Use of prodrugs of dexibuprofen to treat tecpr2 and alzheimer's disease

Abstract

The present disclosure provides novel methods for treatment of patients with autophagy diseases by administering a prodrug of dexibuprofen, such as but not limited to dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof and compositions comprising the same.

Description

[0001] Patent Application

[0002] USE OF PRODRUGS OF DEXIBUPROFEN TO TREAT TECPR2 AND ALZHEIMER'S

[0003] DISEASE

[0004] I. FIELD OF THE INVENTION

[0005] This disclosure pertains to, among other things, the use of prodrugs of dexibuprofen, such as but not limited to dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof, to treat autophagy diseases and compositions comprising the same.

[0006] II. BACKGROUND

[0007] Autophagy is a process employed by cells to break down and destroy old, damaged, or abnormal proteins and other substances. Autophagy also helps destroy bacteria and viruses that cause infection and may prevent normal cells from becoming cancer cells. Recent studies show that autophagy dysfunction plays a role in neurodegenerative diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD), liver diseases, heart diseases, kidney diseases, diabetes, and tumorigenesis (Ichimiya, T. et al. Autophagy and Autophagy-Related Diseases: A Review. Int. J. Mol. Sci. 21, 8974 (2020); Klionsky, D. et al. Autophagy in major human diseases. EMBO J. Aug 30,40: 19 (2021)).

[0008] Alzheimer's disease is a progressive brain disorder that affects thinking, memory, and language, interfering with daily life. It is the most common type of dementia and is thought to be caused by the abnormal buildup of proteins in the brain, which leads to nerve cell damage. Early signs often include memory loss that disrupts daily life, such as misplacing things or forgetting recent conversations. While there is no cure, treatments can help slow the progression of symptoms and improve quality of life, and early diagnosis is crucial for managing the disease.

[0009] In AD, axonal spheroids are bulbous structures that form on nerve cell axons near amyloid plaques. They disrupt the flow of electrical signals, impairing neural communication and contributing to disease severity

[0010] TECPR2 (tectonin beta-propeller repeat-containing protein 2) disease is a rare and autosomal recessive disease (OMIM 615031). The TECPR2 protein is multi-functional and responsible for autophagosome formation, scaffolding, protein trafficking, nuclear RNA Patent Application trafficking (Stadel, D. et al., TECPR2 Cooperates with LC3C to Regulate COPII-Dependent ER Export. Mol. Cell 60, 89-104 (2015)). TECPR2 is highly expressed in the human brain, especially in the prefrontal cortex. TECPR2 is activated by ER stress. Many different mutations of the TECPR2 gene lead to disease states in humans. A 1 bp frameshift deletion in the TECPR2 gene leads to a premature stop codon, causing degradation of the TECPR2 protein (Oz-Levi, D. et al., Mutation in TECPR2 reveals a role for autophagy in Hereditary Spastic Paraparesis (HSP). Am. J. Hum. Genet. 91, 1065-1072 (2012)). Other mutations lead to single amino acid changes within the TECPR2 protein. Heterozygote carriers of theses TECPR2 mutations do not appear to have symptoms. However, homozygote children with two mutant copies of the TECPR2 gene are afflicted with TECPR2 related diseases, such as Hereditary Spastic Paraparesis, a group of neurodegenerative disorders that affect about 10 out of 100,000 individuals and characterized by corpus collosum thinning, intellectual disability, central hypoventilation, GI reflux, wake apnea, areflexia, and dysmorphia. In some instances, homozygosity for mutant TECPR2 genes can be lethal in childhood.

[0011] At the present there are no therapies that prevent or slow down disease progression in TECPR2-related disorder, an ultra-rare form of complex HSP with significant morbidity and mortality, usually in the second decade of life (Nalbach et al, 2023; Heimer et al, 2022; Guan et al, 2022; Heimer et al, 2016; Oz-Levi et al, 2012). TECPR2-related disorder is caused by bi-allelic loss-of-function mutations in the TECPR2 gene (Nalbach et al, 2023; Oz-Levi et al, 2012), which encodes for the tectonin beta-propeller repeat-containing protein 2, a scaffolding protein involved in protein sorting (Nalbach et al, 2023) and the lysosomal targeting of autophagosomes (Fraiberg et al, 2021; Stadel et al; 2015). TECPR2 deficiency affects neurons in both the central and peripheral nervous systems, with the most severe manifestations and mortality arising from progressive brain stem dysfunction (Nalbach et al, 2023; Heimer et al, 2022; Patwari et al, 2020). Given the clear understanding of the loss-of-function mechanism and the brain stem neurons as the primary therapeutic target, it is reasonable to explore the potential of intrathecally-delivered gene replacement strategies to reduce mortality.

[0012] Autophagy dysfunction has been implicated in the pathogenesis of several neurodegenerative diseases such as Huntington, Alzheimer and Parkinson diseases, spinocerebellar ataxias (SCAs), and amyotrophic lateral sclerosis (Oz-Levi et al, 2013). JEM-OOl / OIWO 40846 / 3 Patent Application

[0013] Additionally supporting the link between Tecpr2 dysfunction and neurodegenerative diseases, spheroids accumulate around amyloid plaques in the brains of AD patients, and a Tecpr2 variant (rsl0149146) looks to be protective against AD (Yuan et al, 2022; Alexander et al, 2017).

[0014] III. SUMMARY OF THE INVENTION

[0015] The disclosure provides novel methods of treating autophagy diseases in a patient in need thereof comprising administering prodrugs of dexibuprofen (or pharmaceutically acceptable salts thereof), such as but not limited to dexibuprofen dimethylamino ethyl ester (mDex) having the following structure, or a pharmaceutically acceptable salt thereof:

[0016] In one aspect, the disclosure provides methods of treating autophagy diseases in a subject comprising administering a prodrug of dexibuprofen (or pharmaceutically acceptable salts thereof). Dexibuprofen and certain prodrugs thereof are shown below. JEM-OOl / OIWO 40846 / 3

[0017] Patent Application

[0018] In certain embodiments, the methods of the invention comprise administering a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to a patient in need.

[0019] In certain embodiments, the methods of the invention comprise administering a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, in combination with an additional therapeutic agent to a patient in need. In certain embodiments, the methods of the invention involve providing a pharmaceutical composition comprising a pharmaceutically acceptable amount of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof.

[0020] In certain embodiments, the methods of the invention comprise administering a pharmaceutical composition comprising a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof.

[0021] In another aspect, the disclosure provides methods of treating diseases related to a TECPR2 mutation comprising administering a prodrug of dexibuprofen (or pharmaceutically acceptable salts thereof). In certain embodiments, the prodrug is any of formula I-IV as shown above. In certain embodiments, the methods of the invention involve providing a pharmaceutical composition comprising a pharmaceutically acceptable amount of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions are administered to a mammal in need thereof. In particular embodiments, the pharmaceutical compositions are administered to a human patient in need thereof.

[0022] Autophagy diseases include, but are not limited to, Hereditary Spastic Paraparesis (HSP), Multiple Sclerosis (MS), Huntington's disease, spinocerebellar ataxia, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer' s disease, Batten Disease, lewy body dementia, Vici syndrome, neuronal ceroid lipofuscinosis, pallidoluysian atrophy, spinobulbar muscular atrophy, cdkl5 disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia, Lafora disease, P-propeller protein-associated neurodegeneration (BPAN). Some embodiments described herein relate to a method of treating autophagy diseases related to a TECPR2 mutation in a patient, particularly for a patient who is homozygous for mutations of the TECPR2 gene (Ichimiya, T. et JEM-OOl / OIWO 40846 / 3

[0023] Patent Application al. Autophagy and Autophagy -Related Diseases: A Review. Int. J. Mol. Sci. 21, 8974 (2020); Klionsky, D. et al. Autophagy in major human diseases. EMBO J. Aug 30,40: 19 (2021)).

[0024] In one aspect, the disclosure provides a method of treating autophagy diseases in a subject comprising administering a prodrug of dexibuprofen (or pharmaceutically acceptable salts thereof). Tn certain embodiments, the prodrug is any of formula I-TV as shown above. In certain embodiments, methods of the invention involve administering a pharmaceutical composition comprising a pharmaceutically acceptable amount of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof. In a particular aspect, the disease is Alzheimer' s disease. In a particular aspect, the disease is amyotrophic lateral sclerosis (ALS). In a particular aspect, the disease is Parkinson's disease. In a particular aspect, the disease is Huntington's disease.

[0025] In another aspect, the administration is of a solution comprising dexibuprofen dimethylamino ethyl ester (mDex) or pharmaceutically acceptable salt in a concentration between 1 mg / ml and 500 mg / mL.

[0026] In another aspect, dexibuprofen dimethylamino ethyl ester (mDex) or pharmaceutically acceptable salt thereof administered to the patient is in an amount from about 0.1 mg to about 1,000 mg of dexibuprofen dimethylamino ethyl ester (mDex) per kg of body weight of the patient.

[0027] Other embodiments of the disclosure relate to the use of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of autophagy diseases in a patient in need thereof. In some embodiments, the medicament is intended for treating diseases related to a TECPR2 mutation, including Hereditary Spastic Paraparesis in the patient.

[0028] In another aspect, the Autophagy disease is an Autophagy disease related to a TECPR2 mutation in the patient. In another aspect, the method comprises treating Hereditary Spastic Paraparesis in the patient. In another aspect, the medicament further comprises a pharmaceutically acceptable carrier.

