FIELD OF INVENTION

The present invention relates generally to plasmalogens. More specifically, the present invention relates to plasmalogen precursors and cyclic plasmenylethanolamines.

BACKGROUND

Peroxisomes are intracellular membrane-bound organelles present in virtually every cell of the body. Several critical metabolic reactions are carried out exclusively in peroxisomes. One of the most critical reactions performed in peroxisomes is the biosynthesis of plasmalogens. Plasmalogens are a class of glycerophospholipids, characterized by a vinyl-ether-linked alkyl chain at the sn-1 position, an ester-linked long-chain fatty acid at the sn-2 position, and a head group attached to the sn-3 position by a phosphodiester linkage. The general formula for these molecules is represented by formula (I):



In humans, the sn-1 position (which incorporates the R1group) is most commonly derived from C16:0, C18:0 or C18:1 fatty alcohols. The sn-2 (which incorporates the R2group) position may be derived from saturated, monounsaturated or polyunsaturated fatty acids, while sn-3 is a head group, most commonly a phosphoethanolamine or phosphocholine.

Plasmalogens are present in tissues throughout the human body and represent approximately 15-20% of the total phospholipid content of cell membranes. This proportion varies widely by tissue type, with the brain, heart, neutrophils and eosinophils having the highest levels. Plasmalogens play a role in a number of diverse physiological functions including: structural component of cell membranes, secondary messengers, membrane fusion, ion transport, cholesterol efflux and as antioxidants [1,2]. Altered plasmalogen levels have been reported in different human diseases including peroxisomal biogenesis disorders, Zellweger spectrum disorder (Braverman, Raymond et al. 2016), Rhizomelic chondrodysplasia punctata [3,4], Alzheimer's disease [5-7], Parkinson's disease [8,9], Down syndrome [10] and Gaucher disease [11].

Biosynthesis of plasmalogens is initiated in the peroxisome by a series of non-redundant peroxisomal specific enzymes that create the ether bond which is reduced to the vinyl-ether within the endoplasmic reticulum. Peroxisomal biogenesis disorders (PBDs) represent a group of related, but heterogeneous, genetically-based medical conditions resulting from deficient peroxisomal function. These defects may either exist in a single enzyme involved in a peroxisomal—based function or in one of the genes critical for the assembly and biogenesis of the peroxisome. The clinical presentation and severity of these conditions is wide-ranging depending on the underlying genetic cause. Decreased levels of plasmalogens are central in the majority of peroxisomal biogenesis disorders, and are believed to be the main cause of morbidity. In general, plasmalogen levels directly correlate with severity of symptoms and prognosis.

Rhizomelic chondrodysplasia punctata (RCDP) is a subgroup of peroxisomal biogenesis disorders characterized by shortening of the bones, intellectual disability, significant developmental delays, distinctive facial features and/or respiratory problems. Diagnosis usually occurs shortly after birth due to the presence of cataracts and other clinical features, but is confirmed by genetic testing. There are 5 reported subtypes of RCDP, all have indistinguishable clinical features but result from mutations in different genes; Pex7 (RCDP1) [12-14], GNPAT (RCDP2) [15],AGPS (RCDP3) [16], FAR1 (RCDP4) (Buchert, Tawamie, et al., 2014, The American Journal of Human Genetics, 95, 602-610) and Pex5 (RCDP5)(Baroy, Koster et al., 2015, Human Molecular Genetics, 24(20):5845-5854). GNPAT and AGPS are enzymes involved in the biosynthesis of plasmalogens, FAR1 is involved in the biosynthesis of the fatty alcohol precursor of plasmalogen synthesis and Pex7 and Pex5 are involved in the biosynthesis of peroxisomes. All 5 types have depleted plasmalogen levels, with prognosis positively correlated with increasing plasmalogen levels [3,4]. Prevalence is estimated at 1 per 100,000 live births. In patients who survive the first few months of life, only 50% survive until age 5 and nearly all will succumb to the disease by adolescence. Recurrent respiratory infections are common with 80% of deaths in patients who survive past 6 months being reported as secondary to respiratory problems [17]. There are less than 100 cases reported currently in the US, although it is believed that the disorder is under-reported.

There are currently no disease modifying therapies available for RCDP. Attempts to increase plasmalogen levels with dietary plasmalogen precursors have shown modest efficacy, however have ultimately failed in the clinic due to the very high dose and lengthy time-course required to elevate plasmalogen levels [18-21].



Historical studies with other plasmalogen precursors (batyl alcohol and PPI-1011) have suggested that individuals or animals with PBD or RCDP do not effectively metabolize these precursors into the desired plasmalogen species. It is unclear why this process does not function effectively, but the effect of severely reduced or absent plasmalogen levels throughout development is likely leading to this impaired function.

An alternative, additional, and/or improved plasmalogen precursor is desirable.

SUMMARY OF INVENTION

It is an object of the invention to provide plasmalogen precursors for elevating the level of at least one plasmalogen in a cell or subject in need thereof.

