li et al., 2013, Mol Neurobiol.47:673-698; van Paassen et al., 2014, Orphanet J Rare Dis. 9:38. Patients without the PMP22 gene are uncommon, but have been studied, and they present with severe disease. Saporta et al., 2011, Arch Neurol. 68:814-821.

[0009] As noted previously, PMP22 contains a CRAC domain. Saher et al., 2010, Subcell Biochem. 51:489-508. The CRAC domain is important because it is the location where PMP22 interacts with cholesterol and ABCA1 in the regulation of lipid transport in Schwann cells. Zhou eta!., 2020, Glia, 68:2300-2315; Zhou et al., 2019, J Neurosci. 39:5404-5418.

[0010] PMP22-deficiency results in anomalous lipid rafts and cytoskeletal elements of Schwann cells. Lee et al., 2014, J Neurosci. 34:16140-16152. Nerves from such mice contain increased levels of apoE and ABCA1 mRNA and protein, however, ABCA1 is retained intracellular, rather than membrane-associated like in samples from normal wild type (“wt”). Zhou et al., 2019, J Neurosci. 39:5404-5418. Along with ABCA1, abnormal clumping and intracellular sequestration of cholesterol, and increase in the lipidated fraction of ApoE was observed. Moreover, expanding these studies to nerves and Schwann cells from Wt and ABCA1-deficient mice uncovered a functional partnership between PMP22 and ABCA1 in cholesterol transport. Zhou et al., 2019, J Neurosci. 39:5404-5418. Notably, in nerves from ABCA1 knock-out (“KO”) mice, a model of Tangier’s disease, the expression of PMP22 was significantly elevated, and the subcellular processing of the overproduced protein was atypical. In cell culture experiments, the absence of PMP22 impaired the cholesterol efflux capacity of Schwann cells, indicating a deficiency in ABCA1 activity at the plasma membrane. The role of PMP22 in cholesterol transport was confirmed by shRNA PMP22 gene ablation, and exogenous gene replacement strategies. Zhou et al., 2019, J Neurosci. 39:5404-5418.

[0011] CS-6253 is a synthetic amphipathic a-helix peptide derived from ApoE. It was initially identified for activity in enabling cholesterol transport and serum-associated cholesterol conditions such as dyslipidemia, hypercholesterolemia, abnormal glucose metabolism, atherosclerosis, atherosclerotic plaque stabilization, diabetes (Type I, Type II), metabolic syndrome, pre-diabetes, as well as Alzheimer's disease, frontotemporal dementia, and inflammation (US 9,416,162). CS-6253 is also known to have cholesterol synthesis agonist effects in an experimental autoimmune encephalomyelitis (EAE) MS animal model (Itoh et al., PNAS 115(2) E302-E309) by astrocytes, which in turn was associated with CNS remyelination. Molina-Gonzalez etal., Nature Comm. 14: 3372 (2023).BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The accompanying drawings, which are incorporated herein and form a part of the specification, illustrate exemplary embodiments and, together with the description, further serve to enable a person skilled in the pertinent art to make and use these embodiments and others that will be apparent to those skilled in the art. The disclosure will be more particularly described in conjunction with the following drawings, wherein the following:

[0013] FIGs. 1A-1B is a bar graph series showing the effect of CS6253 on Schwann cell plasma membranes from TrJ mice, more specifically (i) stabilization of ABCA1 expression (Fig.1A) and (ii) increase in axial length of the glia (Fig. 1B), which is necessary for myelin formation.

[0014] FIG. 2 is a plot showing the effect of CS6253 on nerve conductive velocity (NCV) on sciatic nerves from TrJ mice, after 6 weeks of ip injections (16 doses at 20 mg / kg).

[0015] Figs. 3A-3C is a bar graph of blood plasma (ng / ml) concentrations of CS6253, 6hr post-single injection of 20 mg / kg (n=4 mice) (Fig 3A) and photomicrograph showing the bioavailability of CS6253 in sciatic nerve (Fig 3B) and in cultured Schwann cells (Fig 3C), as measured by anti-CS6253 rabbit antibodies.

[0016] Fig. 4 is a study design showing biweekly evaluations of neuropathic animals treated with CS6253.SUMMARY

[0017] The current disclosure is directed the use of CS-6253 and variants to treat peripheral nervous system myelination conditions, including neuropathies and / or conditions characterized by abnormal peripheral nerve myelination or myelin damage.

[0018] The present disclosure and accompanying embodiments described herein is based in part on the surprising and unexpected discovery that cholesterol efflux is associated with peripheral nerve myelination. More specifically, the disclosure relates to a method of treating a subject having a peripheral nervous system (PNS) myelination condition, comprising administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a polypeptide having cholesterol efflux activity, wherein the polypeptide is selected from CS6253 and variants thereof.

[0019] In certain embodiments, the PNS myelination condition is selected from the group consisting of: a condition characterized by PMP22 dysfunction in the PNS; a PNS myelination disorder resulting from abnormal ABCA1 regulated cholesterol transport; a Schwann cell regulated cholesterol transport disorder; a demyelinating condition resulting from Schwann cell dysfunction; and a non-hereditary PNS myelination condition.

[0020] In one embodiment, the PMP22 dysfunction causes abnormal regulation of ABCA1. In other embodiments, the PMP22 dysfunction results from one or more PMP22 point mutations, PMP22 overexpression or PMP22 under-expression. In other embodiments, the PMP22 dysfunction is a disorder selected from Charcot-Marie-Tooth Disease Type 1E (CMT1E), Dejerine-Sottas Syndrome (DSS), CMT1A and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP).

[0021] In another embodiment, the demyelinating condition resulting from Schwann cell dysfunction is selected from inflammatory demyelinating neuropathy, acute inflammatory demyelinating polyneuropathy (Al DP), (GBS), acute idiopathic polyneuritis, chronic inflammatory demyelinating polyneuropathy (CIDP) and Anti-MAG peripheral neuropathy.

[0022] In another embodiment, the non-hereditary PNS myelination condition results from inflammation, infection, neurotoxin exposure, asphyxia, physical trauma, ischemia, radiation induced, chemotherapy, copper deficiency, metabolic disorder or idiopathic origins.

[0023] In another embodiment, the subject shows one or more physiological or morphological signs or symptoms of a disorder resulting from PMP22 dysfunction. In other embodiments, the subject has a Charcot-Marie-Tooth Neuropathy Score (CMTNS) below 10. In other embodiments, a Charcot-Marie-Tooth Disease Pediatric Scale score (CMTPedS) below 2. In other embodiments, the subject has an Overall Neuropathy Limitations Scale score (ONLS) of < 6. In other embodiments, the subject is asymptomatic. In other embodiments, the subject is a human. In other embodiments, the human is about 6 months of age or less.

[0024] In another embodiment, the polypeptide having cholesterol efflux activity comprises an amino acid sequence that is an amphipathic a-helix having a non-polar surface and a polar surface, wherein the polar surface comprises charged and uncharged amino acid residues at the lipid-water interface, wherein the amino acid comprises an amino acid sequence: (i) has at least 60% identity to EVcitSKLEEWLAALcitELAEELLARL (SEQ ID NO:1); (ii) has a citrulline, or an uncharged analog of citrulline, that maintains a salt-bridge configuration in the a-helix, at least one of the three positions 3, 14, and 23 of EVcitSKLEEWLAALcitELAEELLARL (SEQ ID NO:1); (iii) comprises a hydrophobic amino acid at positions 2, 6, 9, 10, 13, 16, 17, 20, and 24 of EVcitSKLEEWLAALcitELAEELLARL (SEQ ID NO:1); and (iv) comprises an acidic amino acid residue at positions 1, 7, 8, 15, 18 and 19 of EVcitSKLEEWLAALcitELAEELLARL (SEQ ID NO:1).

[0025] In another embodiment, the amino acid sequence is selected from the group consisting of: (i) an uncharged amino acid at a second of the three positions 3, 14, and 23 of SEQ I D NO: 1; (ii) uncharged amino acid at the second and third of the three_positions 3, 4, and 23 of SEQ ID NO:1; (iii) an a-helix amino acid sequence that is 24 amino acid in length and further comprises a position 25 and 26, wherein position 25 is K or N and position 26 is S or Y;(iv) an amino acid sequence has Q, N, L, V, I, or A at at least one position 3, 14, or 23; (v) an amino acid sequence has Q or N at at least one position 3, 14, or 23; (vi) an amino acid residue at two of positions 3, 14, and 23 that are independently selected from Q, N, L, V, I, or A; (vii) an amino acid sequence comprises R or K at at least one of positions 3, 14, and 23; (viii) an amino acid sequence wherein four, five, six, seven, or all eight of residues at positions 2, 6, 10, 13, 16, 17, 20, and 24 are aliphatic amino acids; and (ix) an amino acid sequence that is SEQ ID NO:3 or SEQ ID NO:4.

[0026] In other embodiments, the amino acid sequence at positions, five, six, seven, or all eight of positions 2, 6, 10, 13, 16, 17, 20, and 24 are aliphatic amino acids. In other embodiments, the aliphatic amino acid is selected from the group consisting of L, V, A, and I. In yet other embodiments, the aliphatic amino acid is selected from the group consisting of L, I, and V at position 10, 13, 16, and 20.

[0027] In other embodiments, the amino acid sequence further comprises a protecting group.

[0028] Other examples of suitable polypeptide having cholesterol efflux activity comprising an a-helix amino acid sequence are disclosed in U.S.P. 10,774,118, USP 11,434,267, WO2014 / 144,708 and U.S.P. 9,416,162, the entire contents of which are incorporated by reference.DETAILED DESCRIPTIONI. Definitions

[0029] A “condition” is any atypical state of health. It can include a disease or disorder, but it includes situations where the symptoms do not meet the specific criteria for a particular disease. Conditions can be chronic (long-lasting) or acute (temporary).

[0030] A “disease” or “disorder” is an abnormal condition affecting the body or disruption to normal physical body function, typically with specific symptoms and signs. The cause or trigger may be known or unknown.

[0031] A “Peripheral Nervous System (PNS) myelination condition” is any abnormal condition of the peripheral nervous system in which the myelin sheath of neurons is damaged. This impairs the conduction of signals in the affected nerves, causing impairment in sensation, movement, or other functions depending on which nerves are involved. As used herein, PNS myelination condition includes (i) PMP22 dysfunction in the PNS; (ii) PNS myelination disorder resulting from abnormal ABCA1 regulated cholesterol transport; (iii) Schwann cell regulated cholesterol transport disorder; (iv) demyelinating condition resulting from Schwann cell dysfunction, and (v) non-hereditary PNS myelination conditions.

[0032] A “condition characterized by PMP22 dysfunction in the PNS” is a condition associated with abnormal functioning of PMP22 in the peripheral nervous system. Such conditions include PMP22 dysfunction which results in abnormal regulation of ABCA1, including Charcot-Marie Tooth (CMT) subtypes associated with PMP22 mutations (e.g., CMT1E, DSS), PMP22 overexpression (e.g., CMT1A) and PMP22 underexpression (Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)).

[0033] PMP22 dysfunction can result from PMP22 mutations, PMP overexpression and / or underexpression. A “PMP22 mutation” is a change in the wild-type (wt) PMP22 encoding nucleic acid sequence, such as a nonsense mutation, a missense mutation, a nucleotide deletion, substitution, or addition, such that the expressed PMP22 polypeptide exhibits an impaired or less effective functionality from wild type PMP22. Diseases characterized by PMP22 mutation include CMT1E, Dejerine-Sottas (DS). A “PMP22 overexpression” is an elevated level, relative to normal physiological expression of PMP22, so as to have a physiological or phenotypic effect in the organism. For example, PMP22 overexpression, such as that which results from PMP22 copy number variation (CNV) of 2 (e.g., duplication, polyploidy), resulting in abnormal cholesterol efflux. Diseases characterized by PMP22 overexpression include CMT1A. Correspondingly, “PMP underexpression” is a diminished level, relative to normal physiological expression of PMP22, so as to have a physiological or phenotypic effect in the organism. For example, PMP22 underexpression resulting from CNV < 1 (e.g., haploidy, deletion), resulting in abnormal cholesterol efflux. Diseases characterized by PMP22 underexpression include HNPP.

[0034] “Charcot-Marie Tooth (CMT)” is a heterogenous group of inheritable disease of the peripheral nervous system. Symptoms of CMT can vary in severity and age of onset. Affected individuals may also develop weakness in the hands, decreased sensitivity to touch, heat, and cold in the feet and lower legs, and occasionally aching or burning sensations. In rare cases, affected individuals experience gradual vision or hearing loss sometimes leading to deafness. The several types of CMT can be differentiated based on their effects on nerve cells and patterns of inheritance. Generally, CMT is a progressive condition, with symptoms appearing between ages 5 and 15, although sometimes not until middle age or later. Symptoms include: muscle weakness in the feet, ankles and legs at first feet that are very highly arched, which can make the ankle unstable, or having very flat feet, curled toes (hammer toes), an awkward or high step and difficulty using the ankle muscles to lift the foot, which makes walking more difficult, a lack of sensation in the arms and feet, cold hands and feet caused by poor circulation, wasting of the muscles in the lower legs, causing legs to have a distinctive "upside-down champagne bottle" shape, feeling tired a lot of the time as a result of the extra effort it takes to move around. Additional symptoms include: uncontrollable tremor or shaking hands, abnormal curvature of the spine (scoliosis), problems speaking, breathing or swallowing (dysphagia), andpain in the hands and other part of the body. CMT patients are diagnosed on the basis of muscle weakness in the arms, legs, hands and feet, decreased muscle bulk and reduced tendon reflexes.

[0035] CMT may be scored differently between pediatric and adult patients. Adult patients (> 18) are based on the severity of CMT Neuropathy Score (CMTNS), with mild (CMTNS < 10), moderate (CMTNS 11 - 20) and severe (CMTNS > 21). CMTNS is the sum of the CMT symptom score (CMTSS) and CMT examination score (CMTES). CMTNS uses nine assessments, three for symptoms, four for signs and two based on neurophysiology. Each measurement is scored on a 0 - 4 point scale for a total possible score of 36. (Burns J, et al., J Peripher Nerv Syst. 2013 Jun;18(2):177-80. doi: 10.1111 / jns5.12024. PMID: 23781965; PMCID: PMC3714225.)

[0036] Pediatric patients (3 - 20 years) use a CMT Pediatric Scale (CMTPedS), which is an 11 -item scale measuring strength, dexterity, sensation, gait, balance, power and endurance to create a raw score. The raw score is turn converted into an a-score, which in is normalized into 0 -4 Likert score. The z-score represents how many standard deviations a patient’s symptoms scores from “normal”. Each measurement is scored on a 0-4 point scale, with 0: normal, 1: very mild, 2: mild, 3: moderate and 4: severe.

[0037] Type 1 (CMT1) is characterized by abnormalities in myelin, slowing nerve impulse transmission, and affecting the health and functioning of the nerve fiber. Type 2 (CMT2) describes abnormalities in the nerve axon; reducing the strength of the nerve impulse. CMT2 may lead to amyotrophic lateral sclerosis (ALS), a condition involving progressive muscle weakness, loss of muscle mass, and an inability to control movement. In intermediate CMT, nerve impulses are both slowed and reduced in strength. CMT4 can affect either the axon or the myelin. CMT subtypes (e.g., CMT1, CMT1E, etc.) indicate different genetic components. CMT3 (Dejerine-Sottas syndrome) refers to a severe early childhood form of CMT, and, depending on the specific gene involved, may be classified as CMT 1 or CMT4. Approximately 75% of CMT cases result from PMP22 mutations. CMT subtypes are classified based on the particular gene involved. CMT1 A and CMT 1 E are associated with alterations in PMP22.

[0038] CMT1A is an autosomal dominant disorder caused by heterozygous duplication of the PMP22 gene. Most CMT1 A patients develop symptoms within the first two decades of life. They often have histories of being slow runners, poor at sports, foot deformities (high arches and hammer toes). Patients with CMT 1 A typically have slowed nerve conduction velocities ranging from 7-40 ms (normal is 50-60 ms). Moreover, variance in this reduced nerve conduction velocity minimally differs between nerves in the same limb with the corresponding nerves of different limbs.

[0039] “Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)” refers to heterozygous deletion or insufficient expression of PMP22. HNPP is an autosomal dominant disorder with recurrent, focal numbness, muscle weakness and atrophy - typically during adolescence. These focal deficits are often evoked by mechanical stress in the peripheral nerves, such as compression, limb stretch or repetitive movement. Strenuous exercise can result in limb paralysis and substantial axon damage. These abnormalities are most prevalent in the elderly. The presence of tomacula or “sausage”-shaped structures in peripheral nerve myelin is the pathological hallmark of HNPP upon histopathological examination of sural nerve biopsies. These structures consist of redundantly overfolded layers in the myelin.

[0040] CMT1E is a CMT subtype caused by autosomal dominant point mutations in PMP22, with clinical manifestations overlapping with other CMT1 subtypes, ranging from mild pressure sensitivity similar to HNPP to severe early-onset dysmelinating neuropathy (similar to Dejerine-Sottas Syndrome). Such phenotypic heterogeneity may be due to the broad varietyof PMP22 point mutations in CMT1E patients that could cause either a toxic gain-of-function (as seen in the Trembler-J mouse), a loss of PMP22 function, or a combination of both. Trembler and Trembler-J mice are believed to exhibit a toxic gain of function mutation in PMP22. After expression, mutant PMP22 fails to transport from the endoplasmic reticulum to the plasma membrane. Instead, mutants form dimers with wt PMP22 in the ER-Golgi intermediate, resulting in protein aggregation. This sequestration of wt PMP22 in turn reduces the amount of wt PMP22 which can be transported to the plasma membrane.

[0041] “Dejerine-Sottas Syndrome (DSS)” also known as “CMT3” is a severe phenotype of Charcot-Marie-Tooth disease characterized by onset occurring in infancy, severe motor weakness, delayed motor development, extremely slow nerve conduction (< 10-12 m / s), areflexia and foot deformity. It is associated with mutations in not only PMP22 (17p12), but also / WPZ (1q22), EGR2 (10q21.1) and PRX (19q13.2).

[0042] “PMP22” or peripheral myelin protein-22, also known as growth arrest specific protein (gas3), is a 22 kDa, 160 amino acid tetraspan membrane glycoprotein mainly expressed in Schwann cells of the peripheral nervous system. The human PMP22 amino acid sequence is:MLLLLLSIIVLHVAVLVLLFVSTIVSQWIVGNGHATDLWQNCSTSSSGNVHHCFSSSPNEWLQSV QATM I LSI I FSI LSLFLFFCQLFTLTKGGRFYITGI FQI LAGLCVMSAAAI YTVRH PEWH LNSDYSYG FAYILAWVAFPLALLSGVIYVILRKRE (SEQ ID NO:5) and has UniProt accession number Q6FH25.

[0043] “ABCA1” or ATP-binding cassette transporter A1, also known as cholesterol efflux regulatory protein (CERP), is a 220 kDa, 2261 amino acid 12-span transmembrane protein that helps regulate cellular cholesterol and phospholipid homeostasis. The human ABCA1 amino acid sequence is:MACWPQLRLLLWKNLTFRRRQTCQLLLEVAWPLFIFLILISVRLSYPPYEQHECHFPNKAMPSA GTLPWVQGIICNANNPCFRYPTPGEAPGVVGNFNKSIVARLFSDARRLLLYSQKDTSMKDMRK VLRTLQQIKKSSSNLKLQDFLVDNETFSGFLYHNLSLPKSTVDKMLRADVILHKVFLQGYQLHLT SLCNGSKSEEMIQLGDQEVSELCGLPREKLAAAERVLRSNMDILKPILRTLNSTSPFPSKELAEA TKTLLHSLGTLAQELFSM RSWSDM RQEVM FLTN VNSSSSSTQI YQAVSRI VCGH PEGGGLKI KS LNWYEDNNYKALFGGNGTEEDAETFYDNSTTPYCNDLMKNLESSPLSRIIWKALKPLLVGKILYT PDTPATRQVMAEVNKTFQELAVFHDLEGMWEELSPKIWTFMENSQEMDLVRMLLDSRDNDHF WEQQLDGLDWTAQDIVAFLAKHPEDVQSSNGSVYTWREAFNETNQAIRTISRFMECVNLNKLE PI ATEVWLI N KSM ELLDERKFWAGI VFTGITPGSI ELPH H VKYKI RM DI DN VERTN KI KDGYWDPG PRADPFEDM RYVWGGFAYLQDWEQAI I RVLTGTEKKTGVYMQQM PYPCYVDDI FLRVMSRSM PLFMTLAWI YSVAVI I KGI VYEKEARLKETM Rl MGLDNSI LWFSWFISSLI PLLVSAGLLVVI LKLGN L LPYSDPSWFVFLSVFAVVTILQCFLISTLFSRANLAAACGGIIYFTLYLPYVLCVAWQDYVGFTLK IFASLLSPVAFGFGCEYFALFEEQGIGVQWDNLFESPVEEDGFNLTTSVSMMLFDTFLYGVMTW YIEAVFPGQYGIPRPWYFPCTKSYWFGEESDEKSHPGSNQKRISEICMEEEPTHLKLGVSIQNL VKVYRDGMKVAVDGLALNFYEGQITSFLGHNGAGKTTTMSILTGLFPPTSGTAYILGKDIRSEMS TIRQNLGVCPQHNVLFDMLTVEEHIWFYARLKGLSEKHVKAEMEQMALDVGLPSSKLKSKTSQ LSGGMQRKLSVALAFVGGSKVVILDEPTAGVDPYSRRGIWELLLKYRQGRTIILSTHHMDEADV LGDRIAIISHGKLCCVGSSLFLKNQLGTGYYLTLVKKDVESSLSSCRNSSSTVSYLKKEDSVSQS SSDAGLGSDHESDTLTIDVSAISNLIRKHVSEARLVEDIGHELTYVLPYEAAKEGAFVELFHEIDD RLSDLGISSYGISETTLEEIFLKVAEESGVDAETSDGTLPARRNRRAFGDKQSCLRPFTEDDAAD PNDSDIDPESRETDLLSGMDGKGSYQVKGWKLTQQQFVALLWKRLLIARRSRKGFFAQIVLPAV FVCIALVFSLIVPPFGKYPSLELQPWMYNEQYTFVSNDAPEDTGTLELLNALTKDPGFGTRCME GNPIPDTPCQAGEEEWTTAPVPQTIMDLFQNGNWTMQNPSPACQCSSDKIKKMLPVCPPGAG GLPPPQRKQNTADILQDLTGRNISDYLVKTYVQIIAKSLKNKIWVNEFRYGGFSLGVSNTQALPP SQEVNDAIKQMKKHLKLAKDSSADRFLNSLGRFMTGLDTKNNVKVWFNNKGWHAISSFLNVIN NAILRANLQKGENPSHYGITAFNHPLNLTKQQLSEVALMTTSVDVLVSICVIFAMSFVPASFWFLI QERVSKAKHLQFISGVKPVIYWLSNFVWDMCNYVVPATLVIIIFICFQQKSYVSSTNLPVLALLLLL YGWSITPLMYPASFVFKIPSTAYVVLTSVNLFIGINGSVATFVLELFTDNKLNNINDILKSVFLIFPHF CLGRGLIDMVKNQAMADALERFGENRFVSPLSWDLVGRNLFAMAVEGWFFLITVLIQYRFFIRP RPVNAKLSPLNDEDEDVRRERQRILDGGGQNDILEIKELTKIYRRKRKPAVDRICVGIPPGECFG LLGVNGAGKSSTFKMLTGDTTVTRGDAFLNKNSILSNIHEVHQNMGYCPQFDAITELLTGREHV EFFALLRGVPEKEVGKVGEWAIRKLGLVKYGEKYAGNYSGGNKRKLSTAMALIGGPPVVFLDEP TTGMDPKARRFLWNCALSWKEGRSVVLTSHSMEECEALCTRMAIMVNGRFRCLGSVQHLKN RFGDGYTIVVRIAGSNPDLKPVQDFFGLAFPGSVLKEKHRNMLQYQLPSSLSSLARIFSILSQSK KRLHIEDYSVSQTTLDQVFVNFAKDQSDDDHLKDLSLHKNQTVVDVAVLTSFLQDEKVKESYV(SEQ ID N0:6) and has UniProt accession number 095477.