[0029] In another aspect, the medicament further comprises another therapeutic agent. In another aspect, the medicament is intended for oral administration, such as a tablet. In another aspect, the medicament is intended for intravenous or subcutaneous administration. Patent Application

[0030] In another aspect, the medicament comprises a solution containing dexibuprofen dimethylamino ethyl ester (mDex) or pharmaceutically acceptable salt in a concentration between 1 mg / ml and 500 mg / mL.

[0031] In another aspect, the medicament contains dexibuprofen dimethylamino ethyl ester (mDex) or pharmaceutically acceptable salt thereof in an amount from about 0.1 mg to about 1 ,000 mg of dexibuprofen dimethylamino ethyl ester (mDex) per kg of body weight of the patient.

[0032] In some embodiments, the use comprises the use of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof substantially as described in the specification.

[0033] IV. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIG. 1 shows the standard curve for the detection of mDex. The standard curve is linear from 1 pg to 500 pg.

[0035] FIG. 2 shows reduced body weight in TECPR2 mice >P120. Compared with WT (n=ll) TECPR2 mice (n=ll) had reduced body weight. Data in FIG. 1 is expressed as relative from control ± SEM; **p<0.005 t-test vs WT.

[0036] FIG. 3 shows reduced mechanical sensory tactile sensitivity in TECPR2 mice >P120. Compared with WT (n=16) TECPR2 mice (n=l 8) had reduced mechanical sensory thresholds as measured using von Frey filaments. Data in FIG. 2 is expressed as 50% of withdrawal threshold (g) ± SEM; *p<0.05 t-test vs WT..

[0037] FIG. 4 shows reduced startle response in TECPR2 mice >P120. KI mice exhibited a significant reduced startle response at all frequencies from 80 to 115db compared with WT littermates (n=18 and 16, respectively). ± SEM; *p<0.05 2way ANPVA followed by Tukey’s.

[0038] FIG. 5 shows reduced auditory brainstem response in TECPR2 mice >P120. Adult mutant mice exhibited a significant reduced response to low frequency stimulation as measured by ABR (n=12). ± SEM; *p<0.05 2way ANPVA followed by Tukey’s. . Patent Application

[0039] FIG. 6 shows reduced distortion product otoacoustic emissions in TECPR2 mice >P120. Adult mutant mice exhibited a significant reduced response to low frequency stimulation as measured by DPOAE (n=12). ± SEM; *p<0.05 2way ANPVA followed by Tukey’s.

[0040] FIG. 7 shows reduced step angle in TECPR2 mice >P120. Adult mutant mice exhibited a significant reduced step angle. Data expressed as relative from control ± SEM; **p<0.005 t-test vs WT.

[0041] FIG. 8 shows reduced step angle in TECPR2 mice >P120. Adult mutant mice exhibited a significant reduced step angle.

[0042] FIG. 9 shows progressive appearance of spheroids in TECPR2 KI mice. Coronal sections of TECPR2 KI mouse brainstem (GR: gracile nuclei; CU: cuneate nuclei; grf: gracile fasciculus; cuf cuneate fasciculus) showing spheroids (indicated by arrows) at different ages (A: Sagittal and B Coronal control (WT) P45; C: P45; D: P90; E: P>120.

[0043] FIG. 10 shows body weight change in mice treated with vehicle or 15 mg / Kg, 30 mg / Kg, 60 mg / Kg mDex

[0044] FIG. 11 shows mDex brain concentration in mice treated with vehicle or 15 mg / Kg, 30 mg / Kg, 60 mg / Kg mDex

[0045] FIG. 12 shows spheroids reduction in 5xFAD mice Pl 20. Compared with vehicle treated, mDex- treated 5xFAD mice had mean 49% reduction in spheroids.

[0046] FIG. 13 shows spheroids reduction in 5xFAD mice Pl 50. Compared with vehicle treated, mDex- treated 5xFAD mice had mean 65% reduction in spheroids.

[0047] FIG. 14 shows behavioral rescue (intoeing) in 5xFAD mice P60, P90, and P120 treated with mDex.

[0048] FIG. 15 shows weight distribution over time in vehicle-treated and mDex-treated WT and 5xFAD mice.

[0049] FIG. 16 shows behavioral rescue (% novel object exploration)) in 5xFAD mice P120 treated with mDex. JEM-OOl / OIWO 40846 / 3

[0050] Patent Application

[0051] FIG. 17 shows behavioral rescue (% novel object exploration)) in 5xFAD mice P120 combined WT treated with mDex.

[0052] FIG. 18 shows behavioral rescue (% novel object exploration)) in 5xFAD mice Pl 20 combined WT treated with mDex.

[0053] FIG. 19 shows reduced discrimination of the novel object in 5xFAD mice.

[0054] FIG. 20 shows amyloid plaque load (hippocampus) in 5xFAD mice treated with vehicle of mDex.

[0055] FIG. 21 shows amyloid plaque load (cortex) in 5xFAD mice treated with vehicle of mDex.

[0056] FIG. 22 shows p62 levels (cortex) in 5xFAD mice treated with vehicle of mDex.

[0057] FIG. 23 shows p62 levels (hippocampus) in 5xFAD mice treated with vehicle of mDex.

[0058] V. DETAILED DESCRIPTION

[0059] In the following disclosure, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the methods and uses described herein may be practiced without these details. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0060] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term JEM-OOl / OIWO 40846 / 3

[0061] Patent Application

[0062] “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0063] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0064] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

[0065] Autophagy is a process employed by cells to break down and destroy old, damaged, or abnormal proteins and other substances. Autophagy also helps destroy bacteria and viruses that Patent Application cause infection and may prevent normal cells from becoming cancer cells. Recent studies show that autophagy dysfunction plays a role in neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease, liver diseases, heart diseases, kidney diseases, diabetes, and tumorigenesis (Ichimiya, T. et al. Autophagy and Autophagy-Related Diseases: A Review. Int. J. Mol. Sci. 21, 8974 (2020); Klionsky, D. et al. Autophagy in major human diseases. EMBO J. Aug 30,40: 19 (2021)).

[0066] TECPR2 (tectonin beta-propeller repeat-containing protein 2) disease is a rare and autosomal recessive disease (OMIM 615031). The TECPR2 protein is multi-functional and responsible for autophagosome formation, scaffolding, protein trafficking, nuclear RNA trafficking (Stadel, D. et al., TECPR2 Cooperates with LC3C to Regulate COPII-Dependent ER Export. Mol. Cell 60, 89-104 (2015)). TECPR2 is highly expressed in the human brain, especially in the prefrontal cortex. TECPR2 is activated by ER stress. Many different mutations of the TECPR2 gene lead to disease states in humans. A 1 bp frameshift deletion in the TECPR2 gene leads to a premature stop codon, causing degradation of the TECPR2 protein (Oz-Levi, D. et al., Mutation in TECPR2 reveals a role for autophagy in Hereditary Spastic Paraparesis (HSP). Am. J. Hum. Genet. 91, 1065-1072 (2012)). Other mutations lead to single amino acid changes within the TECPR2 protein. Heterozygote carriers of theses TECPR2 mutations do not appear to have symptoms. However, homozygote children with two mutant copies of the TECPR2 gene are afflicted with TECPR2 related diseases, such as Hereditary Spastic Paraparesis (HSP), a group of neurodegenerative disorders that affect about 10 out of 100,000 individuals and characterized by corpus collosum thinning, intellectual disability, central hypoventilation, G1 reflux, wake apnea, areflexia, and dysmorphia. In some instances, homozygosity for mutant TECPR2 genes can be lethal in childhood.

[0067] In AD, axonal spheroids are bubble-like swellings filled with proteins, organelles, and cytoskeletal elements that form on nerve cell axons near amyloid plaques. They disrupt the flow of electrical signals, impairing neural communication and contributing to disease severity. Targeting the mechanisms of spheroid growth, such as modulating endolysosomal function, is a potential therapeutic strategy for AD.

[0068] TECPR2 gene encodes for the tectonin beta-propeller repeat-containing protein 2, a scaffolding protein involved in protein sorting (Nalbach et al, 2023) and the lysosomal targeting JEM-001 / 01WG 40846 / 3

[0069] Patent Application of autophagosomes (2,3). Its loss causes an ultra-rare form of complex hereditary spastic paraplegia (HSP) with significant morbidity and mortality, usually in the second decade of life (HSP-49; Nalbach et al, 2023; Heimer et al, 2022; Guan et al, 2022; Heimer et al, 2016; Oz-Levi et al, 2012). Additionally, recent evidence suggests that TECPR2 could also play a critical role in neurodegenerative disorders such as Alzheimer and Parkinson disorders.

[0070] Dexibuprofen is shown below, along with exemplary prodrugs of dexibuprofen.

[0071] Dexibuprofen dimethylamino ethyl ester (mDex), shown above as structure I, is a prodrug of dexibuprofen shown to exhibit enhanced brain distribution when compared with dexibuprofen in in vitro and in vivo studies (Zhang, X. et al. In vitro and in vivo investigation of dexibuprofen derivatives for CNS delivery. Acta Pharmacologica Sinica (2012) 33: 279-288; Li, Y. et al. Mechanism of brain targeting by dexibuprofen prodrugs modified with ethanolamine-related structures. Journal of Cerebral Blood Flow & Metabolism (2015) 35, 1985-1994). Dexibuprofen dimethylamino ethyl ester (mDex) has the following structure: Patent Application

[0072] Dexibuprofen is the 5-(+)-isomer of ibuprofen and has been evaluated for the treatment of Alzheimer’s disease (Ettcheto, M. et al. Dexibuprofen prevents neurodegeneration and cognitive decline in APPswe / PSldE9 through multiple signaling pathways. Redox Biology 13 (2017) 345- 3; Ettcheto, M. et al. Dexibuprofen ameliorates peripheral and central risk factors associated with Alzheimer’s disease in metabolically stressed APPswe / PSldE9 mice. Cell Biosci (2021) 11: 141). Dexibuprofen has been identified as a potential candidate for the treatment of patients suffering from TECPR2-related mutation (U.S. 2024 / 0173279).