In one embodiment, there is provided a method of elevating at least one plasmalogen level in a subject. The method comprises:administering to the subject a pharmaceutically effective amount of at least one cyclic plasmenylethanolamine having formula A:

or a pharmaceutically acceptable salt or solvate thereof,wherein R1and R2are each, independently, a saturated, unsaturated, or polyunsaturated, optionally substituted hydrocarbon group, wherein following administration, the cyclic plasmenylethanolamine is converted to at least one plasmalogen species, thereby elevating the plasmalogen level in the subject.

In certain embodiments, R1may be selected (in chain length and saturation level) to provide a hydrocarbon chain of a desired fatty alcohol group for the sn-1 position, and R2may be selected (in chain length and saturation level) to provide a hydrocarbon chain of a desired fatty acid group for the sn-2 position. In certain embodiments, the fatty acid, fatty alcohol, or both, may be an endogenously occurring fatty acid and/or fatty alcohol.

In certain embodiments, R1, R2, or both, may be an optionally substituted C1-C28hydrocarbon group which may be an alkane, alkene, or alkyne hydrocarbon group. In certain embodiments, R1, R2, or both, may each independently have up to 6 double bonds. In certain embodiments, R1, R2, or both, may be a C1-C28hydrocarbon group which is, optionally, hydroxylated (i.e. which features one or more


which comprises one or more alkene and/or alkyne functional groups, which comprises one or more ketone functional groups, which comprises one or more lower alkyl (C1-C6) hydrocarbon groups, or any combination thereof.

In certain embodiments, R1, R2, or both, may be an optionally substituted C8-C26hydrocarbon group.

Typically, R1will be selected (in chain length and saturation level) to provide the hydrocarbon chain of a desired fatty alcohol group for the sn-1 position, and R2will be selected (in chain length and saturation level) to provide the hydrocarbon chain of a desired fatty acid group for the sn-2 position. The fatty alcohol or fatty acid may be naturally derived or synthetically produced.

In other embodiments of the described method, the subject may suffer from a plasmalogen deficiency, a peroxisomal biogenesis disorder, or both. For example, the subject may suffer from rhizomelic chondrodysplasia punctata (RCDP), Zellweger spectrum disorder or other plasmalogen deficiency disorder. In still another embodiment, the subject may be a subject having Alzheimer's disease (AD), or Parkinson's disease (PD).

In particular embodiments, the cyclic plasmenylethanolamine may be:

or a pharmaceutically acceptable salt and/or solvate thereof;or any combination thereof.

Also described herein is the use of at least one cyclic plasmenylethanolamine having formula A as described above for elevating at least one plasmalogen level in a subject in need thereof, wherein the cyclic plasmenylethanolamine is for administration to the subject followed by conversion to at least one plasmalogen species, thereby elevating the plasmalogen level in the subject. The cyclic plasmenylethanolamines of formula A may also be used in the manufacture of a medicament for elevating plasmalogen levels, as described.

In further embodiments there is also provided a plasmalogen precursor having formula A:

or a pharmaceutically acceptable salt or solvate thereof,

wherein R1and R2are as described above.

There is also provided a pharmaceutical composition comprising the plasmalogen precursor, and at least one pharmaceutically acceptable carrier, diluent, or excipient. Kits are also described, which include the described plasmalogen precursor, in which the kit is for elevating a plasmalogen level in a cell, or in a subject in need thereof. Such kits may, in certain embodiments, include instructions for formulating and/or administering the plasmalogen precursor to the cell or subject and/or may include a container for the plasmalogen precursor.

In another embodiment, there is provided herein a method of increasing long term potentiation (LTP) between neurons, said method comprising:treating the neurons with at least one cyclic plasmenylethanolamine having formula A:


or a pharmaceutically acceptable salt or solvate thereof,wherein R1and R2are each, independently, a saturated, unsaturated, or polyunsaturated, optionally substituted hydrocarbon group.

In another embodiment, there is provided herein a method of increasing long term potentiation (LTP) in a subject in need thereof, said method comprising:administering to said subject at least one cyclic plasmenylethanolamine having formula A:

or a pharmaceutically acceptable salt or solvate thereof,wherein R1and R2are each, independently, a saturated, unsaturated, or polyunsaturated, optionally substituted, hydrocarbon group.

In certain embodiments, the subject may have Alzheimer's disease or Parkinson's disease.

In another embodiment, there is provided herein a method of treating or preventing Alzheimer's disease or Parkinson's disease in a subject in need thereof, said method comprising:administering to said subject at least one cyclic plasmenylethanolamine having formula A:

or a pharmaceutically acceptable salt or solvate thereof,wherein R1and R2are each, independently, a saturated, unsaturated, or polyunsaturated, optionally substituted hydrocarbon group.

In still another embodiment, there is provided herein a method of treating or preventing a plasmalogen deficient neurodegenerative disease in a subject in need thereof, said method comprising:administering to said subject at least one cyclic plasmenylethanolamine having formula A:

or a pharmaceutically acceptable salt or solvate thereof,wherein R1and R2are each, independently, a saturated, unsaturated, or polyunsaturated, optionally substituted hydrocarbon group.