[0044] A “PNS myelination disorder resulting from abnormal ABCA1 regulated cholesterol transport” is a disorder of the PNS resulting from ineffective cholesterol transportor efflux which is at least in part regulated by ABCA1. Hence, while ABCA1 plays a role in cholesterol homeostasis in various tissues widely expressed throughout the body, this definition is limited to the subset of conditions impacted by ABCA1 regulation of cholesterol transport in the peripheral nervous system. The reverse cholesterol transport pathway or centripetal cholesterol efflux is another name for the process which removes cholesterol from peripheral nervous tissues to the liver and intestine in which ABCA1 plays the initial step. In the PNS, the most important cells expressing ABCA1 involved in myelination are glial cells known as Schwann cells. Example conditions include Charcot-Marie-Tooth Syndrome and Tangier disease

[0045] Schwann cells (“SCs”) are glial cells surround and support nerve axons of the peripheral nervous system. There are two primary categories of SCs: myelinating and nonmyelinating. The myelinating SCs form the myelin sheath of axons. The non-myelinating cells ensheath small axons forming unmyelinated fibers, called Remak bundles, or they migrate toward the neuromuscular junctions, covering the axon terminals, where they become terminal / perisynaptic / teloglia SCs. However, non-myelinating SC (NMSC) are also vital in maintaining the structural integrity and function of unmyelinated axons, playing a role in nerve regeneration and axon-Schwann cell interactions. NMSC are found at the distal end of motor nerve junctions and serve different functions based on location, such as maintenance of the axon and NMJ, peripheral nerve regeneration or remodeling of the NMJ. Abnormalities in nonmyelinating Schwann cells are linked to the development of certain peripheral nerve tumors, particularly neurofibromas, which can arise from genetic mutations affecting Schwann cell proliferation and differentiation.

[0046] A “demyelinating condition resulting from Schwann cell dysfunction” is a condition characterized by demyelination, dysmyelination or impairment of remyelination resulting from impaired myelinating Schwann cell function. Example conditions include inflammatory demyelinating neuropathy, acute inflammatory demyelinating polyneuropathy (“AIDP”), Guillain-Barre syndrome, acute idiopathic polyneuritis, chronic inflammatory demyelinating polyneuropathy (“CIDP”), and Anti-MAG peripheral neuropathy.

[0047] A “Schwann cell regulated cholesterol transport disorder” is a disorder or condition in which normal Schwann cell function is disrupted by an impairment in cholesterol transport in the Schwann cell membrane. It differs from “demyelinating conditions resulting from Schwann cell dysfunction by further encompassing disorders affecting both myelinating and non-myelinating Schwann cells. Disorders resulting from non-myelinating Schwann cells include disorders or conditions affecting axon maintenance, nerve regeneration and remodeling of neuromuscular junction (NMJ) and neurofibromatosis (NF), which are Schwann cell tumors.

[0048] Inflammatory demyelinating polyneuropathy is an autoimmune condition directed against the myelin components of the PNS characterized by progressive weakness, and impaired sensory function. It is often described in at two distinct forms - acute (AIDP) (akaGuillain-Barré syndrome (GBS) or acute idiopathic polyneuritis) and chronic (CIDP), which differ in onset, progress and causation. AIDP can occur suddenly, usually after an infection, surgery or vaccination, while CIDP has a gradual onset over at least 8-weeks. AIDP symptoms progress rapidly over days to weeks, while CIDP progresses more slowly. AIDP is thought to be caused by immunologic attack on myelin components, while CIDP is thought to an autoimmune disease caused by an abnormal immune response that attacks the myelin cover of the nerves which is not typically linked to infection. The symptoms of CIDP can very from mild to severe, and a course of the disease may involve period of relapse and remission. In AIDP, the symptoms typically peak in 2-4 weeks then plateau, with most patients recovering within 6 months to 2 years.

[0049] Acute inflammatory demyelinating polyneuropathy (AIDP) is an autoimmune condition characterized by progressive areflexic weakness and mild sensory changes. Sensory symptoms often precede motor weakness. About 20% of patients end up with respiratory failure. AIDP is the most common form of Guillain-Barre syndrome ) (GBS) in North America and Europe (AIDP comprises approximately 90% of cases.).

[0050] Guillain-Barre syndrome (“GBS”) also known as acute idiopathic polyneuritis) is a condition caused by the immune system attacking the PNS resulting in damage to myelin. GBS refers to a group of heterogeneous but related disorders of peripheral nerves with an acute onset, which is considered to be due to an autoimmune process and is usually postinfectious. It is often associated with patients who have experienced an infection before onset. While there is no known cure, typically involve plasmapheresis or intravenous immunoglobulin therapy (i.e. removal of neuron attacking antibodies). The two most common forms of GBS are AIDP and acute motor axonal neuropathy (AMAN), with the latter comprising 10% of GBS cases. An overview of GBS is provided at emedicine.medscape.com / article / 315632-overview.

[0051] Chronic inflammatory demyelinating polyneuropathy (“CIDP”) is an acquired autoimmune disease of the peripheral nervous system characterized by progressive weakness and impaired sensory function in the legs and arms resulting from the body’s production of antimyelin antibodies. While specific triggers of CIDP vary, it may appear as a complication with other disorders such as chronic hepatitis, diabetes, Camphylobacter jejuni infection, HIV / AIDS, immune system disorders due to cancer, inflammatory bowel disease, systemic lupus erthematosus, cancer of the lymph system, overactive thyroid. When CIDP occurs in diabetic patients, it is sometimes referred to as demyelinating diabetic neuropathy.

[0052] “Anti-MAG peripheral neuropathy” is a CIDP-like neuropathy which targets myelin-associated glycoprotein (MAG), a protein that helps maintain the myelin sheaths that protect nerves. This attack can cause the myelin to unravel, which can slow or stop electrical signals in the nerves. Anti-MAG neuropathy is more common in men than women, and usually affects people in their 60s or 70s. It's often associated with monoclonal gammopathy ofundetermined significance (MGUS), a condition that causes an overproduction of serum immunoglobulins.

[0053] Non-hereditary PNS myelination condition are conditions or neuropathies in which the myelin sheath of peripheral neurons is damaged, without a known genetic origin. The term includes peripheral neuropathy. The damaged myelin impairs the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition, or other functions depending on which nerves are involved. Non-hereditary PNS myelination conditions can be caused by inflammation, infectious agents (e.g., virus, bacteria, prion, microorganism), neurotoxins, autoimmune reactions, traumatic or ischemic injury, asphyxia, metabolic disorder, radiation induced, chemotherapy, copper deficiency, mechanical compression and some by unknown factors (idiopathic). Organophosphates, a class of chemicals which are the active ingredients in commercial insecticides, herbicides and fungicides will also demyelinate nerves. Neuroleptics can cause demyelination. Common symptoms of neuropathies include: inflammation, fatigue, dizziness, malaise, elevated fever and high body temperature, extreme sensitivity to cold in the hands and feet, weakness and stiffness in muscles and joints, weight changes, digestive or gastrointestinal problems, low or high blood pressure, irritability, anxiety, or depression, blurred or double vision, ataxia, clonus, dysarthria, fatigue, clumsiness, hand paralysis, hemiparesis, genital anesthesia, incoordination, paresthesia, ocular paralysis, impaired muscle coordination, weakness (muscle), loss of sensation, impaired vision, neurological symptoms, unsteady gait, spastic paraparesis, incontinence, hearing problems, or speech problems.

[0054] Trigeminal neuralgia (TN), also known as douloureux, is a chronic pain disorder known as one of the most painful types of neuropathy that can be associated with a variety of conditions. It affects the trigeminal nerve as it exits the brain stem, which provides feeling and signaling to the head and face, (www.ninds.nih.gov / trigeminal-neuralgia-fact-sheet.) The trigeminal nerve is myelinated by Schwann cells like other peripheral nerves. Three TN branches supply sensation to different cranial regions: (i) ophthalmic (upper) - scalp, forehead and front of head; (ii) maxillary (middle) - cheek, upper jaw, top lip, teeth and gums, side of nose; (iii) mandibular (lower) - lower jaw, teeth and gums, bottom lip. In classic TN, blood vessels press on the trigeminal nerve as it exits the brain stem. In secondary TN, symptoms appear in association with another disorders (such as multiple sclerosis, tumor or arteriovenous malformation). It is unknown why in some individuals this compression causes damage to the myelin and associated extreme pain.

[0055] Neuropathy symptoms can be measured using the Overall Neuropathy Limitations Scale (ONLS) or the Overall Disability Sum Scale (ODSS). The ONLS is a newer version of ODSS which further evaluates a patient’s ability to walk, run or climb stairs. The ONLS and ODSS focus on upper and lower limb functions, scoring 0-5 on the upper limb and 0-7 on lowerlimb - with 0 indicating no limitation and 5-7 no purposeful movement. ONLS is calculated by adding the arm and leg scores, with a total ranging from 0 - 12.

[0056] There are two main types of peripheral neve injury. One is axonotmesis, in which axons are disrupted but the connective tissue sheaths and the Schwann cell containing basal lamina tubes remain intact. When this is modeled in rodents by nerve crush, axonal regeneration is remarkably effective and function is restored in 3-4 wk. The other is neurotmesis, in which axons, connective sheaths, and basal lamina tubes are interrupted. The end result of neurotmesis is Wallerian degeneration, an active process of degeneration that results when a nerve fiber is cut or crushed at the part of the axon distal to the injury. Wallerian degeneration occurs after axonal injury in both the peripheral nervous system (PNS) and central nervous system (CNS). It occurs in the section of the axon distal to the site of injury and usually begins within 24-36 hours of a lesion. Prior to degeneration, the distal section of the axon tends to remain electrically excitable. After injury, the axonal skeleton disintegrates, and the axonal membrane breaks apart. Axonal degeneration is followed by degradation of the myelin sheath and infiltration by macrophages. The macrophages, accompanied by Schwann cells, serve to clear the debris from the degeneration.

[0057] The term “therapeutically effective amount” or “effective amount” of a compound described herein means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art. The effective amount of a compound of the disclosure in such a therapeutic method is, for example, from about 0.01 mg / kg / day to about 1000 mg / kg / day, about 0.1 mg / kg / day to about 100 mg / kg / day, about 1 mg / kg / day to 100 mg / kg / day, 10 mg / kg / day to 100 mg / kg / day or about 20 mg / kg / day.

[0058] The term “excipient” as used herein refers to an inert or inactive substance that may be used in the production of a drug or pharmaceutical composition, such as a tablet containing a compound as described herein (or pharmaceutically acceptable salt) as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a diluent, filler or extender, binder, disintegrant, humectant, coating, emulsifier or dispersing agent, compression / encapsulation aid, cream or lotion, lubricant, solution for parenteral administration, material for chewable tablets, sweetener or flavoring, suspending / gelling agent, or wet granulation agent. Binders may include, e.g., carbomers, povidone, xanthan gum, etc.; coatings may include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include e.g. calcium carbonate, dextrose, fructose de (de - “directly compressible"), honey de,lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch de, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g. dextrose, fructose de, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose de, sorbitol, sucrose de, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0059] “Pharmaceutically acceptable carrier” includes any solvents, dispersion media, or coatings that are physiologically compatible and that preferably does not interfere with or otherwise inhibit the activity of the polypeptide or peptidomimetic. Preferably, the carrier is suitable for intravenous, intramuscular, oral, intraperitoneal, transdermal, topical, or subcutaneous administration. Pharmaceutically acceptable carriers can contain one or more physiologically acceptable compound(s) that act, for example, to stabilize the composition or to increase or decrease the absorption of the active agent(s). Physiologically acceptable compounds can include, for example, carbohydrates, such as glucose, sucrose, or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, compositions that reduce the clearance or hydrolysis of the active agents, or excipients or other stabilizers and / or buffers.

[0060] Other physiologically acceptable compounds include, but are not limited to, wetting agents, emulsifying agents, dispersing agents or preservatives which are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid. One skilled in the art will appreciate that the choice of pharmaceutically acceptable carrier(s), including a physiologically acceptable compound depends, for example, on the route of administration of the polypeptide(s) or peptidomimetic(s) and on the particular physio-chemical characteristics of the polypeptide(s) or peptidomimetic(s).

[0061] A “pharmaceutically acceptable carrier” and their formulations are well-known and generally described in, for example, Remington's Pharmaceutical Science (18thEd., ed.Gennaro, Mack Publishing Co., Easton, Pa., 1990). Various pharmaceutically acceptable excipients are well-known in the art and can be found in, for example, Handbook of Pharmaceutical Excipients (4thed., Ed. Rowe et al., Pharmaceutical Press, Washington, D. C.). Again, the pharmaceutical composition can be formulated as a solution, microemulsion, liposome, capsule, tablet, or other suitable form. The active component may be coated in a material to protect it from inactivation by the environment prior to reaching the target site of action.

[0062] “Treatment” or “treating” is an action for obtaining beneficial or desired results including but not limited to clinical results. Beneficial or desired results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with die disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying die spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease or condition, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival). Also encompassed by ’’treatment” or “treating” is a reduction of pathological consequence of demyelination.

[0063] Myelin is a lipid rich material surrounding nerve cell axons, insulating them and increasing the rate which electrical impulses pass along the axon. Myelin is made by glial cells, which in the PNS are Schwann cells, which exist to provide nutritional and homeostatic support to the axons. Myelin comprises about 40% water, 60-75% lipid and 15-25% protein. PNS myelin differs from CNS myelin by replacing proteolipid protein (PLP) with myelin protein zero (MPZ or P0) which serves to hold together the multiple concentric layers of glial cell membranes comprising the myelin sheath.

[0064] The term “amphipathic alpha (a) helix” refers to a polypeptide sequence that can adopt a secondary structure that is helical with one surface, / .e., face, being polar and comprised primarily of hydrophilic amino acids (e.g., Asp, Glu, Lys, Arg, His, Gly, Ser, Thr, Cys, Tyr, Asn and Gin), and the other surface being a nonpolar face that comprises primarily hydrophobic amino acids (e.g., Leu, Ala, Vai, lie, Pro, Phe, Trp and Met) (see, e.g., Kaiser and Kezdy, Ann. Rev. Biophys. Biophys. Chem., 16:561 (1987), and Science, 223:249 (1984)).

[0065] The polar face of an amphipathic a helix can, in some instances, display an “alignment of negatively charged amino acids” or “an alignment of acidic amino acids,” i.e., a series of negatively charged or acidic amino acids (e.g., Asp and / or Glu) positioned approximately evenly (e.g., at about every one, two or three helical turns) within the polypeptide secondary structure. Amphipathic a helices play a role in both intra- and inter-molecular proteinprotein interactions, and proteins and lipoproteins (e.g., including apolipoproteins) comprising amphipathic a helices have been postulated to play a role in lipid (e.g., HDL) transport and metabolism (see, e.g., Anantharamaiah etal., Adv. Exp. Med. Biol., 285:131-40 (1991)). The structure and function of amphipathic a helices has been reviewed in, e.g., Segrest et al., Proteins, 8(2):103-17 (1990). In silico methods of identifying amphipathic a helices have been described by, e.g., Jones etal., J. Lipid Res., 33(2):141-66 (1992). Multiple proteins comprisingamphipathic a helices have been identified including, e.g., apolipoproteins and serum amyloid proteins.

[0066] The terms “cholesterol efflux” and “cholesterol efflux activity” refer to efflux of cholesterol from any cell type. For example, Schwann cells export cholesterol to appropriate acceptors, such as apolipoproteins and / or HDL. A compound that mediates cholesterol efflux enhances the release, / .e., movement, of cholesterol out of the cell and into the extracellular medium or compartment to a similar extent to that of full-length apolipoproteins (e.g., ApoA1 and ApoE). Cholesterol efflux is often accompanied by or preceded by, / .e., follows, the efflux of phospholipids from cells. The coordinated release of both cholesterol and phospholipids produces HDL in the presence of a suitable lipid acceptor, e.g., apolipoprotein or peptide. A compound that enhances the release of cholesterol from cells increases the amount of cholesterol and / or phospholipids appearing outside the cell by at least 25%, 50%, 75%, 100% or by at least 2-fold, 4-fold, 8-fold, 10-fold or more compared to the level of cholesterol efflux in the absence of the compound.

[0067] The term “ABCA stabilization activity” or “ABCA1 stabilization” refers to enhancing and / or extending the half-life of an ABCA protein by preventing its degradation. A compound that has ABCA1 stabilization activity will significantly delay the protein’s degradation. This will produce an increase in cellular (including membrane) ABCA1 protein levels or reduce its degradation by at least 25%, 50%, 75%, 100% or at least 2-fold, 4-fold, 8-fold, 10-fold or higher compared to ABCA1 protein detected in the absence of the compound.

[0068] The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. “Naturally occurring amino acids” includes both (i) “essential amino acids” - those encoded by the genetic code, as well as (ii) those amino acids that are later modified physiologically, e.g., hydroxyproline, y-carboxyglutamate, O-phosphoserine, and citrulline. The amino acids may be neutral, positive or negative depending on the substituents in the side chain. "Neutral amino acid" means an amino acid containing uncharged side chain substituents. Examples of neutral amino acids include alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine and cysteine."Positive amino acid" means an amino acid in which the side chain substituents are positively charged at physiological pH. Examples of positive amino acids include lysine, arginine and histidine. "Negative amino acid" means an amino acid in which the side chain substituents bear a net negative charge at physiological pH. Examples of negative amino acids include aspartic acid and glutamic acid. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups(e.g., norleucine) or modified polypeptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. Amino acid is also meant to include amino acids having L or D stereochemistry at the a-carbon. A more detailed description of amino acid as well as conservative amino acid substitutions is provided below in the section entitled “Polypeptides.”

[0069] A "non-natural amino acid" is an amino acid that is synthetic or is not found in nature, whether commonly or rarely (e.g., selenocysteine or pyrrolysine). Other terms that may be used synonymously with the term "non-natural amino acid," including "non-naturally encoded amino acid," "unnatural amino acid," "non-naturally-occurring amino acid," and variously hyphenated and non-hyphenated versions thereof. Examples of naturally-occurring amino acids that are not naturally-encoded include, but are not limited to, N-acetylglucosaminyl-L-serine, N-acetylglucosaminyl-L-threonine, and O-phosphotyrosine. Additionally, the term "non-natural amino acid" includes, but is not limited to, amino acids which do not occur naturally and may be obtained synthetically or may be obtained by modification of non-natural amino acids.

[0070] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0071] Citrulline is a non-essential amino acid related to arginine wherein the guanidino group [H2N-(C=NH)-NH-] in the side chain is replaced with a ureido group [H2N-(C=O)-NH-]. Citrulline is closely related to arginine, retaining the polar characteristics while being uncharged, and is readily converted to arginine. Citrulline is generated by a family of enzymescalled peptidylarginine deiminases (PADs), which convert arginine into citrulline in a process called citrullination or deimination with the help of calcium ions. It is generally understood that citrullination of myelin can inhibit compaction and alters electrostatic interactions with other proteins and lipids. Arginine citrullination may also play a role in pathogenesis of multiple sclerosis. Moscarello et al., Neurochem. Res. 2007, 32(2): 251-256.

[0072] CS6253 peptides and analogs as disclosed herein can be synthetically assembled, for example, by solid phase synthesis. Citrulline can be incorporated as an amino acid residue during synthesis.