[0073] FIG. 10 and FIG. 11 show body weight change and dexibuprofen dimethylamino ethyl ester (mDex) brain concentration, respectively, in WT mice (P7, P30, and P60) administered with dexibuprofen dimethylamino ethyl ester (mDex) at various doses.

[0074] The inventors have found that mDex is able to penetrate the brain and show reduction of spheroids and effect in intoeing in 5xFAD mice.

[0075] In some embodiments, the present disclosure provides a pharmaceutical composition comprising dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof.

[0076] In certain embodiments, the methods of the invention comprise administering a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to a patient in need.

[0077] In certain embodiments, the methods of the invention comprise administering a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, in combination with an additional therapeutic agent to a patient in need.

[0078] In certain embodiments, the additional therapeutic agent comprises gene therapy. In certain embodiments, the additional therapeutic agent comprises a AAV9 / TECPR2 gene replacement vector

[0079] In certain embodiments, the methods of the invention comprise administering a pharmaceutical composition comprising a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof. JEM-OOl / OIWO 40846 / 3

[0080] Patent Application

[0081] In certain embodiments, the methods of the invention comprise administering a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to a patient in need.

[0082] In certain embodiments, the methods of the invention comprise administering a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, in combination with an additional therapeutic agent to a patient in need.

[0083] In some embodiments, the present disclosure provides a method of modulating TECPR2 in a patient in need thereof, comprising administering an effective amount of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0084] In some embodiments, the present disclosure provides a method of treating an autophagy disease in a patient in need thereof, comprising administering an effective amount of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0085] In some embodiments, the present disclosure provides a method of treating Alzheimer' s disease in a patient in need thereof comprising administering a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient,

[0086] In some embodiments, the present disclosure provides a method of treating Huntigton1s disease in a patient in need thereof comprising administering a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient,

[0087] In some embodiments, the present disclosure provides a method of treating spinocerebellar ataxias (SCAs) in a patient in need thereof comprising administering a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient, JEM-OOl / OIWO 40846 / 3

[0088] Patent Application

[0089] In some embodiments, the present disclosure provides a method of treating amyotrophic lateral sclerosis (ALS) in a patient in need thereof comprising administering a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient,

[0090] In some embodiments, the present disclosure provides a method of treating Alzheimer1s disease in a patient in need thereof comprising administering a pharmaceutical composition comprising a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient,

[0091] In some embodiments, the present disclosure provides a method of treating Huntigton' s disease in a patient in need thereof comprising administering a pharmaceutical composition comprising a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient,

[0092] In some embodiments, the present disclosure provides a method of treating spinocerebellar ataxias (SC As) in a patient in need thereof comprising administering a pharmaceutical composition comprising a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient,

[0093] In some embodiments, the present disclosure provides a method of treating amyotrophic lateral sclerosis (ALS) in a patient in need thereof comprising administering a pharmaceutical composition comprising a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient,

[0094] In some embodiments, the present disclosure provides a method of treating a TECPR2- related disorder in a patient in need thereof comprising administering a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient,

[0095] In some embodiments, the present disclosure provides a method of treating a TECPR2- related disorder in a patient in need thereof comprising administering a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient, JEM-OOl / OIWO 40846 / 3

[0096] Patent Application

[0097] In some embodiments, the present disclosure provides a method of treating a TECPR2- related disorder in a patient in need thereof comprising administering a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient,

[0098] In some embodiments, the present disclosure provides a method of treating a TECPR2- related disorder in a patient in need thereof comprising administering a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient,

[0099] In some embodiments, the present disclosure provides a method of treating a TECPR2- related disorder in a patient in need thereof comprising administering a pharmaceutical composition comprising a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient,

[0100] In some embodiments, the present disclosure provides a method of treating a TECPR2- related disorder in a patient in need thereof comprising administering a pharmaceutical composition comprising a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient,

[0101] In some embodiments, the present disclosure provides a method of treating a TECPR2- related disorder in a patient in need thereof comprising administering a pharmaceutical composition comprising a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient,

[0102] In some embodiments, the present disclosure provides a method of treating a TECPR2- related disorder in a patient in need thereof comprising administering a pharmaceutical composition comprising a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex), or a pharmaceutically acceptable salt thereof, to the patient,

[0103] In some embodiments, mDex modulates TECP2 to mitigate the onset and progression of both HSP49 and neurodegenerative disorders in a patient in need.

[0104] Autophagy diseases include, but are not limited to, Hereditary Spastic Paraparesis, Multiple Sclerosis, Huntington's disease, spinocerebellar ataxia, amyotrophic lateral sclerosis JEM-OOl / OIWO 40846 / 3

[0105] Patent Application

[0106] (ALS), Parkinson's disease, Alzheimer' s disease, Batten Disease, lewy body dementia, Vici syndrome, neuronal ceroid lipofuscinosis, pallidoluysian atrophy, spinobulbar muscular atrophy, cdkl5 disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia, Lafora disease, P- propeller protein-associated neurodegeneration (BPAN).

[0107] In some embodiments, the present disclosure provides a method of treating autophagy diseases related to a TECPR2 mutation in a patient, particularly for a patient who is homozygous for mutations of the TECPR2 gene. In one embodiment, the method includes administering to the patient a composition comprising a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof.

[0108] In one embodiment, the disclosure provides pharmaceutical compositions comprising dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. In accordance with another aspect of the disclosure there is also provided a process for the preparation of a pharmaceutical composition including dexibuprofen dimethylamino ethyl ester (mDex) or pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable excipients. The pharmaceutical composition can be for use in the treatment and / or prophylaxis of any of the conditions described herein.

[0109] Generally, a provided compound is administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like. Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. JEM-OOl / OIWO 40846 / 3

[0110] Patent Application

[0111] Generally, dexibuprofen dimethylamino ethyl ester (mDex) is administered in a pharmaceutically effective amount. The amount of dexibuprofen dimethylamino ethyl ester (mDex) actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.

[0112] Preferred unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Such unit doses may therefore be administered once or more than once a day. Such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.

[0113] Pharmaceutical compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, inhaled, intranasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).

[0114] Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or nonaqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

[0115] For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert excipient JEM-OOl / OIWO 40846 / 3

[0116] Patent Application such as ethanol, glycerol, water and the like. Powders are prepared by reducing the compound to a suitable fine size and mixing with a similarly prepared pharmaceutical excipient such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.

[0117] Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Excipients including glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

[0118] Moreover, when desired or necessary, excipients including suitable binders, glidants, lubricants, sweetening agents, flavors, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing a provided compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an alginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and / or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. A provided compound can also be combined with a free-flowing inert JEM-OOl / OIWO 40846 / 3

[0119] Patent Application carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

[0120] Oral fluids such as solution, suspensions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.

[0121] Where appropriate, dosage unit compositions for oral administration can be microencapsulated. The composition can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.

[0122] The compound of the disclosure may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.

[0123] Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

[0124] For treatments of the eye or other external tissues, for example mouth and skin, the compositions are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in- water cream base or a water-in-oil base. JEM-OOl / OIWO 40846 / 3

[0125] Patent Application

[0126] Pharmaceutical compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

[0127] Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.

[0128] Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or as enemas.

[0129] Dosage forms for nasal or inhaled administration may conveniently be formulated as aerosols, solutions, suspension drops, gels or dry powders.

[0130] Compositions for intranasal administration include aqueous compositions administered to the nose by drops or by pressurized pump. Suitable compositions contain water as the diluent or carrier for this purpose. Compositions for administration to the lung or nose may contain one or more excipients, for example one or more suspending agents, one or more preservatives, one or more surfactants, one or more tonicity adjusting agents, one or more co-solvents, and may include components to control the pH of the composition, for example a buffer system. Further, the compositions may contain other excipients such as antioxidants, for example sodium metabisulphite, and taste-masking agents. Compositions may also be administered to the nose or other regions of the respiratory tract by nebulization. Intranasal compositions may permit a provided compound or pharmaceutically acceptable salt thereof to be delivered to all areas of the nasal cavities (the target tissue) and further, may permit the provided compound or pharmaceutically acceptable salt thereof to remain in contact with the target tissue for longer periods of time. A suitable dosing regimen for intranasal compositions would be for the patient to inhale slowly through the nose subsequent to the nasal cavity being cleared. During inhalation, the composition would be administered to one nostril while the other is manually compressed. This procedure would then be repeated for the other nostril. Typically, one or two sprays per nostril would be administered by the above procedure one, two, or three times each day, ideally once daily. Of particular interest are intranasal compositions suitable for once-daily administration.