In another embodiment, the plasmalogen deficient neurodegenerative disease may be Alzheimer's disease or Parkinson's disease.

In yet another embodiment, there is provided herein a method of elevating at least one plasmalogen level in a subject in need thereof, said method comprising:administering to said subject at least one compound of formula A′:

or a pharmaceutically acceptable salt or solvate thereof,wherein R1is a saturated, unsaturated, or polyunsaturated, optionally substituted hydrocarbon group,wherein following administration, said compound is converted to at least one plasmalogen species, thereby elevating the plasmalogen level in the subject.

In yet another embodiment, R1may be an optionally substituted C1-C28hydrocarbon group. In still another embodiment, R1may comprise up to 6 double bonds. In another embodiment, R1may be a hydrocarbon chain of a fatty alcohol or fatty acid.

In still another embodiment, the subject may be a subject suffering from a plasmalogen deficiency. In another embodiment, the subject may be a subject having a peroxisomal biogenesis disorder. In still another embodiment, the subject may be a subject having rhizomelic chondrodysplasia punctata (RCDP) or Zellweger spectrum disorder. In still another embodiment, the subject may be a subject having Alzheimer's disease or Parkinson's disease

In another embodiment, there is provided herein a use of a compound of formula A′, or a pharmaceutically acceptable salt or solvate thereof, for elevating at least one plasmalogen level in a subject in need thereof, wherein said compound is for administration to the subject followed by conversion to at least one plasmalogen species, thereby elevating the plasmalogen level in the subject.

In another embodiment, there is provided herein a use of at least one compound of formula A′, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for elevating at least one plasmalogen level in a subject in need thereof, wherein said compound is for administration to the subject followed by conversion to at least one plasmalogen species, thereby elevating the plasmalogen level in the subject.

In yet another embodiment, there is provided herein a compound of formula A′:

or a pharmaceutically acceptable salt or solvate thereof,wherein R1is a saturated, unsaturated, or polyunsaturated, optionally substituted hydrocarbon group,for use in elevating at least one plasmalogen level in a subject in need thereof, wherein said compound is for administration to the subject followed by conversion to at least one plasmalogen species, thereby elevating the plasmalogen level in the subject.

In still another embodiment, there is provided herein a plasmalogen precursor having formula A′:

or a pharmaceutically acceptable salt or solvate thereof,wherein R1is a saturated, unsaturated, or polyunsaturated, optionally substituted hydrocarbon group.

In another embodiment, there is provided herein a pharmaceutical composition comprising at least one compound, cyclic plasmenylethanolamine, or plasmalogen precursor as defined herein, and, optionally, at least one pharmaceutically acceptable carrier, diluent, or excipient.

In another embodiment, there is provided herein a kit for elevating a plasmalogen level in a cell, or in a subject in need thereof, the kit comprising:at least one plasmalogen precursor having formula A′:

or a pharmaceutically acceptable salt or solvate thereof,wherein R1is a saturated, unsaturated, or polyunsaturated, optionally substituted hydrocarbon group; andinstructions for administering the plasmalogen precursor to the cell or subject.

In yet another embodiment, there is provided herein a compound of formula A′:

or a pharmaceutically acceptable salt or solvate thereof,wherein R1is a saturated, unsaturated, or polyunsaturated, optionally substituted hydrocarbon group.

In another embodiment, there is provided herein a method of increasing long term potentiation (LTP) between neurons, said method comprising:treating the neurons with at least one compound of formula A′:

or a pharmaceutically acceptable salt or solvate thereof,wherein R1is a saturated, unsaturated, or polyunsaturated, optionally substituted hydrocarbon group.

In still another embodiment, there is provided herein a method of increasing long term potentiation (LTP) in a subject in need thereof, said method comprising:administering to said subject at least one compound of formula A′:

or a pharmaceutically acceptable salt or solvate thereof,wherein R1is a saturated, unsaturated, or polyunsaturated, optionally substituted, hydrocarbon group.

In another embodiment, the subject may be a subject having Alzheimer's disease or Parkinson's disease.

In yet another embodiment, there is provided herein a method of treating or preventing Alzheimer's disease or Parkinson's disease in a subject in need thereof, said method comprising:administering to said subject at least one compound of formula A′:

or a pharmaceutically acceptable salt or solvate thereof,wherein R1is a saturated, unsaturated, or polyunsaturated, optionally substituted hydrocarbon group.

In still another embodiment, there is provided herein a method of treating or preventing a plasmalogen deficient neurodegenerative disease in a subject in need thereof, said method comprising:administering to said subject at least one compound of formula A′:

or a pharmaceutically acceptable salt or solvate thereof,wherein R1is a saturated, unsaturated, or polyunsaturated, optionally substituted hydrocarbon group.

In yet another embodiment, the plasmalogen deficient neurodegenerative disease may be Alzheimer's disease or Parkinson's disease.

In another embodiment, there is provided herein a pharmaceutical composition comprising two or more compounds selected from:formula (A) as described herein;formula (A′) as described herein; and/orformula (B) as described herein,or pharmaceutically acceptable salts or solvates thereof.