[0073] The term "aliphatic," as used herein, includes both saturated and unsaturated, nonaromatic, straight chain (i.e., unbranched), branched, acyclic, and cyclic (i.e., carbocyclic) hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, "aliphatic" is intended herein to include, but is notlimited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, as used herein, the term "alkyl" includes straight, branched and cyclic alkyl groups. An analogous convention applies to other generic terms such as "alkenyl," "alkynyl," and the like. Furthermore, as used herein, the terms "alkyl," "alkenyl," "alkynyl," and the like encompass both substituted and unsubstituted groups. In certain embodiments, as used herein, "aliphatic" is used to indicate those aliphatic groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms. Aliphatic group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0074] “Polypeptides” are polymers of amino acids. Polypeptides can comprise naturally occurring amino acids and non-naturally occurring amino acids. Polypeptides can comprise one or more amino acid residues which are an artificial chemical mimetics of a corresponding naturally occurring amino acid. Amino acid polymers may comprise entirely L-amino acids, entirely D-amino acids, or a mixture of L and D amino acids. The use of the term "peptide or peptidomimetic" in the current application merely emphasizes that peptides comprising naturally occurring amino acids as well as modified amino acids are contemplated. Peptides may also have reversed or inverted sequence. The term “peptide” generally refers to polypeptides comprising no more than 50 amino acid residues. The term “protein” generally refers to polypeptides having a higher order structure.

[0075] The terms “identical” or percent “identity,” in the context of two or more polypeptide sequences (or two or more nucleic acids), refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same e.g., 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity over a specified region, when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection. Such sequences are then said to be “substantially identical.” This definition also refers to the complement of a test nucleic acid sequence.

[0076] For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default programparameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters. For sequence comparison of nucleic acids and polypeptides, the BLAST and BLAST 2.0 algorithms and the default parameters may be used.

[0077] The terms “numbered with reference to”, or “corresponding to”, or “determined with reference to” when used in the context of the numbering of a given amino acid, refers to the numbering of the residues of a specified reference sequence when the given amino acid sequence is compared to the reference sequence. Thus, a residue in a polypeptide “corresponds to” an amino acid at a position in SEQ ID NO:1 when the residue aligns with the amino acid in an alignment of SEQ ID NO:1 to the variant polypeptide. The polypeptide that is aligned to the reference sequence need not be the same length as the reference sequence.

[0078] The terms “nucleic acid” and “polynucleotide” are used interchangeably herein to refer to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or doublestranded form. The term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, polypeptide-nucleic acids (PNAs). Unless otherwise indicated, a particular nucleic acid sequence also encompasses “conservatively modified variants” thereof (e.g., degenerate codon substitutions) and complementary sequences, as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (Batzer etal., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem., 260:2605-2608 (1985); Rossolini etal., Mol. Cell. Probes, 8:91-98 (1994)). The term nucleic acid is used interchangeably with gene, cDNA, mRNA, oligonucleotide, and polynucleotide.

[0079] A “label” or “detectable label” is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, or chemical means. For example, useful labels include radioisotopes (e.g.,3H,35S,32P,51Cr, or125l), fluorescent dyes, electron-dense reagents, enzymes (e.g., alkaline phosphatase, horseradish peroxidase, or others commonly used in an ELISA), biotin, digoxigenin, or haptens and proteins for which antisera or monoclonal antibodies are available (, e.g., by incorporating a radiolabel into the polypeptide, and used to detect antibodies specifically reactive with the polypeptide).

[0080] As used herein, “ameliorate” means alleviate, lessen, or decrease the extent of a symptom or decrease the number of occurrences of episodes of a disease manifestation.

[0081] The term “preventing” is art-recognized, and when used in relation to a condition, such as recurrence or onset of a disease, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.

[0082] As used herein, “inhibits” means that the amount is reduced as compared with the amount that would occur in a control sample. In a preferred embodiment, inhibits means that the amount is reduced by at least 15%, at least 25% at least 50%, at least 75%, or even 100%.

[0083] A “subject,” “patient” or “mammal” to be treated by the methods disclosed herein can mean either a human or non-human animal. A “patient” is a subject under the care of a health care professional.II. Description of the DisclosureA. PMP22

[0084] PMP22 plays a role in the formation and maintenance of compact myelin. Watila et al., J. Neurol. Sci. 355 (1-2); 18-24 (2015). When Schwann cells come into contact with a neuronal axon, expression of PMP is significantly up-regulated, while PMP22 is downregulated during axonal degradation or transactions. Watila, supra.; Parker et al., Mol. Neurobiology 47 (2): 673-698 (2013). Interestingly, PMP22 does not appear to play a similar role in astrocytes and oligodendrocytes, the CNS myelinating equivalent to Schwann cells in the PNS. PMP22 mRNA is downregulated in astrocytes and oligodendrocytes.

[0085] Improper expression levels of PMP22 can result in aberrant protein synthesis and impair functioning of the myelin sheath. Too much PMP22 (e.g., such as that resulting from gene duplication, leads to Charcot-Marie Tooth type 1A (CMT1A), while too little (e.g., PMP22 gene deletion, haploinsufficiency) results in Hereditary Neuropathy with Liability to Pressure Palsy (HNPP), whereas PMP22 point mutations lead to Dejerine-Sottas Syndrome (DSS or CMT3) and Charcot-Marie Tooth type 1E (e.g., L16P, CRAC-domain). Hence, attenuating overexpression, amplifying under expression and correcting misexpression of PMP22 are objects of this disclosure.

[0086] Overexpression of PMP22 can result in the apoptosis of Schwann cells. Moreover, elevated PMP22 copy number reduced the expression of cholesterol metabolism genes - such as HMG-CoA synthase, HMG-CoA reductase, cytochrome P450, sterol-C4-methyloxidase-like and sterol-C5-desaturase. Giambonini-Brugnoli G, et al. Neurobiol Dis. 2005;18:656–668.Deficiency of cholesterol synthesis during development of peripheral nerves also impairs myelination, including reduced myelin thickness.

[0087] As determined by coimmunoprecipitation, PMP22 interacts with cholesterol biosynthesis enzymes, including PGRMC1, EMC4, DHCR7, DHCR24, TMEM97 and SURF4. Stefanski et al., Biochem Soc. Trans. 2024, 52: 1747-1756.

[0088] Peripheral neuropathies can occur alone, or as a complication of other conditions. They can significantly impact the quality of life with symptoms ranging from severe pain to paralysis. Hereditary neuropathies are often more severe compared to idiopathic neuropathies. In the case of PMP22-mediated neuropathies, they can cause extreme weakening and wasting of skeletal muscles, gait abnormalities, loss of tendon reflexes, numbness respiratory dysfunction - any or all of which significantly impact quality of life and reduce life expectancy.B. ABCA1

[0089] ABCA1 regulates cholesterol and phospholipid homeostasis by mediating their transport across the cell membrane to lipid-poor apoliproteins (ApoA1, ApoE), which form nascent high-density lipoproteins (HDL). It also mediates the transport of lipids between the Golgi and cell membranes and is widely expressed throughout the body. ABCA1 is also present in elevated levels in tissues that are involved in lipid turnover, such as the liver, small intestine and adipose tissue. Wagner et al., Access Science, “ABC lipid transporters" (2014). ABCA1 is an ABC transporter that is the primary cholesterol efflux transporter in SCs, responsible for HDL formation. Loss of function mutations in ABCA1 cause Tangier disease, which includes intracellular accumulation of cholesterol esters in SCs and polyneuropathy (Züchne et al., 2003, Brain 126, 920–927; Karabudak et al., J. Clin. Lipidol. 18, e285–e289. By regulating cholesterol homeostasis and plasma membrane dynamics, ABCA1 is involved in many physiological and pathological processes. ABCA1 protects cells from cholesterol toxicity by promoting cholesterol efflux. In addition, by regulating plasma membrane dynamics, ABCA1 plays a role in cell signaling and microparticle formation. Through these mechanisms, ABCA1 is involved in the pathogenesis of a broad array of diseases including dyslipidemia, atherosclerosis, coronary heart disease, type 2 diabetes, thrombosis, CNS neurological disorders, age-related macular degeneration, glaucoma, viral infection, and cancer progression.

[0090] The therapeutic target of the present disclosure is the restoration of cholesterol transport via engagement with the ATP-binding cassette subfamily A transporter (ABCA1) in neuropathic glial cells (e.g. Schwann cells). ABCA1 plays a major role in regulating cholesterol efflux and the cholesterol content of the plasma membrane (Jacobo-Albavera et al., 2021, Int J Mol Sci. 22. Recent studies also implicate ABCA1 in the redistribution of cholesterol between membrane microdomains and in modulating the solubility of cholesterol in the membrane (Plummer et al., 2021, Annu Rev Physiol. 83:153181). These are critical properties for myelin, ahighly-specialized plasma membrane of Schwann cells and oligodendrocytes. ABCA1 is studied widely because of its interaction with apolipoprotein E (apoE). In the peripheral nervous system (PNS), apoE is upregulated during nerve regeneration and when applied exogenously as a mimetic peptide, it stimulates axonal regrowth and remyelination (Li et al., 2010, J Pharmacol Exp Ther. 334:106 115. Without being limited to any specific mechanism, it is believed that the present disclosure, because CS6253 is a synthetic carboxyl-tail peptide fragment of apoE, activates ABCA1 -mediated cholesterol transport in neuropathic Schwann cells. This is especially the case when such cholesterol transport is inactive or reduced from mutant, reduced or overexpressed PMP22 - the Schwann cell ABCA1 binding partner.C. Polypeptide variants having cholesterol efflux activity

[0091] Methods of treating a PNS myelinization condition in a subject comprise administering to the subject an effective amount of peptide CS6253, and variants thereof.1. CS6253

[0092] CS6253 has the amino acid sequence EVcitSKLEEWLAALcitELAEELLARLKS (SEQ ID NO:3), wherein cit refers to citrulline.

[0093] Variants of CS6253 include those with at least any of 60%, 65%, 70%, 75, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least 99% sequence homology with CS6253. Polypeptides suitable for use with the present disclosure are a family of non-naturally occurring polypeptides having cholesterol efflux activity comprising (i) EVcitSKLEEWLAALcitELAEELLARL (SEQ ID NO:1), (ii) variants wherein leucine residues at positions 10, 13, 16, 20 is replaced with isoleucine EVcitSKLEEWIAAIcitEIAEEILARL (SEQ ID NO:2), or non-naturally occurring variants of SEQ ID NOS: 1 or 2. Amino acid positions of variants of SEQ ID NO:1 or SEQ ID NO:2 are determine with reference to SEQ ID NO:1 or SEQ ID NO:2, respectively and “cit” refers to citrulline. In some embodiments, the polypeptide variant further comprises amino acids at positions 25 and 26, numbered with reference to SEQ ID NO:1. In some embodiments, the amino acid residue at position 25 is K or N and the amino acid residue at position 26 is S or Y. More specifically, the amino acid at position 25 is K and the amino acid at position 26 is S. In some embodiments, the peptide comprises the amino acid sequence EVcitSKLEEWIAAIcitEIAEEILARLKS (SEQ ID NO:4), wherein “cit” refers to citrulline. These variant polypeptides stimulate ABCA1-dependent cholesterol efflux with a molar potency similar to that of apolipoproteins (e.g., Apo A-l, Apo E, etc.). In addition to being potent and selective mediators of ABCA1-dependent cholesterol efflux, the polypeptides have little or no toxicity when administered at high doses. The polypeptides of the present disclosure also haveABCAI stabilization activity.

[0094] In some embodiments, peptide variants of SEQ ID NO:1 or SEQ ID NO:2 may have an acidic amino acid residue at position 1, 7, 8, 15, 18, and 19 as numbered with reference to SEQ ID NO:1. In some embodiments, a variant has an uncharged residue at the polar surface, e.g., at at least one of positions 3, 14, or 23 as numbered with reference to SEQ ID NO:1. In some embodiments, the variant has citrulline at two or three of positions 3, 14, or 23, and positively charged amino acids at the remaining positions, as numbered with reference to SEQ ID NO:1, and positively charged amino acid at the remaining positions. In some embodiments, a variant has citrulline at positions 3 and 14, positions 3 and 23, or positions 14 and 23. In some embodiments, a variant has citrulline at positions 3 and 14 and an R or K at position 23; citrulline at positions 3 and 23 and an R or K at position 14; or citrulline at positions 14 and 23 and an R or K at position 3. In some embodiments, a variant has no more than two R residues. For example, in some embodiments, a variant may have an R at position 5 and an R at position 23. In some embodiments, the amino acid sequence comprises an uncharged residue at one or two of positions 3, 14, and 23 where the residue is a hydrophobic amino acid, such as Q, N, Y, W, A, I, L, V. In some embodiments, the uncharged residue at one or two of positions 3, 14, and 23 is an aliphatic amino acid, such as A, I, L, or V. In embodiments when there is a hydrophobic or aliphatic amino acid at one or two of positions 3, 14, and 23, the third positions is an R, K, or citrulline. In some embodiments, a variant comprises a hydrophobic amino acid at position 2, 6, 9, 10, 13, 16, 17, 20, 21, 22, and 24 as determined with reference to SEQ ID NO:1. In some embodiments, a variant comprises an aliphatic amino acid at at least one, or at least two, three, four, five, six, seven, eight, or nine of positions 2, 6, 10, 13, 16, 17, 20, 21, 22, and 24. In some embodiments, a variant comprises an aliphatic residue at each of positions 2, 6, 10, 13, 16, 20, 21, and 24. In some embodiments, the aliphatic amino acid is L, V, or I. In some embodiment, the aliphatic amino acid residue at position 2, 6, 10, 13, 16, 20, and 21 is L. In some embodiment, the aliphatic amino acid residue at position 2, 6, 10, 13, 16, 20, and 21 is I. In some embodiments, the aliphatic amino acid residue at position 2 is V. In some embodiments, the aliphatic amino acid residue at position 2 is V and the aliphatic amino acid residue at position 6, 10, 13, 16, 20, and 21 is L. In some embodiments, the aliphatic amino acid at each of positions 10, 13, 16, and 20 is the same amino acid. In some embodiments, the aliphatic amino acid is a branched chain amino acid. In some embodiments, the aliphatic amino acid at each of positions 10, 13, 16, and 20 is the same amino acid selected from the group consisting of L, I, or V. In some embodiments, the aliphatic amino acid at each of positions 10, 13, 16, and 20 is I. In some embodiments, the aliphatic amino acid at each of positions 10, 13, 16, and 20 is L. In some embodiments, the aliphatic amino acid at position 2 is V, the aliphatic amino acid at position 6, 21, and 24 is L, and the aliphatic amino acid residue at position 10, 13, 16, and 20 is I or L. In some embodiments, a variant comprises A at positions 11 and 12. In some embodiments, a peptide of the disclosure stimulates ABCA1-dependent cholesterol efflux with a molar potency similar to that of apolipoproteins (e.g., Apo A-l, Apo E, etc.). In addition to beingpotent and selective mediators of ABCA1 -dependent cholesterol efflux, the polypeptides have little or no toxicity when administered at high doses. The polypeptides of the present disclosure also haveABCAI stabilization activity.

[0095] As used herein, the term “little or no toxicity” is used interchangeably with “little or no cytotoxicity” to refer to a level of cytotoxicity for a peptide of the disclosure administered at a high pharmacological dose that typically is essentially equivalent to that obtained using a control only, i.e., a vehicle such as PBS that does not contain the peptide. Toxicity can be measured in an in vitro or in vivo assay. For example, in a rat, mouse, or rabbit model in which a peptide is administered IP at a dose of 300 mg / kg a response 50% or more above PBS, and in some embodiments, 40%, 30%, or 20% above PBS is considered toxic.

[0096] In amphipathic a-helix peptides, hydrophobic amino acids are concentrated on one side of the helix, usually with polar or hydrophilic amino acids on the other. This arrangement is common in alpha helices of apolipoproteins and globular proteins, where one face of the helix is oriented toward the hydrophobic core and one face is oriented toward the water-exposed surface. Different amino-acid sequences have different propensities for forming a-helical structure. Methionine, alanine, leucine, glutamate, and lysine all have especially high helixforming propensities, whereas proline, glycine, tyrosine, and serine have relatively poor helixforming propensities. Proline tends to break or kink helices because it cannot donate an amide hydrogen bond (having no amide hydrogen), and because its side chain interferes sterically. Its ring structure also restricts its backbone dihedral angle to the vicinity of -70°, which is less common in a-helices. One of skill understands that although proline may be present at certain positions in the sequences described herein, the presence of more than three prolines within the sequence would be expected to disrupt the helical structure. Accordingly, the polypeptides of the disclosure do not have more than three prolines, and commonly do not have more than two prolines present at positions in the alpha-helix forming sequence. Typically, when a proline is present in the sequence of a core helical structure of a polypeptide of the disclosure, e.g., a polypeptide variant of SEQ ID NO:1, it is present in only one position of the core helix sequence.

[0097] A polypeptide having cholesterol efflux activity suitable for use in the disclosure comprises an amino acid sequence that is an amphipathic a-helix having a non-polar surface and a polar surface where the polar surface comprises charged and an uncharged amino acid residues at the lipid-water interface. In some embodiments, a polypeptide of the disclosure comprises an amino acid sequence of SEQ ID NO:1 or SEQ ID NO:2, or variants thereof, wherein the variants comprises an amino acid sequence having at least 50%, typically at least 55%, at least 60%, at least 65%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95%, or greater identity to SEQ ID NO:1 or SEQ ID NO:2. In typical embodiments, a variant has an uncharged residue at at least one of positions 3, 14, or 23 as numbered with reference to SEQ ID NO:1. Alternatively, the polypeptides further comprise additional aminoacid residues K or N or position 25 and S or Y at position 26 with reference to SEQ ID NO:1 or SEQ ID NO:2. In one embodiment, a polypeptide of the disclosure comprises the amino acid sequence of SEQ ID NO:3 or SEQ ID NO:4.

[0098] In some embodiments, the polypeptide has a citrulline, or analog of citrulline, that is present at the lipid-water interface, for example at 3, 14, or 23 as numbered with reference to SEQ ID NO:1. In some embodiments, a variant has a citrulline at position 3 and 14, position 3 and 23, or position 14 and 23.