[0131] The suspending agent(s), if included, will typically be present in an amount of from 0.1 to 5% (w / w), such as from 1.5% to 2.4% (w / w), based on the total weight of the composition. JEM-OOl / OIWO 40846 / 3

[0132] Patent Application

[0133] Examples of pharmaceutically acceptable suspending agents include, but are not limited to, Avicef (microcrystalline cellulose and carboxymethylcellulose sodium), carboxymethylcellulose sodium, veegum, tragacanth, bentonite, methylcellulose, xanthan gum, carbopol and polyethylene glycols.

[0134] Compositions for administration to the lung or nose may contain one or more excipients may be protected from microbial or fungal contamination and growth by inclusion of one or more preservatives. Examples of pharmaceutically acceptable antimicrobial agents or preservatives include, but are not limited to, quaternary ammonium compounds (for example benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, lauralkonium chloride and myristyl picolinium chloride), mercurial agents (for example phenylmercuric nitrate, phenylmercuric acetate and thimerosal), alcoholic agents (for example chlorobutanol, phenylethyl alcohol and benzyl alcohol), antibacterial esters (for example esters of p-hydroxybenzoic acid), chelating agents such as disodium edetate (EDTA) and other antimicrobial agents such as chlorhexidine, chlorocresol, sorbic acid and its salts (such as potassium sorbate) and polymyxin. Examples of pharmaceutically acceptable antifungal agents or preservatives include, but are not limited to, sodium benzoate, sorbic acid, sodium propionate, methylparaben, ethylparaben, propylparaben, and butylparaben. The preservative(s), if included, may be present in an amount of from 0.001 to 1% (w / w), such as from 0.015% to 0.5% (w / w) based on the total weight of the composition. Compositions (for example wherein at least one compound is in suspension) may include one or more surfactants which functions to facilitate dissolution of the medicament particles in the aqueous phase of the composition. For example, the amount of surfactant used is an amount which will not cause foaming during mixing. Examples of pharmaceutically acceptable surfactants include fatty alcohols, esters, and ethers, such as polyoxyethylene (20) sorbitan monooleate (Polysorbate 80), macrogol ethers, and poloxamers. The surfactant may be present in an amount of between about 0.01 to 10% (w / w), such as from 0.01 to 0.75% (w / w), for example about 0.5% (w / w), based on the total weight of the composition.

[0135] One or more tonicity-adjusting agent(s) may be included to achieve tonicity with body fluids (e.g., fluids of the nasal cavity) resulting in reduced levels of irritancy. Examples of pharmaceutically acceptable tonicity-adjusting agents include, but are not limited to, sodium chloride, dextrose, xylitol, calcium chloride, glucose, glycerine, and sorbitol. A tonicity-adjusting Patent Application agent, if present, may be included in an amount of from 0.1 to 10% (w / w), such as from 4.5 to 5.5% (w / w), for example about 5.0% (w / w), based on the total weight of the composition.

[0136] The compositions of the disclosure may be buffered by the addition of suitable buffering agents such as sodium citrate, citric acid, trometamol, phosphates such as disodium phosphate (e.g., dodecahydrate, heptahydrate, dihydrate and anhydrous forms), or sodium phosphate and mixtures thereof.

[0137] A buffering agent, if present, may be included in an amount of from 0.1 to 5% (w / w), for example 1 to 3% (w / w) based on the total weight of the composition.

[0138] Examples of taste-masking agents include sucralose, sucrose, saccharin or a salt thereof, fructose, dextrose, glycerol, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, menthol, eucalyptus oil, camphor, a natural flavoring agent, an artificial flavoring agent, and combinations thereof.

[0139] One or more co-solvent may be included to aid solubility of the medicament compound(s) and / or other excipients. Examples of pharmaceutically acceptable co-solvents include, but are not limited to, propylene glycol, dipropylene glycol, ethylene glycol, glycerol, ethanol, polyethylene glycols (for example PEG300 or PEG400), and methanol. In one embodiment, the co-solvent is propylene glycol.

[0140] Co-solvent(s), if present, may be included in an amount of from 0.05 to 30% (w / w), such as from 1 to 25% (w / w), for example from 1 to 10% (w / w) based on the total weight of the composition.

[0141] Compositions for inhaled administration include aqueous, organic or aqueous / organic mixtures, dry powder or crystalline compositions administered to the respiratory tract by pressurized pump or inhaler, for example, reservoir dry powder inhalers, unit-dose dry powder inhalers, pre-metered multi-dose dry powder inhalers, nasal inhalers or pressurized aerosol inhalers, nebulizers or insufflators. Suitable compositions contain water as the diluent or carrier for this purpose and may be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like. Aqueous compositions may also be administered to the nose and other regions of the respiratory tract by nebulization. Such compositions may be aqueous JEM-OOl / OIWO 40846 / 3

[0142] Patent Application solutions or suspensions or aerosols delivered from pressurized packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant.

[0143] Compositions for administration topically to the nose (for example, for the treatment of rhinitis) or to the lung, include pressurized aerosol compositions and aqueous compositions delivered to the nasal cavities by pressurized pump. Compositions which are non-pressurized and are suitable for administration topically to the nasal cavity are of particular interest. Suitable compositions contain water as the diluent or carrier for this purpose. Aqueous compositions for administration to the lung or nose may be provided with conventional excipients such as buffering agents, tonicity-modifying agents and the like. Aqueous compositions may also be administered to the nose by nebulization.

[0144] A fluid dispenser may typically be used to deliver a fluid composition to the nasal cavities. The fluid composition may be aqueous or non-aqueous, but typically aqueous. Such a fluid dispenser may have a dispensing nozzle or dispensing orifice through which a metered dose of the fluid composition is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser. Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid composition, the doses being dispensable upon sequential pump actuations. The dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid composition into the nasal cavity.

[0145] Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatin, orblisters of for example laminated aluminum foil, for use in an inhaler or insufflator. Powder blend compositions generally contain a powder mix for inhalation of a provided compound or pharmaceutically acceptable salt thereof and a suitable powder base (carrier / diluent / excipient substance) such as mono-, di-, or polysaccharides (e.g., lactose or starch). Dry powder compositions may also include, in addition to the drug and carrier, a further excipient (e.g., a ternary agent such as a sugar ester for example cellobiose octaacetate, calcium stearate, or magnesium stearate.

[0146] Pharmaceutical compositions adapted for parental administration include aqueous and nonaqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and JEM-001 / 01WG 40846 / 3

[0147] Patent Application aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (e.g., lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0148] It should be understood that in addition to the ingredients particularly mentioned above, the compositions may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.

[0149] A therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof will depend upon a number of factors including, for example, the age and weight of the subject, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. In particular, the subject to be treated is a mammal, particularly a human.

[0150] Dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof may be administered in a daily dose. This amount may be given in a single dose per day or more usually in a number (e.g., two, three, four, five, or six) of sub-doses per day such that the total daily dose is the same.

[0151] Suitably, the amount of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof administered may be an amount selected from 0.01 mg to 10 g per day (calculated as the free or unsalted compound). In some embodiments, mDex or a pharmaceutically acceptable salt thereof is administered in an amount selected from 0.01 mg to 9 g per day (calculated as the free or unsalted compound). In some embodiments, mDex or a pharmaceutically acceptable salt thereof is administered in an amount selected from 0.01 mg to 8 g per day (calculated as the free or unsalted compound). In some embodiments, mDex or a pharmaceutically acceptable salt thereof is administered in an amount selected from 0.01 mg to 7 g per day (calculated as the free or unsalted compound). In some embodiments, mDex or a Patent Application pharmaceutically acceptable salt thereof is administered in an amount selected from 0.01 mg to 6 g per day (calculated as the free or unsalted compound). In some embodiments, mDex or a pharmaceutically acceptable salt thereof is administered in an amount selected from 0.01 mg to 5 g per day (calculated as the free or unsalted compound). In some embodiments, mDex or a pharmaceutically acceptable salt thereof is administered in an amount selected from 0.01 mg to 4 g per day (calculated as the free or unsalted compound). In some embodiments, mDex or a pharmaceutically acceptable salt thereof is administered in an amount selected from 0.01 mg to 3 g per day (calculated as the free or unsalted compound). In some embodiments, mDex or a pharmaceutically acceptable salt thereof is administered in an amount selected from 0.01 mg to 2 g per day (calculated as the free or unsalted compound). In some embodiments, mDex or a pharmaceutically acceptable salt thereof is administered in an amount selected from 0.01 mg to 1 g per day (calculated as the free or unsalted compound)

[0152] In some embodiments, dexibuprofen dimethylamino ethyl ester (mDex) is administered systemically. For instance, dexibuprofen dimethylamino ethyl ester (mDex) can be administered intravenously, intramuscularly, or subcutaneously to a patient in need.

[0153] In particular embodiments, dexibuprofen dimethylamino ethyl ester (mDex) can be used to treat Hereditary Spastic Paraparesis (HSP), Multiple Sclerosis (MS), Huntington's disease, spinocerebellar ataxia, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer' s disease, Batten Disease, lewy body dementia, Vici syndrome, neuronal ceroid lipofuscinosis, pallidoluysian atrophy, spinobulbar muscular atrophy, cdkl5 disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia, Lafora disease, -propeller protein-associated neurodegeneration (BPAN).