[0099] Variants of SEQ ID NO:1 or SEQ ID NO:2 typically have only a limited number of unmodified R (Arg) amino acid residues, typically no more than two R residues. For example, in some embodiments, a variant may have an R at position 5 and an R at position 23. In some embodiments, a variant may have a citrulline at position 3 and 14 and an R at position 23; or a citrulline at positions 3 and 23 and an R at position 14; or a citrulline at positions 14 and 23 and an R as position 3. In some embodiments, an R at an indicated position may be substituted with a K residue. Thus, in some embodiments, a variant may have a K at position 5 and an R at position 23, or an R at position 5 and a K at position 23, or a K at both positions 5 and 23. In some embodiments, a variant may have a citrulline at position 3 and 14 and a K at position 23; or a citrulline at positions 3 and 23 and a K at position 14; or a citrulline at positions 14 and 23 and a K at position 3. In other embodiments, the polypeptide variants further comprise additional amino acid residues K or N or position 25 and S or Y at position 26 with reference to SEQ ID NO:1 or SEQ ID NO:2.[000100] In some embodiments, a variant polypeptide comprises a hydrophobic amino acid, typically an aliphatic amino acid, at least one, or at least two, three, four, five, six, seven, eight, nine, or ten of positions 2, 6, 9, 10, 13, 16, 17, 20, 21, 22, and 24 as determined with reference to SEQ ID NO:1. In some embodiments, a variant of SEQ ID NO:1 or SEQ ID NO:2 comprises no more than three or no more than two, or no more than one aromatic amino acids. In some embodiments a variant comprises an aliphatic residue at each of positions 2, 6, 10, 13, 16, 20, 21, and 24. In some embodiments, the aliphatic amino acid is L, V, A, or I. In some embodiments, a polypeptide of the disclosure comprises the same aliphatic amino acid at each of positions 10, 13, 16, and 20. In some embodiments, the same aliphatic amino acid at each of positions 10, 13, 16, and 20 is a branched chain aliphatic amino acid. In some embodiments, the same aliphatic amino acid at each of positions 10, 13, 16, and 20 is selected from the group consisting of L, I, or V. In some embodiments, the amino acid residue at position 10, 13, 16, and 20 is I. In some embodiments, the amino acid residue at position 10, 13, 16, and 20 is L. In some embodiments, the aliphatic amino acid residue at position 2 is V or L. In some embodiments, the aliphatic amino acid residue at position 2 is V and the aliphatic amino acid residue at position 10, 13, 16, and 20 is I or L. In some embodiments, the aliphatic amino acid at position 2 is V, the aliphatic amino acid at position 6, 21, and 24 is L, and the aliphatic aminoacid residue at position 10, 13, 16, and 20 is I or L. In some embodiments, a variant comprises A at positions 11 and 12.[000101] In some embodiments, a variant polypeptide further comprises amino acids at positions 25 and 26, as numbered with reference to SEQ ID NO:1. In typical embodiments, the amino acid residue at position 25 is K or N and the amino acid residue at position 26 is S, Y, or P. In some embodiments, the amino acid at position 25 is K and the amino acid at position 26 is S. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO:3 or SEQ ID NO:4.[000102] It will be readily understood by those of skill in the art that the foregoing polypeptides are not fully inclusive of the family of polypeptides of the present disclosure. In fact, using the teachings provided herein, other suitable polypeptides (e.g., additional conservative variants) can be routinely produced by, for example, conservative or semi-conservative substitutions (e.g., D replaced by E), extensions, deletions and the like. In addition, using the assays provided herein, other suitable polypeptides can be routinely screened for desired biological activities.[000103] Non-identical amino acid residues can be naturally or non-naturally occurring. The term “percent identical” refers to sequence identity between two amino acid sequences (or between two nucleotide sequences, which are also provided by the present disclosure). Identity can each be determined by comparing a position in each sequence that may be aligned for purposes of comparison. When an equivalent position in the compared sequences is occupied by the same amino acid or base, then the molecules are identical at that position; when the equivalent site is occupied by the same or a similar amino acid residue (e.g., similar in steric and / or electronic nature), then the molecules can be referred to as homologous (similar) at that position. Expression as a percentage of homology, / .e., similarity, or identity refers to a function of the number of similar or identical amino acids at positions shared by the compared sequences. Various alignment algorithms and / or programs can be used, including, for example, FASTA, BLAST and ENTREZ. FASTA and BLAST are available as a part of the GCG sequence analysis package (University of Wisconsin, Madison, Wis.), and can be used with, e.g., default settings. ENTREZ is available through the National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD. In one embodiment, the percent identity of two sequences can be determined by the GCG program with a gap weight of 1, e.g., each amino acid gap is weighted as if it were a single amino acid mismatch between the two sequences.[000104] In another embodiment, variants of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 or SEQ ID NO:4 are substituted with conservative (or semi-conservative) amino acid residues. The term “conservative amino acid substitutions” refers to the substitution of an amino acid from one such group with a different amino acid from the same group, wherein the group isdefined by amino acid sharing similar structure, function or other properties. A functional way to define common properties between individual amino acids is to analyze the normalized frequencies of amino acid changes between corresponding proteins of homologous organisms (see, e.g., Schulz, G. E. and R. H. Schirmer, Principles of Protein Structure, Springer-Verlag). Such interspecies variability can be evaluated in nature by considering the impact on protein function and overall structure (see, e.g., Schulz, G. E. and R. H. Schirmer, Principles of Protein Structure, Springer-Verlag). Groupings can also be made based on the nature of the side chain. Examples include (i) side chain charge’. Negative or acidic - Glu and Asp; Positive or basic -Lys, Arg, His; (ii) aromatic. Phe, Tyr and Trp; (iii) nitrogen containing ring: His and Trp; (iv) large aliphatic nonpolar group: Vai, Leu and lie; (v) Slightly-polar Met and Cys; (vi) small-residue group: Ser, Thr, Asp, Asn, Gly, Ala, Glu, Gin and Pro; (vii) aliphatic: Vai, Leu, lie, Met and Cys; and (vii) a small hydroxy: Ser and Thr. In the context of this disclosure, reference to the charge of an amino acid refers to the charge at physiological pH.[000105] In another embodiment, which can overlap with the above, “conservative amino acid substitution” can refer to the substitution of an amino acid for another that is similar in molecular weight or similar in hydrophobicity. More specifically “similar molecular weight” and “similar hyrdrophobicity” is meant a value that is within 25%, more preferably 20%, 15%, 10%, or less than 10% of the respective value. Data for amino acid molecular weights and hydrophobicities are set forth in Table 1. A hydrophobicity ranking is set forth in Table 2; a conservative substitution includes exchanging an amino acid that is designated “=” to another (e.g., Tyr = Trp) and exchanging one amino acid for another that is adjacent to it in the ranking order as delineated by the greater and lesser than symbols. Hydrophobicity plots are readily used to help identify polar domains that are exposed to cytoplasm or serum from internal or lipid exposed membrane domains. In general, a “hydrophobic amino acid” refers to amino acid residues with hydrophobic side sides, for example, glycine (Gly), alanine (Ala), valine (Vai), leucine (lie), proline (Pro), phenylalanine (Phe), methioinine (Met) and tryptophan (Trp).2. TABLE 1:t The molecular weights given are those of the neutral, free amino acids; residue weights can be obtained by subtraction of one equivalent of water (18 g / mol).t The hydrophobicities given are the "Scaled" values from computational log(P) determinations by the "Small Fragment Approach" (see, "Development of Hydrophobicity Parameters to Analyze Proteins Which Bear Post- or Cotranslational Modifications" Black, S. D. and Mould, D. R., Anal. Biochem., 193:72-82 (1991)). The equation used to scale raw log(P) values to the scaled values given is as follows: Scaled Parameters = (Raw Parameters + 2.061) / 4.484.3. Table 2:[000106] Another indication that two polypeptides are conservative variants of one another is that the two polypeptides carry out the same function and, in preferred embodiments, the same function at the same or very similar level of activity. Thus, in one embodiment, a conservative variant of a polypeptide of this disclosure will comprise an activity of at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of that found in a polypeptide of SEQ ID NO:1 or SEQ ID NO:2; and will also not exhibit toxicity when administered at high doses. Again, in some embodiments, the polypeptides of this disclosurewill possess more than one activity. For example, a polypeptide of the disclosure can comprise cholesterol efflux mediating activity, ABCA stabilization activity or both. Conservative variants can have one or more of the same activities and, ideally, all of the same activities. The screening assays described herein can be readily used by those of skill in the art to determine whether two or more polypeptides possess similar activities. In addition, those of skill in the art will know of other screening assays that can be used to determine whether two or more polypeptides possess similar biological properties or activities.[000107] In some embodiments, a peptide of the disclosure may be joined to another peptide that has a short half-life to provide a bi-peptide that has a longer half-life than the latter peptide when administered to a subject at a comparable molar dose. In some embodiments, a peptide of the disclosure may be joined to another physiologically active peptide to provide a dual function hybrid polypeptide. In some embodiments, a polypeptide of the disclosure may be joined to another physiologically active peptide from a cellular protein, or the physiologically active peptide may target a cellular protein, such as a receptor. For example in some embodiments, SEQ ID NO:1 or SEQ ID NO:2, or variants thereof as described herein, may be joined to A and B-naturetic peptides (ANP, BNP and variants thereof), which have short half-lifes; bivalidrudin (and other thrombin and Xa inhibitors); or glucose regulating peptides (GLP-1, glucagon and variants of them).[000108] In yet another embodiment, peptidomimetic variants of the polypeptides of the present disclosure are provided. A “peptidomimetic” includes any modified form of an amino acid chain, including, but not limited to, phosphorylation, capping, fatty acid modifications and including unnatural backbone and / or side chain structures. It will be readily apparent to those of skill in the art that a peptidomimetic comprises the structural continuum between an amino acid chain and a non-peptide small molecule. Peptidomimetics generally retain a recognizable polypeptide-like polymer unit structure. Thus, a peptidomimetic typically retains the function of binding to any target molecule that a natural polypeptide binds to. Examples of suitable peptidomimetics are disclosed in U. S. Patent Application Publication No. 2006 / 0069030, the teachings of which are incorporated by reference for all purposes. Other peptidomimetics and methods of making same will be known to those of skill in the art.[000109] Peptidomimetics variants generally fall into one of two categories: (i) surrogates; and (ii) analogs. Numerous surrogates have been developed for the amide bond of polypeptides. Frequently exploited surrogates for the amide bond include, but are not limited to, the following groups: (i) trans-olefins, (ii) fluoroalkene, (iii) methyleneamino, (iv) phosphonamides, and (v) sulfonamides. Examples of such surrogates are disclosed in U. S. Patent Application Publication No. 2006 / 0069030. Additionally, peptidomimetics based on more substantial modifications of the backbone of a polypeptide can be used. Peptidomimetics that fall in this category include (i)retro-inverso analogs, and (ii) N-alkyl glycine analogs (so-called peptoids). Again, examples of such analogs are disclosed in U. S. Patent Application Publication No. 2006 / 0069030.[000110] In one embodiment, the polypeptide or peptidomimetic is a retro-inverso analog. Retro-inverso analogs can be made according to the methods known in the art, in a manner similar to synthesizing L-amino acid based polypeptides. More specifically, examples of methods suitable for preparing such retro-inverso analogs are described in U. S. Patent No. 4,522,752, which issued to Sisto etal. The final product, or intermediates thereof, can be purified by HPLC or any other suitable chromatographic method known to those of skill in the art.[000111] In another embodiment, the polypeptide or peptidomimetic is a retro-enantio analog. Retro-enantio analogs can be synthesized from commercially available D-amino acids (or analogs thereof) using standard solid- or solution-phase polypeptide-synthesis techniques.[000112] In still another embodiment, the peptidomimetic is a trans-olefin surrogate peptide or derivative. Such trans-olefin peptides can be readily synthesized according to the method of Shue et al., Tetrahedron Lett., 28:3225 (1987). In addition, other methods known in the art can also be used. It will be appreciated that variations in the procedure of Sjue et al., or other procedures available, may be necessary depending on the nature of the reagents used in synthesizing the trans-olefin derivative.[000113] In still another embodiment, the pseudodipeptides synthesized by the above method may be coupled to other pseudodipeptides, to make pseudopeptides with several olefinic functionalities in place of amide functionalities. For example, pseudodipeptides corresponding to certain di-peptide sequences can be made and then coupled together by standard techniques to yield an analog of the polypeptide that has alternating olefinic bonds between residues.[000114] Another still another class of peptidomimetic derivatives includes phosphonate derivatives. The synthesis of such phosphonate derivatives can be adapted from known synthesis schemes (see, for example, Loots et al. in “Peptides: Chemistry and Biology,” (Escom Science Publishers, Leiden, p. 118, 1988); Petrillo et al. in “Peptides: Structure and Function (Proceedings of the 9th American Peptide Symposium),” (Pierce Chemical Co. Rockland, III., 1985).[000115] In other embodiments, a polypeptide of the disclosure can be modified by combining with carbohydrate or lipid moieties. Such modifications can change the solubility of the polypeptides in various mediums so that they can advantageously be prepared as a suitable pharmaceutical composition. Modifying lipid groups include, but are not limited to, farnesyl groups and myristoyl groups. Modifying carbohydrate groups include, but are not limited to, single sugars or oligosaccharides of any naturally occurring and / or synthetic sugar and sugaralcohols including, for example, glucose, galactose, rhamnose, mannose, arabinose, and other sugars, and their respective alcohols.[000116] In certain embodiments, a polypeptide of the disclosure may further comprise modifications analogous to post-translational modifications. Such modifications include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation. As a result, the modified peptidomimetics may contain non-amino acid elements, such as polyethylene glycols, lipids, poly- or mono-saccharide, and phosphates. Effects of such non-amino acid elements on the functionality of a peptidomimetic can be tested using the assay methods disclosed herein.[000117] In particular embodiments, the peptidomimetics include at least one backbone linkage that is not an amide linkage in the amino to carboxy direction, such as a retro-inverso polypeptide relative to a naturally-occurring polypeptide, or at least one backbone linkage that is not an amide linkage.[000118] In other embodiment, peptidomimetics include circular peptides. A linear peptide can be converted into a cyclic peptide through a process called cyclization. Cyclization can be achieved through a variety of methods known in the art, including:• Enzyme-based: Uses enzymes that can cyclize their own substrates;• Scaffold-based: Uses reactions between chemical compounds and specific amino acid functional groups;• Amide bond formation: Uses the same coupling chemistry as linear peptide bond formation;• Bis-electrophilic linker: Reacts linear peptides with thiol groups to create two thioether bonds in the final product;• Disulfide based: Oxidative reduction of cysteine to form disulfide intrachain bonds. Can be used as intermediate in combination with one or more above techniques.Cyclic peptides are more rigid than linear peptides, which allows them to have more specific interactions. They can also have improved membrane permeability and oral availability.[000119] As previously described, reference to an “amino acid” in the present context refers to both naturally occurring and non-naturally occurring amino acids. Accordingly, a polypeptide of present disclosure may comprise one or more amino acid analogs. Examples of amino acid analogs, include, but are not limited to, the following: an alkyl, aryl, acyl, azido, cyano, halo, hydrazine, hydrazide, hydroxyl, alkenyl, alkynyl, ether, thiol, sulfonyl, sulfo, seleno, ester, thioacid, borate, boronate, phospho, phosphono, heterocyclic, enone, imine, aldehyde, alkoxyamine, hydroxylamine, keto, or amino substituted amino acid, or any combination thereof; a glycosylated or carbohydrate modified amino acid; a keto containing amino acid; a sugar substituted amino acid, e.g., a sugar substituted serine or the like; a carbon-linked sugar-containing amino acid; a sugar-substituted cysteine; a redox-active amino acid; an a-hydroxy containing acid; an amino thio acid containing amino acid; an a,a-disubstituted amino acid; a p-amino acid; sulfotyrosine, 4-borono-phenylalanine, an aminooxy amino acid, an aminooxy lysine, an aminooxy ornithine, an aminooxy tyrosine, or a cyclic amino acid other than proline. Other unnatural amino acids include, but are not limited to, unnatural amino acids comprising any one or more of the following functional groups: an aldehyde moiety, a keto moiety, a betadiketo moiety, an alkoxyamine moiety, an acyl hydrazide moiety, a dehydroalanine moiety, a thioester moiety, an ester moiety, a boronate moiety, an azide moiety, an acetylenic moiety, an olefinic moiety, a vicinal thiol amine moiety, and the like. Unnatural amino acids include, / V-substituted glycines, / V-methyl amino acids, phenylalanine analogs, and derivatives of lysine (Lys), ornithine (Orn) and a, y-diaminobutyric acid (Dbu) in either the L- or D-configuration that function in a manner similar to the naturally-occurring amino acids.[000120] Additional examples of unnatural amino acids include, but are not limited to, azetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisbutyric acid, 2-aminopimelic acid, tertiary-butylglycine, 2,4-diaminoisobutyric acid, desmosine, 2,2'-diaminopimelic acid, 2,3-diaminopropionic acid, N-ethylglycine, N-ethylasparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalanine, norvaline, ornithine, pentylglycine, pipecolic acid, thioproline, aminophenylalanine, hydroxytyrosine, and aminotyrosine. In some other embodiments, an unnatural amino acid may be 1 -aminocyclopentane- 1 -carboxylic acid (Acp), 1-aminocyclobutane-1-carboxylic acid (Acb), 1-aminocyclopropane-1-carboxylic acid (Acpc), homocitrulline (HoCit), a-aminohexanedioic acid (Aad), 3-(4-pyridyl)alanine (4-Pal), 3-(3-pyridyl)alanine (3-Pal), propargylglycine (Pra), a-aminoisobutyric acid (Aib), a-aminobutyric acid (Abu), norvaline (Nva), a,p-diaminopropionic acid (Dpr), a, y-diaminobutyric acid (Dbu), a-terf-butylglycine (Bug), 3,5-dinitrotyrosine Tyr(3,5-di NO2), norleucine (Nle), 3-(2-naphthyl)alanine (Nal-2), 3-(1-naphthyl)alanine (Nal-1), cyclohexylalanine (Cha), di-n-propylglycine (Dpg), cyclopropylalanine (Cpa), homoleucine (Hie), homoserine (HoSer), homoarginine (Har), homocysteine (Hey), methionine sulfoxide (Met(O)), methionine methylsulfonium (Met (S-Me)), a-cyclohexylglycine (Chg), 3-benzo-thienylalanine (Bta), taurine (Tau), hydroxyproline (Hyp), O-benzyl-hydroxyproline (Hyp(Bzl)), homoproline (HoPro), p-homoproline ( HoPro), thiazolidine-4-carboxylic acid (Thz), nipecotic acid (Nip), isonipecotic acid (IsoNip), 3-carboxymethyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (Cptd), tetrahydro-isoquinoline-3-carboxylic acid (3-Tic), 5 / 7-thiazolo [3,2-a]pyridine-3-carboxylic acid (Btd), 3-aminobenzoic acid (3-Abz), 3-(2-thienyl)alanine (2-Thi), 3-(3-thienyl)alanine (3-Thi), a-aminooctanedioc acid (Asu), diethylglycine (Deg), 4-amino-4-carboxy-1,1-dioxo-tetrahydrothiopyran (Acdt), 1 -amino- 1-(4-hydroxycyclohexyl) carboxylic acid (Ahch), 1-amino-1-(4-ketocyclohexyl)carboxylic acid (Akch), 4-amino-4-carboxytetrahydropyran (Actp), 3-nitrotyrosine (Tyr(3-NC>2)), 1-amino-1 -cyclohexane carboxylic acid (Ach), 1-amino-1-(3-piperidinyl)carboxylic acid (3-Apc), 1-amino-1-(4-piperidinyl)carboxylic acid (4-Apc), 2-amino-3-(4-piperidinyl) propionic acid (4-App), 2-aminoindane-2-carboxylic acid (Aic), 2-amino-2-naphthylacetic acid (Ana), (2S, 5R)-5-phenylpyrrolidine-2-carboxylic acid (Ppca), 4-thiazoylalanine (Tha), 2-aminooctanoic acid (Aoa), 2-aminoheptanoic acid (Aha), ornithine (Orn), azetidine-2-carboxylic acid (Aca), a-amino-3-chloro-4,5-dihydro-5-isoazoleacetic acid (Acdi), thiazolidine-2-carboxylic acid (Thz(2-C00H)), allylglycine (Agl), 4-cyano-2-aminobutyric acid (Cab), 2-pyridylalanine (2-Pal), 2-quinoylalanine (2-Qal), cyclobutylalanine (Cba), a phenylalanine analog, a lysine derivative, a ornithine (Orn) derivative, an a, y-diaminobutyric acid Dbu derivative, stereoisomers thereof, and combinations thereof (see, Liu and Lam, Anal. Biochem., 295:9-16 (2001)). As such, the unnatural a-amino acids are present either as unnatural L-a-amino acids, unnatural D-a-amino acids, or combinations thereof. Additional suitable amino acid analogs include, without limitation, p-amino acids and y-amino acids.Suitable R groups for - or y-amino acids include, but are not limited to, side-chains present in naturally-occurring amino acids and unnatural amino acids. N-methyl amino acids include / V-methyl-Ala, / V-methyl-Cys, / V-methyl-Asp, / V-methyl-Glu, / V-methyl-Phe, / V-methyl-Gly, / V-methyl-His, / V-methyl-lle, / V-methyl-Arg, / V-methyl-Lys, / V-methyl-Leu, / V-methyl-Met, / V-methyl-Asn, / V-methyl-GIn, / V-methyl-Ser, / V-methyl-Thr, / V-methyl-Val, / V-methyl-Trp, / V-methyl-Tyr, / V-methyl-Acp, / V-methyl-Acb, / V-methyl-Acpc, / V-methyl-Cit, / V-methyl-HoCit, / V-methyl-Aad, / V-methyl-4-Pal, / V-methyl-3-Pal, / V-methyl-Pra, / V-methyl-Aib, / V-methyl-Abu, / V-methyl-Nva, / V-methyl-Dpr, / V-methyl-Dbu, / V-methyl-Nle, / V-methyl-Nal-2, / V-methyl-Nal-1, / V-methyl-Cha, / V-methyl-Cpa, / V-methyl-Hle, / V-methyl-HoSer, / V-methyl-Har, / V-methyl-Hcy, / V-methyl-Chg, / V-methyl-Bta, A / -methyl-2-Thi, A / -methyl-3-Thi, / V-methyl-Asu, / V-methyl-Acdt, / V-methyl-Ahch, / V-methyl-Akch, / V-methyl-Actp, / V-methyl-Tyr(3-NO2), / V-methyl-Ach, / V-methyl-3-Apc, / V-methyl-4-Apc, / V-methyl-4-App, / V-methyl-Tha, / V-methyl-Aoa, / V-methyl-Aha, / V-methyl-Orn, / V-methyl-Aca, / V-methyl-Agl, / V-methyl-Cab, / V-methyl-2-Pal, / V-methyl-Cba, / V-methyl-HoPhe, / V-methyl-Phg, / V-methyl-Phe(4-NH2), / V-methyl-4-Phe(4-Me), / V-methyl-Phe(4-F), / V-methyl-Phe(4-CI), / V-methyl-Phe(2-Br), / V-methyl-Phe(3-Br), / V-methyl-Phe(4-Br), / V-methyl-Phe(3- CF3), / V-methyl-Phe(4- CF3), / V-methyl-Phe(4-NO2), / V-methyl-Phe(4-CN), / V-methyl-Bpa, / V-methyl-Phg(4-CI), / V-methyl-Phg(4-Br), / V-methyl-Tyr(Me), stereoisomers thereof, and combinations thereof.[000121] Derivatives of Orn and Dbu are similar to the lysine derivatives with corresponding carboxylic acid attached to the side chain of Orn and Dbu, respectively. Hydrophobic amino acid analogs of leucine, valine, isoleucine, glycine, alanine, methionine include norvaline (Nva), 1-aminocyclopropane-1-carboxylic acid (Acpc), 1-aminocyclobutane-1-carboxylic acid (Acb), a-cyclohexylglycine (Chg), a-aminoisobutyric acid (Aib), a-aminobutyric acid (Abu), 3-(2-thienyl)alanine (2-Thi), 3-(3-thienyl)alanine (3-Thi), 3-(3-pyridyl)alanine (3-Pal), 3-(2-naphthyl)alanine (Nal-2), 2-amino-2-naphthylacetic acid (Ana), 3,5-dinitrotyrosine (Tyr(3,5-di NO2)), diethylglycine (Deg), 4-amino-4-carboxy-1,1-dioxo-tetrahydrothiopyran (Acdt), 1-amino-1-(4-hydroxycyclohexyl) carboxylic acid (Ahch), 1 -amino- 1-(4-ketocyclohexyl)carboxylic acid (Akch), 4-amino-4-carboxytetrahydropyran (Actp), 3-nitrotyrosine (Tyr(3-NC>2)), 1-amino-1-cyclohexane carboxylic acid (Ach), 2-aminoindane-2-carboxylic acid (Aic), (2S, 5R)-5-phenylpyrrolidine-2-carboxylic acid (Ppca), 4-thiazoylalanine (Tha), 2-aminooctanoic acid (Aoa), 2-aminoheptanoic acid (Aha), and a stereoisomer thereof. Preferably, the proline analog is hydroxyproline.[000122] Analogs of negatively charged amino acids include a-aminohexanedioic acid, a-aminooctanedioc acid, homoaspartic acid, y-carboxy-glutamic acid, 4-carboxyphenylalanine, and a stereoisomer thereof.4. Protecting Groups[000123] The polypeptides and peptidomimetics of the present disclosure may be modified so that the R-groups on the constituent amino acids and / or the terminal amino acids are blocked, / .e., protected, by a protecting group. Blocking or protection, particularly of the amino and / or carboxy termini, can greatly improves oral delivery and significantly increases serum half-life. As used herein, “protecting group” refers to a temporary substituent that protects a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups generally include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nded.; Wiley: New York, 1991).[000124] A wide number of protecting groups are suitable for this purpose. Such groups include, but are not limited to, acetyl, CH3-(CH2)n-CO-, amide, Fmoc, t-butoxycarbonyl (t-BOC), 9-fluoreneacetyl group, 1 -fluorenecarboxylic group, 9-fluorenecarboxylic group, 9-fluorenone-1-carboxylic group, benzyloxycarbonyl, Xanthyl (Xan), Trityl (Trt), 4-methyltrityl (Mtt), 4-methoxytrityl (Mmt), 4-methoxy-2,3,6-trimethyl-benzenesulphonyl (Mtr), Mesitylene-2-sulphonyl (Mts), 4,4-dimethoxybenzhydryl (Mbh), Tosyl (Tos), 2,2,5,7,8-pentamethyl chroman-6-sulphonyl (Pmc), 4-methylbenzyl (MeBzl), 4-methoxybenzyl (MeOBzl), Benzyloxy (BzIO), Benzyl (Bzl), Benzoyl (Bz), 3-nitro-2-pyridinesulphenyl (Npys), 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde), 2,6-dichlorobenzyl (2,6-DiCI-Bzl), 2-chlorobenzyloxycarbonyl (2-CI-Z), 2-bromobenzyloxycarbonyl (2-Br-Z), Benzyloxymethyl (Bom), cyclohexyloxy (cHxO), t-butoxymethyl (Bum), t-butoxy (tBuO), t-Butyl (tBu), and Trifluoroacetyl (TFA). The variable “n” is an integer from 0 to 12, typically 0 to 6 such as 0 to 4. Other suitable protecting groups are disclosed in U. S. Patent No. 6,933,279, the teachings of which are incorporated by reference.[000125] In one embodiment, preferred protecting groups include, but are not limited to, acetyl, amide, and alkyl groups with acetyl and alkyl groups being particularly preferred for N-terminal protection and amide groups being particularly preferred for carboxyl terminal protection. In one preferred embodiment, an acetyl group is used to protect the amino terminus and an amide group is used to protect the carboxyl terminus. In this embodiment, acetylation can be accomplished during the synthesis when the polypeptide is on the resin using acetic anhydride. Amide protection can be achieved by the selection of a proper resin for the synthesis. For instance, a rink amide resin can be used. After the completion of the synthesis, the semipermanent protecting groups on acidic bifunctional amino acids, such as Asp and Glu, and basic amino acids, such as Lys, as well as the hydroxyl of Tyr, are all simultaneously removed. The polypeptides released from such a resin using acidic treatment comes out with the N-terminal protected as acetyl and the C-terminal protected as NH2, with the simultaneous removal of all of the other protecting groups.[000126] In a particularly preferred embodiment, the polypeptides of the present disclosure comprise one or more D-amino acids as described herein. In certain embodiments, every amino acid (e.g., every enantiomeric amino acid) is a D-amino acid. It has been found that polypeptides comprising all D-amino acids stimulate cholesterol efflux with high-capacity and high-affinity like the L-amino acid polypeptides. D-amino acids are readily incorporated at one or more positions in the polypeptide simply by using a D-form derivatized amino acid residue in the chemical synthesis. D-form residues for solid phase polypeptide synthesis are commercially available from a number of suppliers (see, e.g., Advanced Chem Tech, Louisville, KY; Nova Biochem, San Diego, CA; Sigma, St Louis, MO; Bachem California Inc., Torrance, CA, etc.). The D-form amino acids can be incorporated at any position in the polypeptide as desired. Thus, for example, in one embodiment, the polypeptide can comprise a single D-amino acid, while in other embodiments, the polypeptide comprises at least two, generally at least three, more generally at least four, most generally at least five, preferably at least six, more preferably at least seven and most preferably at least eight D amino acids. In one embodiment, essentially every other (enantiomeric) amino acid is a D-form amino acid. In certain embodiments, at least 80%, preferably at least 90%, more preferably at least 95% of the enantiomeric amino acids are D-form amino acids. In one particularly preferred embodiment, essentially every enantiomeric amino acid is a D-form amino acid.[000127] While in preferred embodiments, the polypeptides of this disclosure utilize naturally-occurring amino acids or D forms of naturally occurring amino acids, substitutions with non-naturally occurring amino acids (e.g., methionine sulfoxide, methionine methylsulfonium, norleucine, episilon-aminocaproic acid, 4-aminobutanoic acid, tetrahydroisoquinoline-3-carboxylic acid, 8-aminocaprylic acid, 4-aminobutyric acid, Lys(N(epsilon)-trifluoroacetyl), a-aminoisobutyric acid, and the like) can be used in the polypeptides of the present disclosure. Aswith the other amino acid substitutions, non-naturally occurring amino acids are typically substituted so that, upon substitution, they retain the spatial and ionic or non-ionic character of the residue that they substitute.[000128] In some embodiments, a citrulline is replaced with a citrulline analog amino acid. Such analogs and their preparation are known to the person skilled in the art. For example, Sonke, et al., in Stereoselective Biocatalysis (2000), pp. 23-58, and Greene: Protective Groups in Organic Synthesis (Wiley, New York 1999). Example of citrulline amino acid analogs can be found in U. S. Patent No. 7,888,133), which is hereby incorporated by reference in its entirety.[000129] In some embodiments, non-naturally occurring amino acids are employed at positions in the polypeptide where non-naturally occurring amino acids have long, e.g., C5-8, carbon alkenyl or alkanyl side chains.5. Preparation of polypeptides[000130] Polypeptides suitable for the disclosure can be prepared using known techniques. For example, peptides can be chemically synthesized using methods well known in the art including, e.g., solid phase synthesis (see, e.g., Merrifield, J. Am. Chem. Soc., 85:2149-2154 (1963) and Abelson etal., Methods in Enzymology, Volume 289: Solid-Phase Peptide Synthesis (1st ed. 1997)). Polypeptide synthesis can be performed to generate a full-length peptide. Alternatively, various fragments of the polypeptide can be chemically synthesized separately and then combined using chemical methods to produce the full -ength polypeptide.[000131] The polypeptides described herein can also be expressed recombinantly, especially when the polypeptide does not comprise a “D” amino acid residues. This embodiment relies on routine techniques in the field of recombinant genetics. Generally, the nomenclature and the laboratory procedures in recombinant DNA technology described herein are those well known and commonly employed in the art. Standard techniques are used for cloning, nucleic acid isolation, amplification and purification. Many manuals that provide direction for performing recombinant DNA manipulations are available, e.g., Sambrook & Russell, Molecular Cloning, A Laboratory Manual (3rd Ed, 2001); and Current Protocols in Molecular Biology (Ausubel, et al., John Wiley and Sons, New York, 2009, supplements through 2013). One of skill can generate a nucleic acid encoding a polypeptide of the disclosure and obtain high level expression using known techniques.[000132] To obtain high level expression of a nucleic acid sequence, such as the nucleic acid sequences encoding a polypeptide of this disclosure, one typically subclones a nucleic acid sequence that encodes a polypeptide sequence of the disclosure into an expression vector that is subsequently transfected into a suitable host cell for expresion. Expression vector components, including promoters, sequences encoding selectable markers and the like are well known in the art. The particular expression vector used to transport the genetic information intothe cell is not particularly critical. Any of the conventional vectors used for expression in eukaryotic or prokaryotic cells may be used.D. METHODS OF IDENTIFYING POLYPEPTIDES WITH DESIRED ACTIVITY [000133] The polypeptides or peptidomimetics suitable for the present disclosure can be readily evaluated fortheir ability to mediate cholesterol efflux and / or stabilize ABCA (e.g., ABCA1) using methods well known to those of skill in the art. Peptides may be additionally evaluated for toxicity.[000134] A number of different screening protocols can be utilized to identify polypeptides or peptidomimetics of the present disclosure that mediate cholesterol efflux and / or stabilize ABCA (e.g., ABCA1). In one embodiment, the screening methods involve screening a plurality of test polypeptides to identify those polypeptides that mediates cholesterol efflux and / or stabilizes ABCA (e.g., ABCA1) in, e.g., mammalian cells, including human cells.[000135] In addition to screening for their ability to mediate cholesterol efflux and / or stabilize ABCA, candidate test polypeptides can also be screened for other activities including, e.g., antioxidant activities and anti-inflammatory activities. A number of different screening protocols can be utilized to identify polypeptides or peptidomimetics of the present disclosure that have antioxidant activity and / or anti-inflammatory activity.[000136] It will be readily apparent to those of skill in the art that numerous other screening assays, in addition to those disclosed herein, can be used to screen the polypeptides or peptidomimetics of the present disclosure for the desired biological activities.1. Activity Assays- Cholesterol Efflux Activity[000137] Suitable cholesterol efflux assays are described in, e.g., Bielicki, J. K and Oda, M. N., Biochemistry, 41:2089-2096 (2002); Jia etal., Biochem. Biophys. Res. Common., 297:206-213 (2002). In some embodiments, a polypeptide known to mediate cholesterol efflux (e.g., helix 9 / 10 of Apo A-l) is used to screen for additional mediators of cholesterol efflux in a cell based assay. For example, cell lines in which cholesterol efflux can be enhanced using a cAMP analog that up-regulates ABCA1 protein expression (e.g., J774 macrophages) can conveniently be used to assess the ability of a polypeptide of the present disclosure to mediate cholesterol efflux. The cells are incubated with labeled cholesterol (e.g., [3H]cholesterol) under conditions appropriate for cholesterol uptake by the cells. Thus, cAMP or cAMP analogs (e.g., CPT-cAMP) are incubated with the cells for a suitable time before the initiation of cellular cholesterol efflux, i.e., prior to contacting the cells with a test polypeptide. Measurement of labeled cholesterol appearing in the medium is used to determine the cholesterol efflux mediating activity of the test polypeptide.2. Activity Assays- ABCA Stabilization Activity[000138] Multiple assays known in the art can be used to measure the ABCA stabilization activity of a polypeptide of the disclosure. For example, binding assays can be used to test the ability of the test polypeptide to bind to ABCA (e.g., ABCA1). It has been found that polypeptides having ABCA stabilization activity are also likely mediators of cholesterol efflux. As such, in a preferred embodiment, the polypeptides or peptidomimetics of the present disclosure have the ability to mediate cholesterol efflux and to stabilize ABCA. In one screening embodiment, the binding assays can be competitive assays. Other assays include, for example, direct measurement of ABCA (e.g., ABCA polypeptide or nucleic acids) following contact with the test polypeptide.3. Binding Assays[000139] Binding assays usually involve contacting ABCA with one or more test polypeptides, and allowing sufficient time for ABCA and the test polypeptides to form a binding complex. Any binding complexes formed can be detected using any of a number of established analytical techniques. Protein binding assays include, but are not limited to, immunohistochemical binding assays, flow cytometry or other assays. In some embodiments, competition assays are used to determine whether a test polypeptide has ABCA stabilization activity. Competition assays are well known in the art. Typically, a competitor compound, / .e., a compound known to bind ABCA, is labeled so that differences in binding to ABCA (e.g., in the presence of increasing amount of a test polypeptide of the disclosure that may bind to ABCA) can be measured. The particular label or detectable group used in the assay is not a critical aspect of the disclosure, as long as it does not significantly interfere with the binding of the test compound to ABCA. As described herein, the detectable group (or, alternatively, detectable moiety or label) can be any material having a detectable physical or chemical property. Such detectable labels have been well-developed in the field of immunoassays and, in general, most any label useful in such methods can be applied to the present disclosure. Thus, a label is any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means. Useful labels in the present disclosure include, but are not limited to, magnetic beads (e.g., DYNABEADSTM), fluorescent dyes (e.g., fluorescein isothiocyanate, Texas red, rhodamine, and the like), radiolabels (e.g., 3H, 1251, 35S, 14C, or32P), enzymes (e.g., horse radish peroxidase, alkaline phosphatase and others commonly used in an ELISA), and colorimetric labels such as colloidal gold or colored glass or plastic beads (e.g., polystyrene, polypropylene, latex, etc.).[000140] In some embodiments, ABCA expressing and non-expressing cells are used to measure the ABCA (e.g., ABCA1) stabilization activity of a test polypeptide by measuring the relative ABCA binding affinities of the test polypeptide and a competitor compound (e.g., full-length Apo A-l A or Apo A-l 9 / 10 polypeptide) for ABCA. In some embodiments, the binding affinity of full-length Apo A-l A to ABCA is compared to the binding affinity of a labeled polypeptide of the disclosure as described in, e.g., Remaley et al., J. Lipid Res., 44:828-836 (2003). Cells expressing ABCA are incubated in the presence and absence of the competitor compound, and then exposed to a range of concentrations of individual labeled test polypeptides (e.g., a radiolabeled polypeptide of the disclosure). Typically, the concentrations of test polypeptides range from about 0.1.g / ml to about 200.g / ml, about 0.5.g / ml to about 100.g / ml, about 1.g / ml to about 40.g / ml, or about 5.g / ml to about 20.g / ml.4. Direct Measurement of ABCA[000141] In some embodiments, the stabilization of ABCA is measured by direct measurement of ABCA (e.g., ABCA polypeptide, or nucleic acid) using a cell based assay. Cell based assays can be performed in any cells in which ABCA is expressed (e.g., J774 macrophages), including cells which have been transfected with ABCA (e.g. HeLa cells). Any cell type can be used. For example, J774 macrophages can be used to assess relative ABCA1 polypeptide levels in the presence and absence of polypeptides of the disclosure. The cells are first contacted with a compound that induces ABCA (e.g., cAMP or a cAMP analogue such as, 8-bromo-cAMP) to upregulate ABCA (e.g., ABCA1) expression, then exposed to synthetic ABCA1 polypeptide levels in the presence and absence of polypeptides of the disclosure in the absence of the cAMP stimulus to evaluate whether ABCA1 polypeptide was stabilized or degraded. Relative levels of ABCA1 polypeptide can be assessed using any means known in the art including, e.g., immunoblot analysis of cell membranes (Oram et al., J. Biol. Chem., 278:52379-52385 (2003)) or hybridization of nucleic acid probes to ABCA mRNA.5. Toxicity Assays[000142] Polypeptides or peptidomimetics suitable for the disclosure can be evaluated for toxicity using known assays. Examples of such assays are illustrated in the Examples section. Toxicity is typically assayed in a rat, rabbit, mouse, monkey or dog model. In an illustrative assay such as that described in Example 1, a polypeptide is administered intravenously using a rabbit or rat model at doses of 3, 30, and 300 mg / kg and vehicle alone is also administered at 48 hour intervals for a total of four injections. Safety chemistry panels including plasma alanine aminotransferase (ALT), aspartate amino transferase (AST), and creatine kinase (CK) can then be determined in the blood. The presence of elevated levels of these enzymes in the blood compared to control normal values is indicative of toxicity. A polypeptide of the disclosure is typically considered to be non-toxic or to have little toxicity, when the results using the highest dose, 300 mg / kg in this illustrative assay, are equivalent (fall within the standard deviation) of the values measured for the control animals that received vehicle alone, or are no more than 2 or 3 times background obtained with vehicle alone. In some embodiments, a toxicity assay isperformed where the toxicity of a polypeptide of the disclosure is compared to that to ATI-5261 (ATI-5261 a 26-amino-acid peptide designed from a sequence derived from the carboxyl (C-terminal) end of Apolipoprotein E (“apoE”)). A polypeptide of the disclosure that has no or little toxicity typically exhibits less than 50%, preferably less than 20%, or more preferably less than 10% of the toxicity observed with ATI-5261 when administered to a mouse, rat or rabbit at a dose of 300 mg / kg, e.g., 4 hours after injection. Other animal models, e.g., monkeys, may also be used to evaluate toxicity.6. Further Testing[000143] Polypeptides that are initially identified as mediating cholesterol efflux or interacting with ABCA can be further tested to validate their ability to mediate cholesterol efflux and / or stabilize ABCA. The basic format of such methods involves administering a lead compound identified during an initial screen to an animal that serves as a model. The animal models utilized in validation studies generally are mammals of any kind. Specific examples of suitable animals include, but are not limited to, primates (e.g., chimpanzees, monkeys, and the like) and rodents (e.g., mice, rats, guinea pigs, rabbits, and the like). In a preferred embodiment, Apo E- / -mice, Apo A-ll - / - mice, or Apo C-lll - / - mice are used. Additional animal models are described in, e.g., Marschang etal., Sem. Cell Dev. Biol., 14:25-35 (2003).[000144] Polypeptides may be screened for activity using any format. For example, high throughput screening (HTS) methods may be used to identify polypeptides or peptidomimetics of the present disclosure that mediate cholesterol efflux and / or stabilize ABCA. HTS methods involve providing a combinatorial polypeptide library containing a large number of potential therapeutic compounds ( / .e., polypeptides or peptidomimetics that mediate cholesterol efflux or stabilize ABCA). Such libraries are then screened in one or more assays, as described herein, to identify those library members ( / .e., particular polypeptides or peptidomimetics) that display a desired characteristic activity. The compounds thus identified can serve as conventional “lead compounds” or can themselves be used as potential or actual therapeutics.E. METHODS OF USE / ROUTES of ADMINISTRATION[000145] In view of their biological activities and, in particular, their ability to mediate cholesterol efflux, the polypeptides of the present disclosure (or peptidomimetics thereof) can be used to treat a PNS myelination condition in a mammal, or to treat prophylactically a mammal at risk of developing a PNS myelination condition. In some embodiments, the polypeptides can be used to treat a patient that has a complication of a disease as described herein. Thus, in some embodiments, the patient has a PNS myelination condition, for example, (i) a condition characterized by PMP22 dysfunction in the PNS; (ii) a PNS myelination disorder resulting from abnormal ABCA1 regulated cholesterol transport; (iii) a Schwann cell regulated cholesteroltransport disorder; (iv) a demyelinating condition resulting from Schwann cell dysfunction; and (v) a non-hereditary PNS myelination condition.[000146] Pharmaceutical compositions comprising polypeptides of this disclosure can be administered to a subject by any suitable route of administration.[000147] In one embodiment of the methods described herein, the route of administration can be oral, intraperitoneal, transdermal, subcutaneous, by intravenous or intramuscular injection, by inhalation, topical, intralesional, infusion; liposome-mediated delivery; topical, intrathecal, gingival pocket, rectal, intrabronchial, nasal, transmucosal, intestinal, ocular or otic delivery, or any other methods known in the art as one skilled in the art may easily perceive. Other embodiments of the compositions of the disclosure incorporate particulate forms protective coatings, protease inhibitors or permeation enhancers for various routes of administration, including parenteral, pulmonary, nasal and oral. The pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method / mode of administration. Suitable unit dosage forms include, but are not limited to, powders, tablets, pills, capsules, lozenges, suppositories, patches, nasal sprays, injectables, implantable sustained-release formulations, etc.[000148] Intravenous administration involves delivering the pharmaceutical composition directly into the bloodstream which facilitates rapid systemic distribution and enables immediate therapeutic action. Intravenous administration can comprise administration of a bolus, or can comprise a slow infusion, depending on the desired pharmacokinetic profile in the therapeutic indication.[000149] Intraperitoneal administration involves introducing the pharmaceutical composition into the peritoneal cavity. This mode of administration is especially useful for diseases localized within the abdominal region, as it offers direct access to the site of pathology.[000150] The pharmaceutical composition can be administered subcutaneously, that is into the fatty tissue underneath the skin.[000151] In intramuscular administration, a pharmaceutical composition is injected into muscle tissue.F. COMBINATION THERAPY[000152] In some embodiments, the polypeptides or peptidomimetics suitable for the present disclosure are administered in combination with one or more additional therapeutic agents for treating or preventing diseases and disorders associated with autoimmune demyelination, such as immunospressants or other immunomodulatory agents. These agents inclide azathioprine, cyclophosphamide, cyclosporin, methotrexate, an anti-CD20 Ab (e.g. rituximab), fingolimod, an anti-IL-2 Ab, and anti-CCR2 Ab, anti-a4-integrin Ab, dimethyl fumarate, tetriflunomide,natalizumab, alemtuzumab, ocrelizumab, siponimod, teriflunomide, laquinimod, cladribine, temsirolimus, corticosteroids (e.g., prednisolone, deflazacort), immunoglobulin and interferon (e.g., -a, -p and -y). Additional agents include antiepileptics such as gabapentin, cabapentin, and antidepressants such as amitriptyline, pregabalin and duloxetine.[000153] In some embodiments, the polypeptides or peptidomimetics suitable the present disclosure can be used in combination, either as separate units or fixed combinations, with one or more of the following: an antibody which binds to an unwanted inflammatory molecule or cytokine such as interleukin-6, interleukin-8, granulocyte macrophage colony stimulating factor, and tumor necrosis factor-a; an enzyme inhibitor such as a protease inhibitor aprotinin or a cyclooxygenase inhibitor; an antibiotic such as amoxicillin, rifampicin, erythromycin; an antiviral agent such as acyclovir; a steroidal anti-inflammatory such as a glucocorticoid; a non-steroidal anti-inflammatory such as aspirin, ibuprofen or acetaminophen; or a non-inflammatory cytokine such as interleukin-4 or interleukin- 10. Other cytokines and growth factors such as interferon-p, tumor necrosis factors, antiangiogenic factors, erythropoietins, thrombopoietins, interleukins, maturation factors, chemotactic protein, and their variants and derivatives that retain similar physiological activities may also be used as an additional therapeutic agents. Finally, inhibitors and modulators of gene transcription including HDAC6, General Control Nonderepressible 2 (GCN2) Protein Kinase, and bromodomain inhibitors may be combined with the polypeptides or peptidomimetics of the invention.[000154] The polypeptide (or peptidomimetics thereof) and the additional therapeutic agent can be administered simultaneously or sequentially. For example, the polypeptide may be administered first, followed by the additional therapeutic agent. Alternatively, the additional therapeutic agent may be administered first, followed by the polypeptide of the disclosure. In some cases, the polypeptide of the disclosure and the additional therapeutic agent are administered in the same formulation. In other cases, the polypeptide and the additional therapeutic agent are administered in different formulations. When the polypeptide and the additional therapeutic agent are administered in different formulations, their administration may be simultaneous or sequential.G. PHARMACEUTICAL FORMULATIONS[000155] In order to carry out the methods of the disclosure, one or more polypeptides of this disclosure or peptidomimetics thereof are administered to an individual diagnosed as having or at risk of having a disease or disorder associated with PNS myelination condition. The polypeptides or peptidomimetics thereof can be administered in their “native” form or, if desired, in the form of, for example, salts, esters, amides, prodrugs, derivatives, and the like, provided that the salt, ester, amide, prodrug or derivative is suitable pharmacologically, / .e., effective in the methods of the present disclosure.[000156] As such, in another aspect, the present disclosure provides pharmaceutical compositions comprising a pharmaceutically effective amount of a polypeptide or peptidomimetic of the present disclosure and an acceptable carrier and / or excipients. A pharmaceutically acceptable carrier includes any solvents, dispersion media, or coatings that are physiologically compatible and that preferably does not interfere with or otherwise inhibit the activity of the polypeptide or peptidomimetic. Preferably, the carrier is suitable for intravenous, intramuscular, oral, intraperitoneal, transdermal, topical, or subcutaneous administration.Pharmaceutically acceptable carriers can contain one or more physiologically acceptable compound(s) that act, for example, to stabilize the composition or to increase or decrease the absorption of the active agent(s). Physiologically acceptable compounds can include, for example, carbohydrates, such as glucose, sucrose, or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, compositions that reduce the clearance or hydrolysis of the active agents, or excipients or other stabilizers and / or buffers.[000157] Other physiologically acceptable compounds include, but are not limited to, wetting agents, emulsifying agents, dispersing agents or preservatives which are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid. One skilled in the art will appreciate that the choice of pharmaceutically acceptable carrier(s), including a physiologically acceptable compound depends, for example, on the route of administration of the polypeptide(s) or peptidomimetic(s) and on the particular physio-chemical characteristics of the polypeptide(s) or peptidomimetic(s).[000158] The composition can be formulated for intravenous injection. Accordingly, the carrier can be an aqueous carrier, such as sterilized water or saline solution (e.g., 0.9% NaCI).Pharmaceutically acceptable carriers will generally be sterile, at least for human use. A pharmaceutical composition will generally comprise agents for buffering and preservation in storage, and can include buffers and carriers for appropriate delivery, depending on the route of administration. Examples of pharmaceutically acceptable carriers include, without limitation, normal (0.9%) saline, phosphate-buffered saline (PBS), Hank’s balanced salt solution (HBSS) and multiple electrolyte solutions such as PlasmaLyte ATM (Baxter).In certain embodiments, the polypeptides or peptidomimetics suitable the disclosure can be administered orally (e.g., via a tablet or capsule) or as an injectable in accordance with standard methods well known to those of skill in the art. In certain embodiments, these solutions will have physiological pH, e.g., around pH 7.4. In other preferred embodiments, the polypeptides or peptidomimetics can also be delivered through the skin using conventional transdermal drug delivery systems, / .e., transdermal “patches,” wherein the polypeptide(s) or peptidomimetic(s) are typically contained within a laminated structure that serves as a drug delivery device to be affixed to the skin. In such a structure, the drug composition is typically contained in a layer, or “reservoir,” underlyingan upper backing layer. It will be appreciated that the term “reservoir” in this context refers to a quantity of “active ingredient(s)” that is ultimately available for delivery to the surface of the skin. Thus, for example, the “reservoir” may include the active ingredient(s) in an adhesive on a backing layer of the patch, or in any of a variety of different matrix formulations known to those of skill in the art. The patch may contain a single reservoir, or it may contain multiple reservoirs.[000159] In one embodiment, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like. Alternatively, the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form. The backing layer in these laminates, which serves as the upper surface of the device, preferably functions as a primary structural element of the “patch” and provides the device with much of its flexibility. The material selected for the backing layer is preferably substantially impermeable to the active agent(s) and any other materials that are present.[000160] Other formulations for topical drug delivery include, but are not limited to, ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. The specific ointment or cream base to be used, as will be appreciated by those skilled in the art, is one that will provide for optimum drug delivery. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing.[000161] Polypeptides comprising L-form or D-form amino acids can be administered without protection against proteolysis by stomach acid, etc. Nevertheless, in certain embodiments, polypeptide delivery can be enhanced by the use of protective excipients, as known in the art (see, e.g., U. S. Patent No. 5,391,377).[000162] Elevated serum half-life can be maintained by the use of sustained-release polypeptide “packaging” systems. Such sustained release systems are well known to those of skill in the art. In one preferred embodiment, the ProLease biodegradable microsphere delivery system for proteins and polypeptides is used (Tracy, Biotechnol. Prog., 14:108 (1998); Johnson et al., Nature Med., 2:795 (1996); Herbert etal., Pharmaceut. Res., 15:357 (1998)), whichinvolves the use of a dry powder composed of biodegradable polymeric microspheres containing the polypeptide in a polymer matrix that can be compounded as a dry formulation with or without other agents.[000163] In another embodiment, one or more components of the solution can be provided as a “concentrate,” e.g., in a storage container (e.g., in a premeasured volume) ready for dilution, or in a soluble capsule ready for addition to a volume of water.[000164] In certain embodiments of the present disclosure, the pharmaceutical compositions are sustained release formulations. Polypeptides or peptidomimetics of the present disclosure may be admixed with biologically compatible polymers or matrices which control the release rate of the copolymers into the immediate environment. Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils). Also contemplated by the disclosure are particulate compositions coated with polymers (e.g., poloxamers or poloxamines). Other embodiments of the compositions of the disclosure incorporate particulate forms, protective coatings, protease inhibitors or permeation enhancers for various routes of administration, including parenteral, pulmonary, nasal and oral. Acceptable carriers include carboxymethyl cellulose (CMC) and modified CMC.[000165] The pharmaceutical composition of the present disclosure is preferably sterile and non-pyrogenic at the time of delivery, and is preferably stable under the conditions of manufacture and storage. These pharmaceutical compositions can be sterilized by conventional, well known sterilization techniques.[000166] In therapeutic applications, the compositions of this disclosure are administered to an individual diagnosed as having or at risk of having a disease or disorder associated with a PNS myelination disorder, in an amount sufficient to cure or at least partially prevent or arrest the disease, condition and / or its complications. An amount adequate to accomplish this is defined as a “therapeutically effective dose.” Amounts effective for this use will depend upon the severity of the disease and the general state of the patient’s health. Single or multiple administrations of the compositions can be administered depending on the dosage and frequency as required and tolerated by the patient. In any event, the composition should provide a sufficient quantity of the active agents, / .e., polypeptides or peptidomimetics, of the formulations of this disclosure to effectively treat (ameliorate one or more symptoms) the individual or patient.[000167] The concentration of polypeptide or peptidomimetic can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, circulating plasma levels of the polypeptide, polypeptide toxicities, progression of the disease (e.g., atherosclerosis), the production of antibodies that specifically bind to the polypeptide, and the like in accordance with the particular mode of administration selected and the patient’s needs. Typically, the doseequivalent of a polypeptide or peptidomimetic is from about 0.1 to about 50 mg per kg, preferably from about 1 to about 25 or 30 mg per kg, or from about 1 to about 20 mg per kg body weight. It will be appreciated that such dosages may be varied to optimize a therapeutic regimen in a particular subject or group of subjects.[000168] For administration, polypeptides of the present disclosure can be administered at a rate determined by the LD50 of the polypeptide, and the side-effects of the polypeptide at various concentrations, as applied to the mass and overall health of the patient. Administration can be accomplished via single or divided doses, e.g., doses administered on a regular basis (e.g., daily) for a period of time (e.g., 2, 3, 4, 5, 6, days or 1-3 weeks or more).[000169] As explained herein, the polypeptides and peptidomimetics of the present disclosure can be modified in a number of different ways. For instance, the polypeptides can be modified so that the side chains on the constituent amino acids and / or the terminal amino acids are blocked, / .e., protected, by a protecting group. It has been found that blockage, particularly of the amino and / or carboxy termini, can greatly improve oral delivery and significantly increases serum half-life. In addition, to enhance delivery and / or biological acitivites in vivo, salts, esters, amides, prodrugs and other derivatives of the polypeptides or peptidomimetics of the present disclosure can be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by March (1992) Advanced Organic Chemistry; Reactions, Mechanisms and Structure, 4th Ed. N. Y. Wiley-lnterscience.[000170] For example, acid addition salts are prepared from the free base using conventional methodology, which typically involves reaction with a suitable acid. Generally, the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added thereto. The resulting salt either precipitates or may be brought out of solution by addition of a less polar solvent. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. An acid addition salt may be reconverted to the free base by treatment with a suitable base. Particularly preferred acid addition salts of the polypeptides described herein are halide salts, such as may be prepared using hydrochloric or hydrobromic acids. Conversely, preparation of basic salts of the polypeptides or peptidomimetics of the present disclosure are prepared in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, or the like. Particularly preferred basic salts include alkali metal salts, e.g., sodium salts and copper salts.[000171] Preparation of esters typically involves functionalization of hydroxyl and / or carboxyl groups that may be present within the polypeptides or peptidomimetics of the present disclosure. The esters are typically acyl-substituted derivatives of free alcohol groups, i.e., moieties that are derived from carboxylic acids of the formula RCOOH, wherein R is alkyl and, preferably, lower alkyl. Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures.[000172] Amides and prodrugs can also be prepared using techniques known to those skilled in the art or described in the pertinent literature. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine. Prodrugs are typically prepared by covalent attachment of a moiety that results in a compound that is therapeutically inactive until modified by an individual’s metabolic system.[000173] The foregoing formulations and administration methods are clearly intended to be illustrative and not limiting in any way. It will be appreciated that, using the teaching provided herein, other suitable formulations and modes of administration can be readily devised.1. Lipid-Based Formulations[000174] In another aspect, the polypeptides and peptidomimetics of the present disclosure are preferably administered in conjunction with one or more lipids. The lipids can be formulated as an excipient to protect and / or enhance transport / uptake of the polypeptides or peptidomimetics or they can be administered separately.[000175] The lipids can be formulated into liposomes, nanocapsules, microparticles, microspheres, lipids particles, lipid vesicles and the like. Such lipid formulations can be used to encapsulated the polypeptides and peptidomimetics of the present disclosure and / or they can be simply complexed / admixed with such polypeptides and peptidomimetics. Those of skill in the art will know how to use such lipid formulations to either encapsulate or complex the polypeptides or peptidomimetics of the present disclosure. For instance, the formation and use of liposomes is generally known to those of skill in the art. Liposomes have been developed with improved serum stability and circulation half-times (see, U. S. Patent No. 5,741,516).Further, various methods of liposome and liposome-like preparations as potential drug carriers have been reviewed (see, U. S. Patent Nos. 5,567,434; 5,552,157; 5,565,213; 5,738,868 and 5,795,587).[000176] In one embodiment, the polypeptides or peptidomimetics of the present disclosure are complexed with a lipid, such as a phospholipid (e.g., 1-palmitoyl-2-oleoyl-sn-glycerol-phosphatidylcholine (“POPC”) in a manner similar to that disclosed in U. S. Patent Application Publication No. 2005 / 0142180, which was published June 30, 2005, the teachings of which are incorporated herein by reference. As such, the present disclosure provides polypeptide-lipidcomplexes (or, alternatively, peptidomimetic-lipid complexes) having an increased ability to efflux cholesterol from cells. Typically, the lipid is mixed with the polypeptide prior to administration. The polypeptides of the present disclosure and lipids can be mixed in an aqueous solution in appropriate ratios and can be complexed by methods known in the art, including, but not limited to, freeze-drying, detergent solubilization followed by dialysis, microfluidization, sonication, and homogenization. Complex efficiency can be optimized, for example, by varying pressure, ultrasonic frequency or detergent concentration. An example of a detergent commonly used to prepare polypeptide-lipid complexes is sodium cholate.[000177] In certain embodiments, the polypeptide-lipid (e.g., phospholipids) complex can be in solution with an appropriate pharmaceutical diluent or carrier. In other embodiments, freeze-dried or lyophilized preparations of the polypeptide-lipid complexes can be hydrated or reconstituted with an appropriate pharmaceutical diluent prior to administration. In another embodiment, the polypeptide-lipid complexes can be frozen preparations that are thawed until a homogenous solution is achieved prior to administration to a subject in need thereof.[000178] The lipid can be any suitable lipid known to those of skill in the art. In one embodiment, non-phosphorus containing lipids can be used, including stearylamine, dodecylamine, acetyl palmitate, (1,3)-D-mannosyl-(1,3)digly- ceride, aminophenylglycoside, 3-cholesteryl-6'-(glycosylthio)hexyl ether glycolipids, N-(2,3-di(9-(Z)-octadecenyloxy))-prop-1-yl-N, N, N-trimethylammonium chloride and fatty acid amides.[000179] In another embodiment, a phospholipids or a mixture of phospholipids is used.Suitable phospholipids include, but are not limited to, can be a small alkyl chain phospholipid, phosphatidylcholine, egg phosphatidylcholine, soybean phosphatidylcholine, dipalmitoylphosphatidylcholine, soy phosphatidylglycerol, egg phosphatidylglycerol, distearoylphosphatidylgly- cerol, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine, dilaurylphosphatidylcholine, 1-myristoyl-2-palmitoylphosphatidylcholine, 1-palmitoyl-2-myristoylphosphatidylcholine, 1-palmitoyl-2-stearoylphospha- tidylcholine, 1-stearoyl-2-palmitoylphosphatidylcholine, dioleoylphosphatidylcholine, 1-palmitoyl-2-oleoylphosphatidylcholine, 1-oleoyl-2-palmitylphosphatidylcholine, dioleoylphosphatidylethanolamine, dilauroylphosphatidylglycerol, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, diphosphatidylglycerol, dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol, phosphatidic acid, dimyristoylphosphatidic acid, dipalmitoylphosphatidic acid, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, dimyristoylphosphatidylserine, dipalmitoylphosphatidylserine, brain phosphatidylserine, sphingomyelin, sphingolipids, brain sphingomyelin, dipalmitoylsphingomyelin, distearoylsphingomyelin, galactocerebroside, gangliosides, cerebrosides, phosphatidylglycerol, phosphatidic acid, lysolecithin,lysophosphatidylethanolamine, cephalin, cardiolipin, dicetylphosphate, distearoylphosphatidylethanolamine and cholesterol and its derivatives. Similarly, the phospholipid can be a derivative or analogue of any of the foregoing phospholipids or, again, a mixture of two or more of any of the foregoing phospholipids. Such phospholipids can be obtained from commercial sources, natural sources or by synthetic or semi-synthetic means known to those of skill in the art.[000180] In preferred embodiments, the polypeptide-lipid complex is a polypeptide-phospholipid-complex. In a more preferred embodiment, the lipid is 1-palmitoyl-2-oleoyl phosphatidylcholine (“POPC”) or (“1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine”).[000181] It will be readily apparent to those of skill in the art that the complex comprising a polypeptide of the present disclosure and a lipid, preferably a phospholipids, can comprise any amount of lipid and any amount of the polypeptide, provided the complex is effective to mediate cholesterol efflux and, in turn, to treat diseases or symptoms associate therewith. As previously mentioned, it has surprisingly been found that when the polypeptides of the present disclosure are complexed with, for example, POPC at ratios ranging from about 1:0.5 to about 1:5 (polypeptide: POPC), distinct lipid-polypeptide particles are formed having sizes of between about 5 and about 20 nm, which result in a significantly enhanced capacity, / .e., ability, to efflux cholesterol from cells. However, the polypeptide-lipid complexes of the present disclosure can comprise complexes with other ratios of phospholipid to polypeptide, such as about 100:1, about 10:1, about 5:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:5, about 1:10 and about 1:100 (wt of polypeptide / wt of lipid).[000182] The polypeptide-lipid complexes of the present disclosure can be made by any method known to one of skill in the art. In some cases, it is desirable to mix the lipid and the polypeptide prior to administration. Lipids can be in solution or in the form of liposomes or emulsions formed using standard techniques, such as homogenization, sonication or extrusion. Sonication is generally performed with a tip sonifier, such as a Branson tip sonifier, in an ice bath. Typically, the suspension is subjected to several sonication cycles. Extrusion can be carried out by biomembrane extruders, such as the Lipex Biomembrane Extruder. TM. (Lipex Biomembrane Extruder, Inc. Vancouver, Canada). Defined pore size in the extrusion filters can generate unilamellar liposomal vesicles of specific sizes. The liposomes can also be formed by extrusion through an asymmetric ceramic filter, such as a Ceraflow Microfilter. TM., which is commercially available from the Norton Company, Worcester, MA, or through a polycarbonate filter or other types of polymerized materials ( / .e., plastics) known to those of skill in the art.[000183] As previously mentioned, the polypeptide-lipid complexes of the present disclosure can be prepared in a variety of forms including, but not limited to, vesicles, liposomes or proteoliposomes. A variety of methods well known to those skilled in the art can be used to prepare the polypeptide-lipid complexes. A number of available techniques for preparingliposomes or proteoliposomes can be used. For example, a polypeptide of the present disclosure (e.g., a polypeptide of SEQ ID NO:1 or SEQ ID NO:2, or a variant thereof) can be cosonicated (using a bath or probe sonicator) with the appropriate lipid to form the polypeptide-lipid complexes. In certain embodiments, the polypeptide can be combined with preformed lipid vesicles resulting in the spontaneous formation of a polypeptide-lipid complex. In another embodiment, the polypeptide-lipid complex can also be made by a detergent dialysis method. In this method, a mixture of the polypeptide, lipid and a detergent, such as sodium cholate, can be dialyzed to remove the detergent and reconstituted to make the polypeptide-lipid complexes (see, e.g., Jonas et al., Methods Enzymol., 128:553-82 (1986)).[000184] In other embodiments, the polypeptide-lipid complexes can be made by colyophilization as described in U. S. Patent Nos. 6,287,590 and 6,455,088, the teachings of both of which are hereby incorporated by reference in their entirety. Other methods are disclosed in, for example, U. S. Patent Nos. 6,004,925, 6,037,323 and 6,046,166, the teachings of all of which are incorporated herein by reference in their entireties. Other methods of preparing polypeptide-lipid complexes will be apparent to those of skill in the art.[000185] In one preferred embodiment, the polypeptide-lipid complexes can be made by homogenization.2. Exosomes[000186] In another aspect, the polypeptides and peptidomimetics of the present disclosure may be administered in conjunction with an exosome. The exosomes can be formulated to encapsulate or conjugate with the polypeptides or peptidomimetics to protect and / or enhance their transport and / or uptake.[000187] Exosomes have been identified as carriers for pharmaceutical drug delivery -especially synthetic biomolecules. Exosomes exist naturally as nanovesicles of endocytic origin, formed by invagination of endosomes with the plasma membrane, which encapsulates a biological payload of proteins, enzymes, nucleic acid or metabolites. Thomas et al., Front. Bioeng. Biotechnol. 2022, 9, 2021. Since exosomes are natural shuttles of endogenously produced bioactive biomolecules, they have been extensively used for active and passive delivery of synthetic biomolecules. Their endogenous nature and nanoparticulate characteristics also allow exosomes to migrate across biological barriers and imparts them with excellent biocompatibility (Akuma et al., 2019, Front. Sustain. Food Sys. 3, 23; Elliott and He, 2021, Pharmaceutics 13(1), 122). They have been identified as a way of overcoming cross-species immunity (Zhou et al., 2017, J. Cell. Biochem. 118(12), 4267-4274; Baldini et al., 2018, Cpb 19(11), 877-885; Chen et al., 2019, Mol. Pharmaceutics 16(6), 2690-2699; Lee, 2019, Ijms 20(6), 1487; Schuh et al., 2019, Translational Res. 210, 80-98) and even organ-specifictargeting (Hoshino et al., 2015, Nature 527 (7578), 329-335; Sancho-Albero et al., 2019, J. Naobiotechnol. 17(1), 16).[000188] In simplest form, exosomes comprise a phospholipid bilayer enriched with donor membrane-derived proteins and an inner aqueous core. They can be isolated from a wide range of tissue and species types. Extracellularly released exosomes can exhibit partial organ selectivity, which is because of its unique proteome and lipid composition, sharing significant similarity with the donor cell, subsequently affecting its cellular uptake (Hoshino et al., 2015; Sancho-Albero et al., 2019).[000189] Naturally occurring exosomes can be isolated using a variety of known techniques, such as differential centrifugation, polymeric isolation, precipitation, immunoaffinity, size exclusion liquid chromatography, ultrafiltration, microfluidics each with its own advantages and disadvantages. Thomas et al., 2021.[000190] Exosomes may also be produced synthetically using known techniques, based on a lipid bilayer and extracellular vesicle associated proteins. WO20211521151A1, WO2019027847A1; W02020101740A1.[000191] Once isolated exosome can be combined with the drug payload using a variety of known techniques, including physical incubation, electroporation, transfection, and conjugation to cell penetrating peptides. Thomas et al., 2021.H. NUCLEIC ACIDS[000192] In another embodiment, the present disclosure provides isolated nucleic acids encoding the polypeptides disclosed herein, expression vectors comprising the nucleic acids, and host cells comprising the expression vectors. More particularly, the present disclosure provides isolated nucleic acids encoding the polypeptides of the present disclosure having cholesterol efflux activities similar to full-length apolipoproteins, on a per molecule basis, and having high selectivity for ABACI in a manner similar to full-length apolipoproteins, the polypeptides including, but not limited to, polypeptides having an amino acid sequence of SEQ ID NO:3 or SEQ ID NO:4, or a variant as described herein. In such sequences, citrulline can be encoded as arginine.[000193] In certain embodiments, nucleic acids encoding the polypeptides of the disclosure are used for transfection of cells in vitro and in vivo. These nucleic acids can be inserted into any of a number of well-known vectors for the transfection of target cells and organisms as described below. The nucleic acids are transfected into cells, ex vivo or in vivo, through the interaction of the vector and the target cell. The nucleic acids, under the control of a promoter, then express a polypeptide of the present disclosure, thereby mitigating the effects of a disease associated with a PNS myelination condition.EXEMPLARY EMBODIMENTS[000194] 1. A method of treating a subject having a PNS (peripheral nervous system) myelination condition, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a polypeptide having cholesterol efflux activity, wherein the polypeptide comprises an amino acid sequence that is an amphipathic a-helix having a non-polar surface and a polar surface, wherein the polar surface comprises charged and uncharged amino acid residues at the lipid-water interface, wherein the amino acid sequence:• has at least 60% identity to EVcitSKLEEWLAALcitELAEELLARL (SEQ ID NO:1); and, with reference to SEQ ID NO:1• has a citrulline, or an uncharged analog of citrulline, that maintains a saltbridge configuration in the a-helix, at one, two or three of positions 3, 14, and 23;• comprises a hydrophobic amino acid at positions 2, 6, 9, 10, 13, 16, 17, 20, and 24; and• comprises an acidic amino acid residue at positions 1, 7, 8, 15, 18 and 19.