[0154] In some embodiments, the disclosure provides a method of treating autophagy diseases in a subject comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable amount of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is Alzheimer' s disease. In some embodiments, the disease is amyotrophic lateral sclerosis (ALS). In some embodiments, the disease is Parkinson's disease. In a particular aspect, the disease is Huntington's disease. JEM-OOl / OIWO 40846 / 3

[0155] Patent Application

[0156] In some embodiments, dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof may be employed alone or in combination with other therapeutic agents. Dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order, by any convenient route in separate or combined pharmaceutical compositions. The amounts of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof and further therapeutic agent(s) may be employed in combination by administration simultaneously in a unitary pharmaceutical composition including both compounds. Alternatively, the combination may be administered separately in separate pharmaceutical compositions, each including one of the compounds in a sequential manner wherein, for example, dexibuprofen dimethylamino ethyl ester (mDex) is administered first and the other second and vice versa. Such sequential administration may be close in time (e.g. simultaneously) or remote in time. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g., one compound may be administered topically and the other compound may be administered orally. Suitably, both compounds are administered orally.

[0157] The combinations may be presented as a combination kit. By the term “combination kit” “or kit of parts” as used herein is meant the pharmaceutical composition or compositions that are used to administer the combination according to the present disclosure. When both compounds are administered simultaneously, the combination kit can contain both compounds in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions. When the compounds are not administered simultaneously, the combination kit will contain each compound in separate pharmaceutical compositions either in a single package or in separate pharmaceutical compositions in separate packages. The combination kit can also be provided by instruction, such as dosage and administration instructions. Such dosage and administration instructions can be of the kind that are provided to a doctor, for example by a drug product label, or they can be of the kind that are provided by a doctor, such as instructions to a patient. JEM-OOl / OIWO 40846 / 3

[0158] Patent Application

[0159] When the combination is administered separately in a sequential manner wherein one is administered first and the other second or vice versa, such sequential administration may be close in time or remote in time. For example, administration of the other agent several minutes to several dozen minutes after the administration of the first agent, and administration of the other agent several hours to several days after the administration of the first agent are included, wherein the lapse of time is not limited. For example, one agent may be administered once a day, and the other agent may be administered 2 or 3 times a day, or one agent may be administered once a week, and the other agent may be administered once a day and the like. It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredients(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates, to optimize the activity and / or stability and / or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.

[0160] When combined in the same composition it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the composition and may be formulated for administration. When formulated separately they may be provided in any convenient composition, conveniently, in such a manner as known for such compounds in the art.

[0161] When dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent active against the same disease, condition, or disorder, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

[0162] In one embodiment, the mammal in the methods and uses of the present disclosure is a human. Dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof is useful in the treatment of diseases and conditions in which modulation of TECPR2 is beneficial.

[0163] In some embodiments, the disclosure provides dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof for use in the treatment of autophagy diseases. JEM-OOl / OIWO 40846 / 3

[0164] Patent Application

[0165] In some embodiments, the disclosure provides a method of treating autophagy diseases comprising administering to a patient in need thereof a therapeutically effective amount of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the disclosure provides the use of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of autophagy diseases.

[0167] The dosage dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof may range broadly, depending upon the desired effects and the therapeutic indication. The daily dosage regimen for an adult human patient may be, for example, a dose of between 0.01 mg and 3000 mg of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg, or between about 0.1 mg and about 1,000 mg of dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof per kg of body weight of the patient. Exemplary doses for a medicament for treating autophagy diseases include 1 mg, 5 mg, 10 mg, 20 mg, 25, mg, 30 mg, 50 mg, 60 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, and 500 mg per unit dosage form. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. In some embodiments, dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof, are administered for a period of continuous therapy, for example for a week or more, or for months or years. In some embodiments dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof, can be administered less frequently compared to the frequency of administration of an agent within the standard of care. In some embodiments, dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof, can be administered one time per day. For example, dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof, can be administered one time per day to a patient suffering from an Autophagy related disease, including those related to a TECPR2 mutation. In some embodiments, the total time of the treatment regime with dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof, can be less compared to the total time of the treatment regime with the standard of care. Patent Application

[0168] In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.01 mg and 3000 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.01 mg and 2000 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.01 mg and 1000 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.01 mg and 900 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.01 mg and 800 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.01 mg and 700 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.01 mg and 600 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.01 mg and 500 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.01 mg and 400 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.01 mg and 300 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.01 mg and 200 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.01 mg and 100 mg.

[0169] In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.1 mg and 3000 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.1 mg and 2000 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable Patent Application salt thereof for an adult human patient may be, for example, a dose of between 0.1 mg and 1000 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.1 mg and 900 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.1 mg and 800 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.1 mg and 700 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.1 mg and 600 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.1 mg and 500 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.1 mg and 400 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.1 mg and 300 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.1 mg and 200 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 0.1 mg and 100 mg.

[0170] In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 1 mg and 3000 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 1 mg and 2000 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 1 mg and 1000 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 1 mg and 900 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 1 mg and 800 mg. In JEM-OOl / OIWO 40846 / 3

[0171] Patent Application some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 1 mg and 700 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 1 mg and 600 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 1 mg and 500 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 1 mg and 400 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 1 mg and 300 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 1 mg and 200 mg. In some embodiments, the daily dosage regimen of mDex or a pharmaceutically acceptable salt thereof for an adult human patient may be, for example, a dose of between 1 mg and 100 mg.

[0172] In instances where human dosages for dexibuprofen dimethylamino ethyl ester (mDex) or a pharmaceutically acceptable salt thereof have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage.

[0173] In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the composition disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.

[0174] Animal models are essential resources in basic research and drug discovery in the field of Alzheimer’s disease (AD). As the main clinical feature in AD is cognitive failure, the ultimate readout for any interventions or the ultimate goal in research should be measures of learning and memory. Although there is a wealth of genetic and biochemical studies on proposed AD pathogenic pathways, the etiology of the illness remains unsolved. Therefore, assessment by cognitive assays should target relevant memory systems without assumptions about pathogenesis. The description of several tests that are available for assessing cognitive functioning in animal models can be found JEM-OOl / OIWO 40846 / 3

[0175] Patent Application in literature. Among the behavioural test, the novel object exploration (NOE) task is a method to measure a specific form of recognition memory. It is based on the spontaneous behaviour of rodents and offers the advantage of not needing external motivation, reward or punishment. Therefore, the NOE test has been increasingly used as an experimental tool in assessing drug effects on memory and investigating the neural mechanisms underlying learning and memory. This review describes the basic procedure, modifications, practical considerations, and the requirements and caveats of this behavioral paradigm to be considered as appropriate for the study of AD. Altogether, NOE test could be considered as a very useful instrument that allows researchers to explore the cognitive status of rodents, and hence, for studying AD related pathological mechanisms or treatments.

[0176] The 5xFAD mouse model is a widely used and aggressive transgenic model for Alzheimer's disease (AD) research. It is characterized by the rapid accumulation of amyloid-beta (AP) plaques, severe neuroinfl animation, and progressive neuronal loss, which together lead to cognitive and motor deficits at a young age. The 5xFAD model was developed to accelerate the pathological changes seen in familial AD (FAD) by incorporating five different FAD-linked mutations into the mouse genome:

[0177] • Three mutations in the human amyloid precursor protein (APP) gene: Swedish (K670N / M671L), Florida (1716V), and London (V717I)

[0178] • Two mutations in the human presenilin 1 (PSEN1) gene: M146L and L286V.

[0179] These synergistic mutations, driven by a neuron-specific promoter, result in high expression of the highly aggregation-prone Ap42 peptide, primarily within neurons.

[0180] 5xFAD mice exhibit increased aggression, particularly in males, which can lead to injuries in group-housed cages. This aggressive behavior, along with other behavioral and psychological symptoms of dementia (BPSD) like social withdrawal, is part of the aggressive progression of Alzheimer' s-like pathology in this model. While aggression is often more severe in transgenic- only cages, the behavior is influenced by social environment, with aggression being more likely when transgenic mice are housed together.

[0181] The TECPR2 knock-in (KI) mouse is a genetically modified mouse model that carries a human-like mutation in the Tecpr2 gene, designed to study TECPR2-related disorders. These JEM-OOl / OIWO 40846 / 3

[0182] Patent Application disorders, such as autosomal recessive spastic paraplegia 49 (SPG49), cause progressive neurological symptoms like gait abnormalities, sensory loss, and intellectual disability. The mice exhibit similar phenotypes, including gait issues, altered sensory thresholds, and age-dependent neurodegeneration with axonal swellings and autophagosome accumulation in the brainstem. TECPR2 mice exhibit multiple abnormalities which parallel the patient condition.

[0183] Tecpr2 knock-in (KI) mice develop several biochemical and behavioral phenotypes related to TECPR2-related disease. Between postnatal day 2 (P45) and 90 (P90), prominent axonal spheroids form in the brainstem nuclei and spinal cord. On a behavioral level this coincides with impaired gait with ataxia and reduced tactile sensitivity. By P120 evidence of brainstem dysfunction with reduced acoustic startle response and diminished auditory brainstem responses are also found. Leveraging a AAV9 / TECPR2 gene replacement vector (AAV9.pUla-hTECPR2) will perform intra-cistema magna injections in Tecpr2 KI mice at P21 (before) and P45 (at onset of phenotypes). In separate cohorts of mice, dexibuprofen dimethylaminoethyl ester (mDex) will be dosed IP from P20-P90. A third cohort of mutant mice will receive both AAV9 / TECPR2 gene replacement vector (AAV9.pUla-hTECPR2) and mDex from P20. Mice will be tested for acoustic startle response, mechanical sensory tactile sensitivity, and gait impairment at P90 and P120. Following behavioral testing, CSF and plasma will be sampled for neurofilament light chain levels, as a marker of axonal degeneration, and brains will be harvested for histology to assess autophagy markers and spheroid formation.