[000195] 2. The method of embodiment 1, wherein, with reference to SEQ ID NO:1, the amino acid sequence comprises one or more of:• an uncharged amino acid at a second of the three positions 3, 14, and 23; • an uncharged amino acid at the second and third of the three positions 3, 14, and 23;• an a-helix amino acid sequence further comprising residues 25 and 26, wherein position 25 is K or N and position 26 is S or Y;• an amino acid sequence in which at least one position 3, 14 or 23 is Q, N, L, V, I, or A;• an amino acid sequence in which at least one position 3, 14 or 23 is Q or N; • an amino acid sequence in which at least two positions 3, 14, and 23 are independently selected from Q, N, L, V, I, or A;• an amino acid sequence in which at least one position 3, 14 and 23 is R or K;• an amino acid sequence in which four, five, six, seven, or all eight of residues at positions 2, 6, 10, 13, 16, 17, 20, and 24 are aliphatic amino acids;• an amino acid sequence that is SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 or SEQ ID NO:4; or• an amino acid sequence that is CS6253.[000196] 3. The method of embodiment 2, wherein, with reference to SEQ ID NO:1,• the amino acid at positions five, six, seven, or eight of positions 2, 6, 10, 13, 16, 17, 20 and 24 are aliphatic amino acids, andthe aliphatic amino acid is selected from the group consisting of L, V, A, and I; or• the aliphatic amino acid is selected from the group consisting of L, I, and V at position 10, 13, 16, and 20.[000197] 4. The method of embodiment 1, wherein the polypeptide does not comprise amino acid analogs.[000198] 5. The method of embodiment 1, wherein the polypeptide comprises SEQ ID NO:3.[000199] 6. The method of embodiments 1 - 4, wherein the amino acids, other than cit, are essential amino acids.[000200] 7. The method of embodiments 1 - 4, wherein the polypeptide further comprises a protecting group.[000201] 8. The method of embodiments 1-6, wherein the PNS myelination condition is selected from the group consisting of:• a condition characterized by PMP22 dysfunction in the PNS;• a PNS myelination disorder resulting from abnormal ABCA1 regulated cholesterol transport;• a Schwann cell regulated cholesterol transport disorder;• a demyelinating condition resulting from Schwann cell dysfunction; and• a non-hereditary PNS myelination condition.[000202] 9. The method of embodiment 8, wherein the PNS myelination condition is characterized by PMP22 dysfunction in the PNS.[000203] 10. The method of embodiment 9, wherein the PMP22 dysfunction causes abnormal regulation of ABCA1.[000204] 11. The method of embodiments 9 or 10, wherein the PMP22 dysfunction results from one or more PMP22 mutations, PMP22 overexpression or PMP22 under-expression.[000205] 12. The method of embodiment 11, wherein the PMP22 dysfunction is at least one PMP22 point mutation.[000206] 13. The method of embodiment 12, wherein the PNS myelination condition is CMT1E.[000207] 14. The method of embodiment 12, wherein the PNS myelination condition is DSS (Dejerine-Sottas Syndrome).[000208] 15. The method of embodiment 11, wherein the PNP22 dysfunction is PMP22 overexpression.[000209] 16. The method of embodiment 15, wherein the PMP22 overexpression results from PMP22 copy number variation (CNV) > 2.[000210] 17. The method of embodiment 15, wherein the PNS myelination condition is CMT1A.[000211] 18. The method of embodiment 11, wherein the PMP22 dysfunction is PMP22 underexpression.[000212] 19. The method of embodiment 18, wherein the PMP22 underexpression results from PMP22 copy number variation (CNV) < 1.[000213] 20. The method of embodiment 18, wherein the PMP22 underexpression results from PMP22 gene deletion.[000214] 21. The method of embodiment 11, wherein the subject has one or more signs or symptoms of PMP22 dysfunction.[000215] 22. The method of embodiment 21, wherein the subject has a Charcot-Marie-Tooth Neuropathy Score (CMTNS) < 10.[000216] 23. The method of embodiment 21, wherein the subject has a Charcot-Marie-Tooth Pediatric Scale score < 2.[000217] 24. The method of embodiment 18 or 19, wherein the PNS myelination condition is HNPP[000218] 25. The method of embodiment 8, wherein the PNS myelination condition is a PNS myelination disorder resulting from abnormal ABCA1 regulated cholesterol transport.[000219] 26. The method of embodiment 8, wherein the PNS myelination condition is a Schwann cell regulated cholesterol transport disorder.[000220] 27. The method of embodiment 26, wherein the Schwann cell regulated cholesterol transport disorder is selected from disorders or conditions affecting axon maintenance, nerve regeneration and remodeling of neuromuscular junction (NMJ) and neurofibromatosis (NF).[000221] 28. The method of embodiment 8, wherein the PNS myelination condition is a demyelinating condition resulting from Schwann cell dysfunction.[000222] 29. The method of embodiment 28, wherein the demyelinating condition is selected from the group consisting of: inflammatory demyelinating neuropathy, acute inflammatory demyelinating polyneuropathy (AIDP), Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), demyelinating diabetic neuropathy, anti-MAG peripheral neuropathy and acute idiopathic polyneuritis.[000223] 30. The method of embodiment 29, wherein the demyelinating condition is inflammatory demyelinating neuropathy.[000224] 31. The method of embodiment 29, wherein the demyelinating condition is acute inflammatory demyelinating polyneuropathy (AIDP).[000225] 32. The method of embodiment 29, wherein the demyelinating condition is Guillain-Barré syndrome (GBS).[000226] 33. The method of embodiment 29, wherein the demyelinating condition is chronic inflammatory demyelinating polyneuropathy (CIDP).[000227] 34. The method of embodiment 29, wherein the demyelinating condition is demyelinating diabetic neuropathy.[000228] 35. The method of embodiment 29, wherein the demyelinating condition is anti-MAG neuropathy.[000229] 36. The method of embodiment 29, wherein the demyelinating condition is acute idiopathic polyneuritis.[000230] 37. The method of embodiment 8, wherein the PNS myelination condition is a non-hereditary PNS myelination condition.[000231] 38. The method of embodiment 37, wherein non-hereditary PNS myelination condition is caused by a trigger selected from the group consisting of: inflammation, infection, neurotoxin exposure, chemotherapy, radiation, neuroleptic drug side effect, organophosphate exposure, autoimmune reaction, trauma, ischemia, asphyxia, metabolic disorder, copper deficiency and idiopathic origins.[000232] 39. The method of embodiment 38, wherein the infection is a virus, bacteria or prion.[000233] 40. The method of embodiment 38, wherein the neurotoxin in an organophosphate.[000234] 41. The method of embodiments 29 - 40 wherein the patient has an Overall Neuropathy Limitations Score (ONLS) of < 6.[000235] 42. The method of any of embodiments 1-41, wherein the pharmaceutical composition comprises one or more lipids.[000236] 43. The method of any of embodiments 1-41, wherein the pharmaceutical composition comprises an exosome.[000237] 44. The method of embodiments 42 or 43, wherein the pharmaceutical composition is administered in combination with an additional therapeutic agent.[000238] 45. The method of any of embodiments 1-44, wherein the pharmaceutical composition is administered intraperitoneally.[000239] 46. The method of any of embodiments 1-44, wherein the pharmaceutical composition is administered intravenously.[000240] 47. The method of any of embodiments 1-44, wherein the pharmaceutical composition is administered subcutaneously, intramuscularly or transdermally.EXAMPLESExample 1:ABCA1 membrane stabilization and glial cell extension[000241] This example shows the effect of CS6253 on non-myelinating Schwann cells from wild type (wt) and neuropathic mice.[000242] Following the procedure of Zhou et al., 2019, J Neurosci. 39:5404-5418, application of CS6253 to the culture medium stabilized membrane exposure of ABCA1 in Schwann cells cultured from the TrJ mouse nerves (Fig 1A), indicating target engagement. Furthermore, application of CS6253 remedied the atypical, shortened cell morphology of neuropathic glia (Lee et al., 2014), and led to an increase in the axial length in combination with membrane expansion (Fig 1B).Example 2:Nerve Conductance Velocity[000243] This example shows the effect of CS6253 on axonal length on wild-type and neuropathic mice.[000244] Following prior studies, CS6253 was administered for six weeks at 20 mg / kg every 48h, (Boehm-Cagan et al., 2016, PLoS One 11:e0166195; and Rawat et al., 2019, J Neurosci.39:9611-9622). 2-mo-old TrJ mice were segregated by sex at weaning, and randomly assigned to treatment or control groups. Over a 5-week period, we completed 16 injections (20 mg / kg), dosing the mice every 48h. Mouse weight was checked weekly and the amount of peptide to maintain the 20 mg / kg dose was readjusted. As Fig 2 shows, the peptide regimen improved nerve conduction velocity (NOV) by -34% in the TrJ. In agreement with our publication (Chittoor-Vinod et al., 2019, ASN Neuro. 5:e00128), the untreated TrJ mice show a reduced NOV of 5.1 m / s, compared with wild type.[000245] NCV measurements: Using the Power Lab system (AD Instruments, Colorado), the NCV signal was recorded by stimulating the sciatic (proximal to sciatic notch) and tibial (distally to ankle) nerve. Exact electrode placement distances were measured with digital calipers, and signal latencies for calculating NCV were analyzed in LabChart (ADInstruments). The recorded signal was used to determine the full NCV.Example 3:CS6253 Bioavailability[000246] The qualitative in vivo bioavailability of CS6253 within target cells and nerve tissue was tested by two different methods, LC / MS / MS and anti-CS6253 antibodies (Fig 3). The mean plasma concentration of CS6253 was -70,000 ng / ml, 6h post injection, and this was similar between Wt and TrJ (Fig 3A). In sciatic nerve lysates (after saline clearing of the mouse tissue), the peptide concentration was -2,000 ng / g of tissue, which is above the EC50 for cholesterol efflux of 1,000 ng / mL tissue or for binding to ABCA1 of 100 ng / mL (not shown). By immunolabeling with rabbit anti-CS6253 antibodies, we detected the peptide in glial cells within sciatic nerve sections (Fig 3B). Furthermore, the uptake of CS6253 by cultured mouse Schwann cells was demonstrated after 16h incubation with 100 pg / ml peptide (Fig 3C).Example 4:Quantitative CS6253 Bioavailability[000247] CS6253 bioavailability in sciatic nerves are evaluated by immunolabeling with rabbit anti-CS6253 antibody using the procedure of Boehm Cagan et al., 2016, PLoS One.11:e0166195. At each age (4-, 16-week), a cohort of 4 mice per group (3 neuropathic and 2 strain matched control groups, as described above) are injected with CS6253, for a total of 40 mice. Twenty-four (24) hours after injection, the animals are sacrificed. The sciatic nerves are dissected out and processed for immunostaining with anti-CS6253 antibody, as shown in the preliminary results (Ex 3). This antibody reliably identifies the peptide in situ, without significant interference of reactivity with the endogenous mouse apoE. We detect the peptide within Schwann cells and endoneural fibroblasts, as both cell types express ABCA1 (Zhou et al., 2019, J Neurosci. 39:5404-5418). At the 24h time point, we anticipate the peptide to be internalized by cells within the sciatic nerve (Rawat et al., 2019, J Neurosci. 39:9611-9622). Anti-S100p or P0 antibodies is used for positive identification of Schwann cells, anti-NF for axons, and anti-l ba-1 for macrophages. Endoneureal fibroblast is identified by lack of S100 immunoreactivity and positive staining with anti-ApoE (Zhou et al., 2019, Exp Neurol. 321:113031). These studies are repeated in 4 independent mice to assure reproducibility. Nerve sections are evaluated by confocal imaging (Zhou et al., 2019, Exp Neurol. 321:113031).[000248] In vivo CS6253 administration to mice: After recording the body weight of each mouse, the exact peptide injection volumes are calculated. At the specific time points, the mice are sacrificed by CO2 inhalation, and blood plasma and peripheral nerves are collected to determine peptide content.[000249] Quantification of CS6253 in blood plasma and sciatic nerves: Peptide concentrations are completed by LC / MS / MS in ng / ml for plasma and ng / g of tissue for the sciatic nerve. The data are averaged for the 4 mice per group, per time point and analyzed for median and standard deviation.[000250] Immunodetection of CS6253 in target tissue: Peptide bioavailability within sciatic nerves is evaluated by immunolabeling with rabbit anti-CS6253 antibody (Boehm-Cagan et al., 2016a). A cohort of 4 mice per study group is injected with CS6253, for a total of 40 mice.Twenty-four hours after injection, the animals are sacrificed. The sciatic nerves are dissected out and processed for immunostaining with anti-CS6253 antibody. This antibody reliably identifies the peptide in situ, without significant interference of reactivity with the endogenous mouse apoE. We detect the peptide within Schwann cells and endoneural fibroblasts, as both cell types express ABCA1 (Zhou et al., 2019b). At the 24h time point, we anticipate the peptide to be internalized by cells within the sciatic nerve (Rawat et al., 2019). Anti-S100p or P0 antibodies are used to positively identify Schwann cells, anti-NF for axons, and anti-lba-1 for macrophages. Endoneureal fibroblasts are identified by lack of S100 immunoreactivity and positive staining with anti-ApoE (Zhou et al., 2019a). These studies are repeated in 4 independent mice to assure reproducibility. Nerve sections are evaluated by confocal imaging (Zhou et al., 2019a).Example 5:Adolescent NCV[000251] This example is a robust evaluation of nerve conductance velocity (NCV) in 4-week and 10-week neuropathic mice.[000252] Rationale: The literature suggests early intervention at young age is most effective for the prevention of demyelinating neuropathies (Fledrich et al., 2018, Nat Commun. 9:3025; Prior et al., 2022; Mol Neurobiol. 59:3414-3430; Saher et al., 2012, Nat Med. 18:1130-1135). While CS6253 has been tested in adult mice, behavioral testing of it in young animals has not been performed. Therefore, motor phenotyping for young mice, and standardization of electrophysiological tests to prepare are performed for reliable detection of potential improvements due to the intervention.[000253] Motor phenotyping: Motor behavior tests are performed according to the literature (Chittoor-Vinod et al., 2019, ACS Chem Neurosci. 10:2890-2902; Madorsky et al., 2009, Neurobiology of disease. 34:146-154; Nicks et al., 2014, Neurobiol Dis. 70:224-236) and are administered at the beginning, during and at the end of the treatment period (see Example 6, Fig 4). The rotarod and grip strength tests for the 4-wk old mice follow the methods described in Prior et al., 2022, Mol Neurobiol. 59:3414-3430.[000254] Rotarod, a constant speed of 15 rpm is used and the average latency to fall from 5 trials per animal is recorded (Norreel et al., 2001, Eur J Neurosci. 13:1625-1634).[000255] Grip Strength: This test measures changes in motor function associated with muscle loss and has been used to characterize differences in muscle strength between neuropathic and Wt mice (Norreel et al., 2001, Eur J Neurosci. 13:1625-1634). The mouse is held by the nape ofits neck and the base of its tail, and its forelimbs or hind limbs are placed on a tension bar. The animal is gently pulled back until it releases the bar. The pulling force needed to overcome their grip is measured in kilograms of resistance by a strain gauge (Chittoor- Vinod et al., 2019, ASN Neuro. 5:e00128). The grip strength test is performed 5 times to determine the average value per mouse.[000256] Sciatic nerve conduction velocity (NCV): After motor phenotyping, a cohort of mice (n=4) from each genotype at 10 wk of age (end point for the young intervention trials in the R33 phase) are subjected to NCV measurement. Using the Power Lab system (AD Instruments, Colorado), the NCV signal is recorded by stimulating the sciatic (proximal to sciatic notch) and tibial (distally to ankle) nerve. In 10-wk old mice, only one recording position at the distal point is measured; due to their small size. Exact electrode placement distances are measured with digital calipers, and signal latencies for calculating NCV are analyzed in LabChart (ADInstruments). The recorded signal is used to determine the full NCV, as described (Saini et al., 2004, Pharmacol Res. 50:593-599).[000257] In situ isometric torque analysis: A second cohort of mice (n=4) from each genotype at 10 wk of age (end point for young intervention trials) is randomly selected for in situ isometric torque analysis on the tibialis anterior (TA) muscle and anterior tibial tendon. Impairment of the TA muscle serves as an indicator of disease progression in CMT 1A patients (Komyathy et al., 2013, Muscle Nerve. 47:493-496) and in mice (Chittoor-Vinod et al., 2019, ACS Chem Neurosci.10:2890-2902). Single stimulations is performed ranging from 15Hz to 200Hz (twitch to tetanic contractions). Recorded data is processed to generate a torque-frequency curve. This measure provides functional data on skeletal muscle strength in untreated neuropathic and Wt animals.[000258] Study design and statistics: For each disease model (CMT1A, CMT1E, HNPP), results from rotarod and grip strength assays from 4-week-old neuropathic mice are compared to those from age-, strain-matched Wt mice using Student’s t-tests (4 mice per group as described above, for a total of 20 mice to detect a large effect with alpha =.05 and power =.80). Additionally, 10-week-old mice from each group are sacrificed for sciatic NCV TA isometric torque analyses (4 mice per group, per test, for a total of 40 mice).[000259] Conclusion: CS6253 is detected by LC / MS / MS at therapeutic concentrations (>1,000 ng / g of tissue, i.e., EC50 for ABCA1 binding) in target nerve tissue 6h post-injection, and localized to Schwann cells and / or endoneurial fibroblasts 24h after injection, at least one of the neuropathic models. Milestones for Example 5 demonstration of CS6253 within target nerve tissue at specific time points of interest, and at two distinct stages of neuropathy (4-week and 16-week of age).Example 6Neurobehavior assessments of CS6253[000260] This example evaluates CS6253 intervention on phenotypic disease behaviors in neuropathic animals. The two neurobehavioral assays administered during the intervention period (rotarod and grip strength), along with the electrophysiological end point assessments for the relevant tissues (nerve and muscle), allows a comprehensive evaluation of CS6253’s efficacy for the treatment of demyelinating neuropathies. The measured physiological parameters are relevant for clinical testing, as weakening of the tibialis anterior is directly linked to foot drop in human patients (Cornett et al., 2019, Muscle Nerve 59:213-217), and reduction in NCV is used as a diagnostic measure in clinical neurology (Baudou et al., 2022, Neuropediatrics 53:182-187).[000261] The objective of Example 6 is to determine the efficacy of CS6253 in ameliorating the neuropathic phenotype of mice, including myelin defects, in two different treatment paradigms: 1) Early treatment for disease prevention / progression (4-10 wk of age) and 2) late treatment to halt / repair myelin damage (16-22 wk of age). While prior studies suggest (Prior et al., 2022, Mol Neurobiol. 59:3414-3430) that early intervention in mice has the best outcome, as many patients become symptomatic only in adulthood, intervention in mature, 16-wk old mice as a surrogate for this subject group.[000262] Phase 1: Demonstrate the therapeutic efficacy of CS6253 in neuropathic mice, by biweekly measuring grip strength and ability to remain on the accelerating rotating rod, during the 16-week-long intervention trial.[000263] Study design and statistics: Following the recommendations for “blinded” study design and unbiased data analyses, as described by Landis and colleagues (Landis et al., Nature. Oct 11;490(7419):187-91 2012), CS6253 is tested in two different paradigms, staggered over two years: 1) Early intervention starting at 4-wk of age; and 2) late treatment initiated at 16-wk of age. Each intervention paradigm entails 21 peptide injections, spaced 48h apart, using 20 mg / kg dose. The chosen age-groups are based on published data showing a significant decline in neuromuscular performance and NCV in neuropathic mice between the ages of 30-72 days (Meekins et al., 2004, J Peripher Nerv Syst. 9:177-182). Mice are earmarked and genotyped before postnatal day 10 and weaned and separated by sex at 3 weeks of age (4 mice / cage). The genotype of the mice is masked and only the mouse numbers are tracked, which is necessary for body weight measurements and accurate drug dosing. At 4-wk of age (young) or at 16-wk (adult) the mice are randomly assigned to a vehicle (clinical grade saline) or CS6253 treatment. The neuropathic model is bred independently and on different genetic backgrounds [C57 / BI6 for TrJ], therefore each intervention study includes untreated Wt littermates for comparison.[000264] In vivo CS6253 administration to mice: Lyophilized CS6253 powder is reconstituted into sterile phosphate buffered saline (PBS), per Artery Therapeutics, Inc. Stock solutions (5 mg / ml) are diluted in sterile PBS just before use and PBS alone is used as a vehicle. Thepeptide administration paradigm is based on published studies using an i.p. injection route, with 20 mg / kg / 48hr (Boehm-Cagan et al., 2016, PLoS One. 11:e0166195). Neuropathic heterozygous TrJ mice are randomly assigned to the 6-week long intervention paradigm, with five male and five female mice / group. By the endpoint, the young cohort is 10-wk old, an age when vehicle treated neuropathic mice exhibit pronounced phenotypes, allowing quantitation of the effects of the peptide treatment on the outcome measures. With the older cohort, the mice are already phenotypic at 16-wk, and vehicle treated animals continue to decline until the 22-wk end point. Wt mice are included as controls for each cohort, but without injection. The young and adult cohorts and the specific neuropathic lines are staggered and repeated with independent cohorts to show reproducibility. The body weight of each mouse is measured weekly and charted by the cage and mouse number. The grooming behavior of the mice are observed and the study terminated if health concerns and / or excessive (over 20%) weight gain / loss are identified. At the end of the intervention, the TA muscle force generation, nerve conduction velocity (NCV) are measured, and the sciatic nerves and the TA are collected for analyses (see below).[000265] Motor phenotyping: As shown in study design cartoon (Fig 4), functional tests are administered at the beginning, during and at the end of the treatment period (Chittoor-Vinod et al., 2019; ACS Chem Neurosci. 10:2890-2902; Madorsky et al., 2009, Neurobiology of disease.34:146-154; Nicks et al., 2014, J Neuropathol Exp Neurol. 72:942-954). During the R61 period the methods are refined to assure reproducible baseline data collection from the 4-week-old mice. Animal genotype is not disclosed to the persons assessing the functional parameters, and the mice are tracked by cage numbers and ear markings. Data obtained by the motor tasks is expressed as the mean score of each group, + / - SEM. Differences between groups are checked by a one-way ANOVA, using a p-value < 0.05 for statistical significance.[000266] Test of motor coordination on a rotating rod: Before data collection, each mouse is trained for 3 consecutive days (3 trials / day) at a low speed (5 rpm) in order to stabilize performance. For the young mice, 15 rpm constant speed is used, and latency to fall is recorded up to a maximum of 300 seconds. This method was recently published for 30 days old mice C3 mice (Prior et al., 2022, Mol Neurobiol. 59:3414-3430). The older mice are tested on a rotating rod that accelerates from 0 to 50 rpm (3 trials / day), using established methods (Chittoor-Vinod et al., 2019, ACS Chem Neurosci. 10:2890-2902.).[000267] Grip Strength: This test is used to monitor muscle strength and determine differences between vehicle-, CS6253- treated neuropathic, and Wt mice (Norreel et al., 2001). The mouse is held by the nape of its neck and the base of its tail, and its forelimbs or hind limbs are placed on a tension bar. The animal is gently pulled back until it releases the bar. The pulling force needed to overcome their grip is measured in kilograms of resistance by a strain gauge. The grip strength test is performed 5 times and the average of 5 trials is used for statistical analyses.[000268] Study design and statistics: A mixed ANOVA is used to compare motor performance between 3 mouse groups (neuropathic mice receiving drug, neuropathic mice receiving vehicle, and age-, strain- matched Wt mice) at 4 timepoints (0, 2, 4, 6 weeks of treatment). Post hoc comparisons are made using the Bonferroni correction method. Assuming a large effect size, alpha =.05 and power =.80, a power analysis indicated each test requires a sample size of 36 mice, or 12 per group. Thus, for the 3 neuropathic models, along with 2 Wt controls to be tested at 2 ages, a total of 216 (36X5) mice are required to complete this objective. However, since the same C57 / BI6 Wt group can be used at both 4 and 16 weeks of age, this number is reduced by 24 to a total of 192 mice (see table in Vertebrate Animal section for specific details).[000269] Phase 2: Demonstrate the in vivo efficacy of CS6253 in reproducibly improving nerve conduction velocity (NCV) and TA skeletal muscle strength, in comparison to placebo treated neuropathic littermates.[000270] Rationale: Nerve conduction velocity shows a significant decline in neuropathic mice between the ages of 30-72 days (Meekins et al., 2004, J Peripher Nerv Syst. 9:177-182).Skeletal muscle atrophy occurs later with noticeable changes after 2 months of age (Nicks et al., 2013, J Neuropathol Exp Neurol. 72:942-954). The temporal occurrence of these changes differ between the 3 studied models. Therefore, since the two intervention periods (4-10 wk; and 16-22 wk) cover these time points, we use the information from the R61 phase to refine and standardize the assays in our test subjects.[000271] Sciatic nerve conduction velocity (NCV): Nerve conduction velocity (NCV) is determined using the Power Lab system (AD Instruments), as described above. Mice younger than two months have only one recording position at the distal point; due to their small size, a second recording site is not possible with the current setup. Exact electrode placement distances are measured with digital calipers, and signal latencies for calculating NCV are analyzed in Lab Chart (ADInstruments). The recorded signal is then analyzed to determine the full NCV of the system as described (Saini et al., 2004, Pharmacol Res. 50:593-599).[000272] In situ isometric torque analysis: At each study end point, under anesthesia mice are randomly selected for in situ isometric torque analysis on the tibialis anterior (TA) muscle and anterior tibial tendon. Impairment of the TA muscle serves as an indicator of disease progression in CMT1A patients (Komyathy et al., 2013, Muscle Nerve. 47:493-496) and in mice (Chittoor- Vinod et al., 2019, ACS Chem Neurosci. 10:2890-2902). Single stimulations are performed ranging from 15Hz to 200Hz (twitch to tetanic contractions). Recorded data are processed to generate a torque-frequency curve. This measure provides functional data on skeletal muscle strength. Myofiber morphometries follow established protocol (Falk et al., 2018, Muscle Nerve. 57:664-671).[000273] Study design and statistics: Upon completion of the 6-week drug treatment protocol as described in Example 2, mice are used to test sciatic NCV and TA isometric torque. For each disease model (CMT1A, CMT1E, HNPP), at each age, a 1-way ANOVA is used to compare NCV and torque results between the 3 groups of mice (neuropathic with drug, neuropathic with vehicle, age-, sex-, strain-matched Wt). Post hoc comparisons are made using the Bonferroni correction method. Power analysis indicated a sample size of 18 mice, or 6 per group, are required for each test to detect a large effect with alpha =.05 and power =.80. Thus, half of the mice are used for NCV and the other half for isometric torque analyses.[000274] Phase 3: Assess target engagement and drug efficacy by unbiased, quantitative proteomic analyses of ABCA1, apoE, HMGCR and myelin proteins, myelin morphometries, cholesterol quantification and distribution in target peripheral nerve tissue of CS6253-treated neuropathic mice.[000275] Nerve protein preparation and digestion: Sciatic nerves from individual mice are solubilized with a RIPA lysis buffer, as described (Fortun et al., 2006, Neurobiology of disease.22:153-164). Undissolved proteins are separated and dissolved in 10 mM Tris HCI 3% SDS and added back to the previously dissolved proteins. The final lysates are briefly sonicated, and protein content is determined before further processing by the UNR Hitchcock Proteomic Core. For each sample, 100 pg of total tissue lysate is digested and separated by liquid chromatography. The peptide sequence of each preparation is determined by liquid chromatography-mass spectrometry (LC-MS).[000276] Proteomic analysis: LCMS is performed using DIA to characterize proteomic changes in target peripheral nerve tissue. Peptides from lysate digests are separated on Ultimate 3000 RSLCnano system (Thermo Scientific). Peptides are then ionized using an EasySpray ionization source prior to mass spectral analysis. Mass Spectral analysis are performed on an Eclipse Tribrid mass spectrometer (Thermo Scientific). DIA analysis is performed on the samples using a staggered window scheme of 8 m / z over a mass range of 385-1015 m / z. Precursor isolation is performed in the Orbitrap at 60,000 resolution with a dynamic maximum injection allowing for a minimum of five points across the peak to achieve greater quantitative accuracy. Statistical analysis is performed by the Nevada Bioinformatics center.[000277] Bioinformatics: Pathway diagrams are generated using iPathwayGuide. Perturbation accounts for the gene’s measured fold-change and the accumulated perturbation propagated from any upstream genes (accumulation). The number of differentially expressed genes annotated to myelination, and cholesterol metabolism are compared to the number of differentially expressed genes expected just by chance. iPathwayGuide uses an overrepresentation approach to compute the statistical significance of observing at least the given number of differentially expressed genes. The p-value is calculated using the hypergeometricdistribution described in the Pathway diagrams, and corrected for multiple comparisons using FDR and Bonferroni. Pathway analyses begins with lipid metabolism and determines if the observed reductions in HMGCR in neuropathic nerves are ameliorated by the peptide intervention. In addition, the levels of myelin proteins are analyzed, which are known to be misexpressed in the untreated neuropathic nerves throughout the lifespan of the animals (Amici et al., 2007, J Neurosci Res. 85:238-249; Chittoor et al., 2013, ASN Neuro. 5:e00128; Notterpek et al., 1997, J Neurosci. 17:4190-4200).[000278] Cholesterol distribution and immunodetection of CS6253 in target nerves: A five (5) mm fragment of the right proximal sciatic nerve is processed for cryosectioning (Chittoor-Vinod et al., 2019, ACS Chem Neurosci. 10:2890-2902), and the bioavailability of the peptide is directly evaluated by immunolabeling, using a rabbit anti-CS6253 antibody, provided by Artery Therapeutics Inc (Boehm-Cagan et al., 2016, PLoS One. 11:e0166195). Peptide detection within Schwann cells and endoneural fibroblasts of treated mice is found as these cells express ABCA1 (Zhou et al., 2019, J Neurosci. 39:5404-5418). Specificity controls include nonspecific rabbit serum as primary antibody and no primary antibody. Cholesterol distribution is evaluated by filipin labeling using our established techniques (Lee et al., 2014, J Neurosci. 34:16140-16152.; Zhou et al., 2019, Exp Neurol. 321:113031; Zhou et al., 2019, J Neurosci. 39:5404-5418). CS6253 treatment ameliorates cholesterol accumulation within neuropathic Schwann cells and restore its distribution to the plasma membrane / myelin. Cholesterol content in tissue lysates is determined by Amplex Red Cholesterol assay kit (Invitrogen), followed by quantification and analyses.[000279] Morphological evaluation of the sciatic nerves and the TA muscle: The left sciatic nerve proximal end (5 mm segment) is isolated from 6 mice from each study group and processed for electron microscopy, as described (Amici et al., 2006, J Neurosci Res. 85:238-249). G ratios of fiber diameter to axon diameter is determined as a standard measure of neuropathy severity and nerve myelination. Tomaculae frequency is counted in the nerves of heterozygous PMP22-deficient mice. The TA muscle is processed for myofiber diameter analysis (Nicks et al., 2014, Neurobiol Dis. 70:224-236). These end point measurements determine if CS6253 effectively restores the myelination of axons and provides benefit in preventing atrophy of skeletal myofibers.[000280] Study design and statistics: The same mice used in Phase 2 are used here. Each group of 6 mice used for NCV analysis in Phase 2 is used for myelin morphometries, and each group of 6 used for torque analysis in Phase 2 is used for proteomics. At each end-point age (10, 22 weeks), a 1-way ANOVA is used to compare results groups (neuropathic with drug, neuropathic with vehicle, age-, strain-matched Wt). Post hoc comparisons are made using the Bonferroni correction method.[000281] Outcome: The 6-week long CS6253 treatment, via i.p. injection route, result in a reduction of neuropathic phenotype, and improve neuromuscular function, nerve myelination, and lessen muscle atrophy. The expression of HMGCR to be restored by the peptide treatment compared to vehicle treated nerves. Based on published literature (Boehm-Cagan et al., 2016, PLoS One. 11:e0166195.; Itoh et al., 2018, Proc Natl Acad Sci U S A. 115:E302-E309; Rawat et al., 2019, J Neurosci. 39:9611-9622), and our pilot results (Figs 2 and 3), no difficulties with the bioactivity or bioavailability of the peptide are found. Therefore, completion of these preclinical studies in mice is determinative if targeting ABCA1-mediated cholesterol transport is a suitable approach for hereditary demyelinating neuropathies. IND enabling 30-day GLP studies in Wistar rats have shown a No Observable Adverse Effect Level (NOAEL) of 250 mg / kg when CS6253 dosed as IV bolus injection every other day. In other studies, exposure in mice and rats was virtually identical. Hence toxicity due to the peptide administration is not found. Nevertheless, collections of liver (known highest exposure organ) and kidney tissue for gross observations and weight assessment may be conducted as an extra safety measure.[000282] Pitfalls and alternatives: If necessary, peptide dose and dosage may be increased to 30 mg / kg / 24h, which was the treatment in the MS study (Itoh et al., 2018, Proc Natl Acad Sci U S A. 115:E302-E309). Alternatively, treatment could be extended to a duration to 10 weeks, or drug delivery started at an earlier time point (10-day postnatal) during the height of myelinogenesis, or at a later time point to test efficacy for symptom reversal. The current study design compares efficacy in early vs. late interventions, and provides critical information for potentially moving CS6253 forward to clinical testing in human patients.[000283] Conclusion: The evaluation of CS6253 results in significant (20% to 40%) improvement in at least two of the following; neuromuscular performance and / or NCV, TA muscle force, along with restoration of the nerve myelin proteome and HMGCR expression, as well as myelin morphology, as compared with placebo treated neuropathic mice.[000284] As used herein, the following meanings apply unless otherwise specified. The words “can” and “may” are used in a permissive sense (i.e., meaning having the potential to), rather than the mandatory sense (i.e., meaning must). The words “include”, “including”, and “includes” and the like mean including, but not limited to. The singular forms “a,” “an,” and “the” include plural referents. Thus, for example, reference to “an element” includes a combination of two or more elements, notwithstanding use of other terms and phrases for one or more elements, such as “one or more.” The phrase “at least one” includes “one”, “one or more”, “one or a plurality”, and, therefore, contemplates the use of the term “a plurality”. The term “or” is, unless indicated otherwise, non-exclusive, i.e., encompassing both “and” and “or.” The term “any of” between a modifier and a sequence means that the modifier modifies each member of the sequence. So, for example, the phrase “at least any of 1, 2 or 3” means “at least 1, at least 2 or at least 3”. The term “about” refers to a range that is 5% plus or minus from a stated numerical value within thecontext of the particular usage. The term "consisting essentially of' refers to the inclusion of recited elements and other elements that do not materially affect the basic and novel characteristics of a claimed combination.[000285] It should be understood that the description and the drawings are not intended to limit the disclosure to the particular form disclosed, but to the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims. Further modifications and alternative embodiments of various aspects of the disclosure will be apparent to those skilled in the art in view of this description. Accordingly, this description and the drawings are to be construed as illustrative only and are for the purpose of teaching those skilled in the art the general manner of carrying out the disclosure. It is to be understood that the forms of the disclosure shown and described herein are to be taken as examples of embodiments. Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed or omitted, and certain features of the disclosure may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the disclosure. Changes may be made in the elements described herein without departing from the spirit and scope of the disclosure as described in the following claims.[000286] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a subject having a PNS (peripheral nervous system) myelination condition, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a polypeptide having cholesterol efflux activity, wherein the polypeptide comprises an amino acid sequence that is an amphipathic a-helix having a non-polar surface and a polar surface, wherein the polar surface comprises charged and uncharged amino acid residues at the lipid-water interface, wherein the amino acid sequence:• has at least 60% identity to EVcitSKLEEWLAALcitELAEELLARL (SEQ I D NO:1); and, with reference to SEQ ID NO:1• has a citrulline, or an uncharged analog of citrulline, that maintains a saltbridge configuration in the a-helix, at one, two or three of positions 3, 14, and 23;• comprises a hydrophobic amino acid at positions 2, 6, 9, 10, 13, 16, 17, 20, and 24; and• comprises an acidic amino acid residue at positions 1, 7, 8, 15, 18 and 19.