[0184] Increasing evidence shows a role of Tecpr2 hypofunction in neurodegenerative diseases, specifically Alzheimer’s Disease. Itwill be tested both the gene replacement therapy (AAV9.pUla- hTECPR2) and small molecule activation of Tecpr2 with mDex in 5xFAD mice, a well-established mouse model of Alzheimer’s disease. Intracerebroventricular (ICV) injections will be performed, delivering AAV9.pUla-hTECPR2 in P2 5xFAD and WT mice. In separate cohorts of mice, dexibuprofen dimethylaminoethyl ester (mDex) will be dosed IP from P20-P120 in 5xFAD and WT mice. Depending on the efficacy shown by the AAV and mDEX there is the option to treat both in combination as for Aiml . 5xFAD mice has already been characterized and we will test these mice using a novel object recognition task, spontaneous alteration Y-maze and cued fear conditioning. Following behavioral testing, CSF and plasma will be sampled for neurofilament JEM-OOl / OIWO 40846 / 3

[0185] Patent Application light chain levels, as a marker of axonal degeneration, and brains will be harvested for histology to assess spheroid formation and amyloid plaque load.

[0186] General health: FIG. 2 shows reduced body weight in TECPR2 mice >P120. Compared with WT (n=ll) TECPR2 mice (n=l 1) had reduced body weight. Data in FIG. 1 is expressed as relative from control ± SEM; **p<0.005 t-test vs WT.

[0187] Sensory function: FIG. 3 shows reduced mechanical sensory tactile sensitivity in TECPR2 mice >P120. Compared with WT (n=16) TECPR2 mice (n=18) had reduced mechanical sensory thresholds as measured using von Frey fdaments. Data in FIG. 2 is expressed as 50% of withdrawal threshold (g) ± SEM; *p<0.05 t-test vs WT.

[0188] Startle response: FIG. 4 shows reduced startle response in TECPR2 mice >P120. KI mice exhibited a significant reduced startle response at all frequencies from 80 to 115db compared with WT littermates (n=18 and 16, respectively). ± SEM; *p<0.05 2way ANPVA followed by Tukey’s.

[0189] Auditory Function: FIG. 5 shows reduced auditory brainstem response in TECPR2 mice >P120. Adult mutant mice exhibited a significant reduced response to low frequency stimulation as measured by ABR (n=12). ± SEM; *p<0.05 2way ANPVA followed by Tukey’s. FIG. 6 shows reduced distortion product otoacoustic emissions in TECPR2 mice >P120. Adult mutant mice exhibited a significant reduced response to low frequency stimulation as measured by DPOAE (n=12). ± SEM; *p<0.05 2way ANPVA followed by Tukey’s.

[0190] Step angle: FIG. 7 and FIG. 8 show reduced step angle in TECPR2 mice >P120. Adult mutant mice exhibited a significant reduced step angle. Data expressed as relative from control ± SEM; **p<0.005 t-test vs WT.

[0191] Histopathological abnormalities: FIG. 9 shows progressive appearance of spheroids in TECPR2 KI mice. Coronal sections of TECPR2 KI mouse brainstem (GR: gracile nuclei; CU: cuneate nuclei; grf: gracile fasciculus; cuf: cuneate fasciculus) showing spheroids (indicated by arrows) at different ages (A: Sagittal and B Coronal control (WT) P45; C: P45; D: P90; E: P>120.

[0192] EXAMPLES

[0193] Dexibuprofen dimethylamino ethyl ester (mDex) was obtained from LifeTein, LLC. Patent Application

[0194] Example 1. Method development for mDex detection.

[0195] The method development followed the following steps:

[0196] • Intraperitoneal injection of 15.73 mg / Kg in mice (C57bl6J WT) for 7 days.

[0197] • Plasma and brainstem collected

[0198] • 3 samples showed 1.09-1.78 pg / pL (1.778 pg / pL, 1.747 pg / pL, 1.092 pg / pL) of mDex in the brainstem.

[0199] Sample Preparation

[0200] Tissue samples were prepared using a modified Bligh and Dyer biphasic extraction procedure. Briefly, brainstem samples were homogenized in methanol containing the internal standard, 2-(dimethylamino)ethyl methacrylate, using garnet beads. The homogenate was subjected to liquid-liquid extraction with a 2: 1 : 1 (v / v / v) mixture of chloroform, methanol, and water. Following phase separation, the lower chloroform layer was collected, evaporated to dryness under a gentle stream of nitrogen, and reconstituted in methanol for subsequent analysis by LC-MS / MS.

[0201] LC-MS / MS Analysis of mDex

[0202] Quantitative analysis of mDex was performed using an Agilent 6460 triple quadrupole mass spectrometer coupled to an Agilent HPLC system. Chromatographic separation was achieved on an Agilent Eclipse XDB-C18 column (150 mm x 4.6 mm i.d., 5 pm particle size) maintained at 30 °C. The mobile phases consisted of (A) water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid. An isocratic elution at 70% A was applied at a flow rate of 0.400 mb min1over a total run time of 6 min. The injection volume was 2 pL for all samples.

[0203] Mass spectrometric detection was carried out in multiple reaction monitoring (MRM) mode. The following transitions were monitored for mDex: m / z 278 —> 162 (collision energy [CE] 25 V) and m / z 278 72 (CE 17 V). For the internal standard, 2-(dimethylamino)ethyl methacrylate, the transitions were m / z 158 —► 113 (CE 9 V) and m / z 158 — 72 (CE 13 V).

[0204] The standard curve is linear from 1 pg to 500 pg and the detection method is able to detect and measure the amount of mDex delivered to plasma and brainstem (FIG. 1). JEM-OOl / OIWO 40846 / 3

[0205] Patent Application

[0206] Example 2. Dose Finding Study

[0207] The dose finding study will follow the following methodology:

[0208] • IP injection of mice (C57bl6J WT) daily for 7 days (mDex)

[0209] • 3 doses tested (n=3 per arm): o 5 mg / Kg o 15 mg / Kg o 25 mg / Kg

[0210] • 3 different ages to ensure no development-specific effects at (P7, P30, P60)

[0211] • Outcomes o Tolerability - cage side observation o Weight - Increased o mDex in brainstem and CNS

[0212] • Maximally tolerated dose over 7 days will be used in long-term study (mDex levels don’t plateau in brainstem tissue)

[0213] Sample Preparation

[0214] Tissue samples were prepared using a modified Bligh and Dyer biphasic extraction procedure. Briefly, brainstem samples were homogenized in methanol containing the internal standard, 2-(dimethylamino)ethyl methacrylate, using garnet beads. The homogenate was subjected to liquid-liquid extraction with a 2: 1 : 1 (v / v / v) mixture of chloroform, methanol, and water. Following phase separation, the lower chloroform layer was collected, evaporated to dryness under a gentle stream of nitrogen, and reconstituted in methanol for subsequent analysis by LC-MS / MS.

[0215] LC-MS / MS Analysis of mDex

[0216] Quantitative analysis of mDex was performed using an Agilent 6460 triple quadrupole mass spectrometer coupled to an Agilent HPLC system. Chromatographic separation was achieved on an Agilent Eclipse XDB-C18 column (150 mm x 4.6 mm i.d., 5 pm particle size) maintained at 30 °C. The mobile phases consisted of (A) water containing 0.1% formic acid and (B) Patent Application acetonitrile containing 0.1% formic acid. An isocratic elution at 70% A was applied at a flow rate of 0.400 mL min1over a total run time of 6 min. The injection volume was 2 pL for all samples.

[0217] Mass spectrometric detection was carried out in multiple reaction monitoring (MRM) mode. The following transitions were monitored for mDex: m / z 278 — 162 (collision energy [CE] 25 V) and m / z 278 — > 72 (CE 17 V). For the internal standard, 2-(di methyl ami nojethyl methacrylate, the transitions were m / z 158 — > 113 (CE 9 V) and m / z 158 — > 72 (CE 13 V).

[0218] Results of weight change in mice treated with vehicle or mDex at 15 mg / Kg, 30 mg / Kg, and 60 mg / Kg doses are shown in FIG. 10. Brains were harvested 10 minutes following dosing for 3 days. Brain tissue was extracted and sent for analysis. Results of concentration of mDex in brain of mice treated with vehicle or mDex at 15 mg / Kg, 30 mg / Kg, and 60 mg / Kg doses are shown in FIG. 11.

[0219] Example 3. Long-term efficacy study

[0220] The dose finding study will follow the following methodology:

[0221] • IP injection of mice daily for 90 days (aged P20-P110)

[0222] • Mice to be injected after genotyping (P20)

[0223] • Dosing o 1 dose: TBD based on dose finding study o Vehicle

[0224] • Rolling enrollment (ongoing dosing)

[0225] • Mice: TECPR2 KI

[0226] • 8-12 animals per arm

[0227] • Outcomes o Weight (once per week) o Intoe-ing (at dosing, P-60, P90, Pl 10 terminal timepoint) o Spheroids (P 110 terminal timepoint)

[0228] For this study:

[0229] TECPR2 mice were bred het x het and genotyped by sequencing by the BCH Molecular Genetics core. Patent Application

[0230] Each arm included 8-12 animals. TECPR2 KI mice were dosed with mDex or vehicle (30 mg / kg IP for 90 days after genotyping (P20), to roughly Pl 10). As control, WT mice were dosed with vehicle. Weight was measured once per week. Intoeing was measured at dosing, p60, p90, and before takedown. Brains were collected for spheroid counts.