2. The method of claim 1, wherein, with reference to SEQ ID NO:1, the amino acid sequence comprises one or more of:• an uncharged amino acid at a second of the three positions 3, 14, and 23;• an uncharged amino acid at the second and third of the three positions 3, 14, and 23;• an a-helix amino acid sequence further comprising residues 25 and 26, wherein position 25 is K or N and position 26 is S or Y;• an amino acid sequence in which at least one position 3, 14 or 23 is Q, N, L, V, I, or A;• an amino acid sequence in which at least one position 3, 14 or 23 is Q or N;• an amino acid sequence in which at least two positions 3, 14, and 23 are independently selected from Q, N, L, V, I, or A;• an amino acid sequence in which at least one position 3, 14 and 23 is R or K;• an amino acid sequence in which four, five, six, seven, or all eight of residues at positions 2, 6, 10, 13, 16, 17, 20, and 24 are aliphatic amino acids;• an amino acid sequence that is SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 orSEQ ID NO:4; or• an amino acid sequence that is CS6253.

3. The method of claim 2, wherein, with reference to SEQ ID NO:1,• the amino acid at positions five, six, seven, or eight of positions 2, 6, 10, 13, 16, 17, 20 and 24 are aliphatic amino acids, and• the aliphatic amino acid is selected from the group consisting of L, V, A, and I; or• the aliphatic amino acid is selected from the group consisting of L, I, and V at position 10, 13, 16, and 20.

4. The method of claim 1, wherein the polypeptide does not comprise amino acid analogs.

5. The method of claim 1, wherein the polypeptide comprises SEQ ID NO:3.

6. The method of claims 1 - 4, wherein the amino acids, other than cit, are essential amino acids.

7. The method of claims 1 - 4, wherein the polypeptide further comprises a protecting group.

8. The method of claims 1-6, wherein the PNS myelination condition is selected from the group consisting of:• a condition characterized by PMP22 dysfunction in the PNS;• a PNS myelination disorder resulting from abnormal ABCA1 regulated cholesterol transport;• a Schwann cell regulated cholesterol transport disorder;• a demyelinating condition resulting from Schwann cell dysfunction; and • a non-hereditary PNS myelination condition.

9. The method of claim 8, wherein the PNS myelination condition is characterized by PMP22 dysfunction in the PNS.

10. The method of claim 9, wherein the PMP22 dysfunction causes abnormal regulation of ABCA1.

11. The method of claims 9 or 10, wherein the PMP22 dysfunction results from one or more PMP22 mutations, PMP22 overexpression or PMP22 under-expression.

12. The method of claim 11, wherein the PMP22 dysfunction is at least one PMP22 point mutation.

13. The method of claim 12, wherein the PNS myelination condition is CMT 1 E.

14. The method of claim 12, wherein the PNS myelination condition is DSS (Dejerine-Sottas Syndrome).

15. The method of claim 11, wherein the PNP22 dysfunction is PMP22 overexpression.

16. The method of claim 15, wherein the PMP22 overexpression results from PMP22 copy number variation (CNV) > 2.

17. The method of claim 15, wherein the PNS myelination condition is CMT 1A.

18. The method of claim 11, wherein the PMP22 dysfunction is PMP22 underexpression.

19. The method of claim 18, wherein the PMP22 underexpression results from PMP22 copy number variation (CNV) < 1.

20. The method of claim 18, wherein the PMP22 underexpression results from PMP22 gene deletion.

21. The method of claim 11, wherein the subject has one or more signs or symptoms of PMP22 dysfunction.

22. The method of claim 21, wherein the subject has a Charcot-Marie-Tooth Neuropathy Score (CMTNS) < 10.

23. The method of claim 21, wherein the subject has a Charcot-Marie-Tooth Pediatric Scale score < 2.

24. The method of claim 18 or 19, wherein the PNS myelination condition is HNPP.

25. The method of claim 8, wherein the PNS myelination condition is a PNS myelination disorder resulting from abnormal ABCA1 regulated cholesterol transport.

26. The method of claim 8, wherein the PNS myelination condition is a Schwann cell regulated cholesterol transport disorder.

27. The method of claim 26, wherein the Schwann cell regulated cholesterol transport disorder is selected from disorders or conditions affecting axon maintenance, nerve regeneration and remodeling of neuromuscular junction (NMJ) and neurofibromatosis (NF).

28. The method of claim 8, wherein the PNS myelination condition is a demyelinating condition resulting from Schwann cell dysfunction.

29. The method of claim 28, wherein the demyelinating condition is selected from the group consisting of: inflammatory demyelinating neuropathy, acute inflammatory demyelinating polyneuropathy (AIDP), Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), demyelinating diabetic neuropathy, anti-MAG peripheral neuropathy and acute idiopathic polyneuritis.

30. The method of claim 29, wherein the demyelinating condition is inflammatory demyelinating neuropathy.

31. The method of claim 29, wherein the demyelinating condition is acute inflammatory demyelinating polyneuropathy (AIDP).

32. The method of claim 29, wherein the demyelinating condition is Guillain-Barré syndrome (GBS).

33. The method of claim 29, wherein the demyelinating condition is chronic inflammatory demyelinating polyneuropathy (CIDP).

34. The method of claim 29, wherein the demyelinating condition is demyelinating diabetic neuropathy.

35. The method of claim 29, wherein the demyelinating condition is anti-MAG neuropathy.

36. The method of claim 29, wherein the demyelinating condition is acute idiopathic polyneuritis.

37. The method of claim 8, wherein the PNS myelination condition is a non- hereditary PNS myelination condition.

38. The method of claim 37, wherein non-hereditary PNS myelination condition is caused by a trigger selected from the group consisting of: inflammation, infection, neurotoxin exposure, chemotherapy, radiation, neuroleptic drug side effect, organophosphate exposure, autoimmune reaction, trauma, ischemia, asphyxia, metabolic disorder, copper deficiency and idiopathic origins.

39. The method of claim 38, wherein the infection is a virus, bacteria or prion.

40. The method of claim 38, wherein the neurotoxin in an organophosphate.

41. The method of claims 29 - 40 wherein the patient has an Overall Neuropathy Limitations Score (ONLS) of < 6.

42. The method of any of claims 1-41, wherein the pharmaceutical composition comprises one or more lipids.

43. The method of any of claims 1-41, wherein the pharmaceutical composition comprises an exosome.

44. The method of claims 42 or 43, wherein the pharmaceutical composition is administered in combination with an additional therapeutic agent.

45. The method of any of claims 1-44, wherein the pharmaceutical composition is administered intraperitoneally.

46. The method of any of claims 1-44, wherein the pharmaceutical composition is administered intravenously.

47. The method of any of claims 1-44, wherein the pharmaceutical composition is administered subcutaneously, intramuscularly or transdermally.

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