[0231] Example 4. 5XFAD mouse model

[0232] Mice original breeders were from MMRRC but bred and fulfdled through Jackson Labs. Animals were bred het male x WT female and genotyped by Transnetyx with probes APPsw Tg, huPsenl Tg and Chr3-6 WT.

[0233] Each arm included 10 animals. 5XFAD mice were dosed with mDex or vehicle (30 mg / kg IP starting at P21 through Pl 50). As control, WT mice were dosed with vehicle. Weight was measured once per week. Intoeing was measured at dosing, P60, P90, and Pl 20. Brains were collected for spheroid counts. Histology on coronal sections of brains including cortex and hippocampus for amyloid with thioflavin-s and autophagy with p62.

[0234] Tissue processing and histopathological analysis

[0235] Animals were deeply anesthetized with pentobarbital and perfused with ice cold PBS and then a 4% paraformaldehyde (PFA) solution in PBS. The brain was dissected and fixed in 4% PFA solution overnight. Samples were then transferred to a 30% sucrose solution until the tissue sank. Samples were immediately frozen in OCT embedding medium and kept in -80oC until further processing. Coronal cryosections (50 pm) were collected through the brainstem and spinal cord for immunostaining and histopathological analysis. Slices were then stained with hematoxylin and eosin (H&E) to identify spheroids or probed with antibodies for neurofilament and autophagic flux. Quantification of spheroids was done measuring the density of spheroids per mm2 in the cuneate and gracile nuclei areas bilaterally in 10-12 sections per animal, then an average density was calculated using QuPath software (Bankhead, et al., 2017).

[0236] Electron microscopy

[0237] Animals were anesthetized with pentobarbital and perfused with 2.5% PFA, 2.5% glutaraldehyde, in 0.1 M cac odylate buffer pH 7.4. Brain samples were fixed with 2.5% PFA, 2.5% glutaraldehyde, in 0.1 M cacodylate buffer containing 5 mM CaC12 (pH 7.4), post-fixed in Patent Application

[0238] 1% osmium tetroxide supplemented with 0.5% potassium hexacyanoferrate trihydrate and potassium dichromate in 0.1 M cacodylate for 1 h, stained with 2% uranyl acetate in doubledistilled water for 1 h, dehydrated in graded ethanol solutions, and embedded in epoxy resin (Agar Scientific, AGR1030). Ultrathin sections (70-90 nm) of brain, obtained with a LeicaUltracut UCT microtome, were stained with lead citrate and then examined using either a Phillips CM-12 transmission electron microscope (TEM) equipped with a Gatan One View camera, or an FEI Tecnai SPIRIT TEM equipped with a bottom-mounted 2 k * 2 k FEI Eagle CCD camera.

[0239] Statistical Analysis

[0240] Data are expressed as the mean ± SEM. Significant differences between groups were assessed with one or two-way ANOVA; once the significance of the group differences (p < 0.05) was established, appropriate post-hoc comparisons between pairs of groups were used. Statistical analyses were done using GraphPad Prism Software.

[0241] Spheroids

[0242] Pl 20 5xFAD mice treated with mDex showed a mean 49% reduction in spheroids compared to P120 5xFAD mice treated with vehicle (FIG. 12).

[0243] Pl 50 5xFAD mice treated with mDex showed a mean 65% reduction in spheroids compared to Pl 20 5xFAD mice treated with vehicle (FIG. 13).

[0244] Behavioral Rescue #1 (Intoeing)

[0245] Intoeing was quantified using a n ovel bottom-up imaging and data acquisition technology and analysis platform that provides automated, quantitative, and objective measures of naturalistic rodent behavior in an observer-independent and unbiased fashion as previously described (Zhang, et al., 2022). The location of the paws was extracted from body frames using the DeepLabCut and the distance between hindpaws (measure of intoeing) in the unit of pixel distance was calculated. Grooming behaviors were calculated by the time the animal spent grooming the face and body in seconds for 10 minutes recording using the ARB EL algorithm, a machine learning tool with lightbased image analysis for automatic classification of 3D behaviors (Barkai, et al., 2024).

[0246] 5xFAD mice treated with mDex showed a higher hind paw angle compared to P1205xFAD mice treated with vehicle (FIG. 14). JEM-OOl / OIWO 40846 / 3

[0247] Patent Application

[0248] Weight change over time in WT and 5xFAD mice treated with vehicle or mDex in shown in FIG. 15.

[0249] Behavioral rescue (cognitive) was assessed in WT and 5xFAD mice treated with vehicle or mDex as shown in FIGs. 16-18.

[0250] Survival, weight and general morphology was examined weekly. All behavioral experiments were performed between 10:00 AM and 3:00 PM. All mice were tested on novel object recognition task, spontaneous alteration Y-maze and cued fear conditioning at Pl 20. Following behavioral testing brains were harvested for histology to assess spheroid formation, autophagy and amyloid plaque load. Behavioral Analyses: novel object recognition task and spontaneous alteration Y-maze were recorded and scored using Noldus Ethovision XT 17. Cued fear conditioning utilizes foot shock and tone boxes made by Ugo Basile, controlled by Noldus Ethovision XT 15. Videos are scored by Noldus Ethovision XT 15. Pathology: To quantify the number and size of cortical spheroids, autophagy and amyloid plaque load, mice were perfused with 4% paraformaldehyde. Brains will be cut into coronal sections containing the hippocampus and cortical structures. For spheroid assessment slices are H&E stained. Neurofdament light chain P62 and amyloid levels were measured using IHC.

[0251] 5xFAD mice are typically very aggressive and aggressors have to be separated and housed separately. The inventors found that, remarkably, mice treated with mDex had a full reduction in aggression and were the exact same as the WT control group.

[0252] In the novel object recognition task mice are introduced to two identical objects in an arena, one of the objects is then replaced with a different “novel” object. The mouse is then allowed to explore both objects in the arena and the time spent interacting with each is scored. Four hours after being exposed to the familiar objects a WT mice will spend more than twice the amount of time exploring the novel object compared to the familiar object. A four-month-old 5xFAD mouse loses this ability to discriminate between novel and familiar objects, to evaluate working memory, 5xFAD and WT littermates were tested on a novel object recognition task. At P120, 5xFAD mice fail to show preference for a novel versus familiar object. N=25 (FIG. 19). Similar results are shown with the spontaneous alternating Y-maze which tests spatial novelty, and it is a hippocampal dependent task and cued fear conditioning, an amygdala-frontal cortex dependent task. JEM-OOl / OIWO 40846 / 3

[0253] Patent Application

[0254] Highlights

[0255] • mDex reduces Amyloid Beta accumulation, Autophagy inhibiting spheroid accumulation, and improves cognitive function in 5xFAD mice.

[0256] • mDex suppresses neuroinflammation and oxidative stress, supporting immune and most importantly, neuronal homeostasis.

[0257] • mDex improves cognitive performance as evidenced by significant novel object exploration improvement, rescued to normal levels.

[0258] • mDex decreases Amyloid Beta concentrations and deposition. Significant reduction in the plaque number was observed in both the Cortex and Hippocampus resulting from mDex treatment. Findings demonstrate that mDex can alleviate pathological changes by inhibiting Amyloid Beta accumulation.

[0259] • mDex alters and improves autophagy. The expression of p62, a marker of autophagic flux, was significantly reduced in the 5xFAD mDex group compared to the 5xFAD group.

[0260] Example 4. Tecpr2 KI mouse

[0261] A novel Tecpr2 KI mouse line (Tecpr2 KI, homozygous c, 1319del variant) has been developed and phenotyped, carrying a loss-of-function variant identified in a significant number of patients due to a founder allele. Axonal spheroid formation has been reported in the brainstem of Spanish Water Dogs carrying naturally occurring TECPR2 mutations (Ahmed et al, 2024). More recently spheroids have been described in adult Tecpr2 knockout mice (Tamim-Yecheskel et al, 2021), prompting us to conduct a characterization of the Tecpr2 KI mice. Briefly, mice were euthanized by inhalation of CO2 and brain and spinal cords were collected for histochemical analyses using hematoxylin and eosin (H&E) stain. In Tecpr2 KI mice axonal spheroids were abundantly present in the gracile and cuneate nuclei of the medulla oblongata (FIG. 9A) and in the cervical-thoracic tract of the spinal cord (not shown), starting as early as P90 and becoming more prominent with age (FIG..9B-E). Of note, no axonal spheroids were found in the cortical areas (not shown), suggesting a degenerative phenotype restricted to the brainstem and spinal cord region, similar to the pattern observed in patients. JEM-OOl / OIWO 40846 / 3

[0262] Patent Application

[0263] Functional abnormalities are consistent with histopathology. Patients with TECPR2 -related disorder have prominent sensory abnormalities. The gracile nucleus in the brainstem is one of the dorsal column nuclei that participate in the sensation of fine touch and proprioception of the lower body. It receives input from A0 neurons originating in the skin and forms the fasciculus cuneatus, the posterior column spinal pathway that carries information regarding proprioception, fine tactile discrimination and vibratory sensations from the upper extremities and upper trunk. Hence, we tested tactile sensory thresholds using von Frey filaments and found significant tactile deficits: Mechanical thresholds were significantly higher in mutant mice older than P120 (FIG. 3). The same age mice showed normal responses to pin prick and thermal place preference test (30 vs. 43°C), indicating that overall nociceptor function was intact (not shown). This indicates specific sensory deficits.

[0264] Given the motor impairment present in children with TECPR2-r elated disorder, we next measured gait using a treadmill-based system (Digigait®) and found multiple gait abnormalities in Tecpr2 KI mice, starting as early as P45 and worsening with age (>P120, Table 1). Mice were trained to run on the treadmill at a fixed speed of 10.8m / min and gait was recorded. Gait parameters were calculated automatically using the Digigait® software. Tecpr2 KI mice spent less time in the swing phase, had shorter strides and greater stride frequency. In addition, the coefficient of variation of the stance width in the forelimbs was increased in Tecpr2 KI mice at relative to WT (P45, 146.6±18.6%, P=0.098: P>120, 150±7.6, P<0.01), indicative of instability and propensity to fall. Although the cohort of P45 mice was underpowered, gait impairment was already detectable, supporting a relatively early onset of deficits.

[0265] Table 1

[0266] Swing duration is the time of the swing phase when no paw is in contact with the belt. Stride length is the spatial length that a paw traverses through a given stride. Stride frequency is the number of Patent Application times / second that a paw takes a complete stride. Data expressed as % of mean WT values (P45, n=3; P>120, n=16), TECPR2-KI (P45 n=4; P>120, n=18). t-test vs WT; *p<0.05, **p<0.01.

[0267] Since brainstem nuclei also relay acoustic stimuli, we systemically tested acoustic startle response in Tecpr2 KI mice and found it to be significantly depressed at P>120 (FIG. 4), but not at P45 (not shown). Grip strength and body weights of >P120 mice were not different from WT littermates ruling out simple differences in muscle function or force as possible reasons for the difference in startle responses. To specifically evaluate auditory function, we performed the auditory brainstem reflex (ABR) response in anesthetized mice. There was a significant depression in the threshold to stimuli at multiple frequencies compared with WT littermates (FIG. 5).

[0268] In summary, our preliminary results demonstrated that Tecpr2 KI mice exhibit phenotypes which parallel major symptoms in patients. We also describe a novel phenotype of reduced acoustic startle and ABR response offering the possibility of non-invasive disease markers in TECPR2- related disorder.

[0269] Example 5. mDex in Tecpr2 KI mice

[0270] Rationale: mDex IP dosage before or at the onset of spheroids phenotype may prevent axonal degeneration and behavioral deficits in Tecpr2 KI mice.

[0271] Approach: We estimate a sample size of 10-15 mice per group. In a separate cohort of mutant and WT mice, we will dose mDex I.P from P20 to P120 30mg / kg, a dose found to maximize brain penetration (FIG. 11). Survival, weight and general morphology will be examined weekly. All behavioral experiments will be performed between 10:00 AM and 3:00 PM and conducted in the Animal Behavior and Physiology core where the mice are housed. All mice will be tested on acoustic startle response, von Frey tactile sensory threshold and PalmReader analysis at P90. Following testing, half of the cohort will be perfused for histology to assess spheroid formation, neurofdament and P62 expression. The remaining half will be tested for acoustic startle response, von Frey tactile sensory threshold and Palmreader gait analysis at P120, followed harvesting of brains for immunohistochemistry. Behavioral Analyses: Acoustic startle responses will be measured from 60 to 115 dB using a Kinder Scientific Startle Reflex system and analyzed using the Kinder Scientific Startle Monitor software. Gait analysis will be performed with the PalmReader system, a machine learning enabled bottom-up imaging system. The PalmReader JEM-OOl / OIWO 40846 / 3

[0272] Patent Application software analyzes the gait characteristics of the mouse. Tactile sensory thresholds will be measured using von Frey filaments using the Up-Down method starting at 0.4g. Pathology: To quantify the number and size of axonal spheroid, mice will be perfused with 4% paraformaldehyde. Brains will be cut into coronal sections containing the gracile and cuneate nuclei, followed by H&E stain. Neurofilament light chain and P62 levels will be measured using IHC. In case of positive effects of both treatments, we will then test a third cohort of animals in which we will combine the treatments starting at P20. Mice will be analyzed as described above.

[0273] Incorporation by Reference

[0274] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, publicly accessible databases, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.

[0275] Equivalents

[0276] Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

JEM-OOl / OIWO 40846 / 3 Patent ApplicationCLAIMS1. A method of treating an autophagy disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound, wherein the compound is a prodrug of dexibuprofen.

2. The method of claim 1 , wherein the prodrug is at least one prodrug selected from the group consisting of:

3. The method of claims 1 or 2, wherein the prodrug is dimethylamino ethyl ester (mDex) or is a pharmaceutically acceptable salt thereof.

4. The method of any one of claims 1-3, wherein the autophagy disease is selected from Hereditary Spastic Paraparesis (HSP), Multiple Sclerosis (MS), Huntington's disease, spinocerebellar ataxia, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer' s disease, Batten Disease, lewy body dementia, Vici syndrome, neuronal ceroid lipofuscinosis, pallidoluysian atrophy, spinobulbar muscular atrophy, cdkl5 disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia, Lafora disease, and P-propeller protein-associated neurodegeneration (BPAN).

5. The method of claim 4, wherein autophagy disease is Alzheimer' s disease, amyotrophic lateral sclerosis (ALS), or Huntington's disease,6. The method of any one of claims 1-5, wherein autophagy disease is an autophagy disease related to a TECPR2 mutation in the patient.Patent Application7. The method of any one of claims 1-6, wherein the compound is administered systemically.8 The method of claim 7, wherein the compound is administered subcutaneously, intraperitoneally, intramuscularly, or intravenously.

9. The method of claim 8, wherein the compound is administered subcutaneously.

10. The method of claim 8, wherein the compound is administered intraperitoneally.

11. The method of claim 8, wherein the compound is administered intramuscularly.

12. The method of claim 8, wherein the compound is administered intravenously.

13. The method of any one of claims 1-6, wherein the compound is administered orally.

14. The method of claim 13, wherein the compound is administered in the form of a capsule or a tablet.

15. The method of any one of claims 1-14, wherein the compound is administered in combination with at least one further therapeutic agent.

16. The method of any one of claims 1-1 , wherein the compound is administered to the patient in an amount from about 0.1 mg to about 1,000 mg of the compound per kg of body weight of the patient.

17. The method of claims 7-12, wherein the compound is administered in a concentration between 1 mg / ml and 500 mg / mL18. A method of treating an autophagy disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition that provides a therapeutically effective amount of a compound, wherein the compound is a prodrug of dexibuprofen.

19. The method of claim 18, wherein the prodrug is at least one prodrug selected from the group consisting of:JEM-OOl / OIWO 40846 / 3Patent Application20. The method of claims 18 or 19, wherein the prodrug is dimethylamino ethyl ester (mDex) or is a pharmaceutically acceptable salt thereof.

21. The method of any one of claims 18-20, wherein the autophagy disease is selected from Hereditary Spastic Paraparesis (HSP), Multiple Sclerosis (MS), Huntington's disease, spinocerebellar ataxia, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer' s disease, Batten Disease, lewy body dementia, Vici syndrome, neuronal ceroid lipofuscinosis, pallidoluysian atrophy, spinobulbar muscular atrophy, cdkl5 disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia, Lafora disease, and P-propeller protein-associated neurodegeneration (BPAN).

22. The method of claim 21, wherein autophagy disease is Alzheimer' s disease, amyotrophic lateral sclerosis (ALS), or Huntington's disease,23. The method of any one of claims 18-22, wherein autophagy disease is an autophagy disease related to a TECPR2 mutation in the patient.

24. The method of any one of claims 18-23, wherein the composition is for systemic administration.25 The method of claim 24, wherein the composition is for subcutaneous, intraperitoneal, intramuscular, or intravenous administration.

26. The method of claim 25, wherein the composition is for subcutaneous administration.

27. The method of claim 25, wherein the composition is for intraperitoneal administration.JEM-OOl / OIWO 40846 / 3 Patent Application28. The method of claim 25, wherein the composition is for intramuscular administration.

29. The method of claim 25, wherein the composition is for intravenous administration.

30. The method of any one of claims 18-23, wherein the composition is for oral administration.

31. The method of claim 30, wherein the compound is administered in the form of a capsule or a tablet.

32. The method of any one of claims 18-31 further comprising administering at least one further therapeutic agent.

33. The method of any one of claims 18-31, wherein the composition comprises from about0.1 mg to about 1,000 mg of the compound per kg of body weight of the patient.

34. The method of claims 24-29, wherein the composition comprises the compound in a concentration between 1 mg / ml and 500 mg / mL35. Use of a compound in the manufacture of a medicament for treating an autophagy disease in a patient in need thereof, wherein the compound a prodrug of dexibuprofen.

36. The use of claim 35, wherein the prodrug is at least one prodrug selected from the group consisting of:

37. The use of claims 35 or 36, wherein the prodrug is dimethylamino ethyl ester (mDex) or is a pharmaceutically acceptable salt thereof.JEM-OOl / OIWO 40846 / 3Patent Application38. The use of any one of claim35-37, wherein the autophagy disease is selected from Hereditary Spastic Paraparesis (HSP), Multiple Sclerosis (MS), Huntington's disease, spinocerebellar ataxia, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer' s disease, Batten Disease, lewy body dementia, Vici syndrome, neuronal ceroid lipofuscinosis, pallidoluysian atrophy, spinobulbar muscular atrophy, cdkl5 disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia, Lafora disease, and P-propeller protein-associated neurodegeneration (BPAN).

39. The use of claim 38, wherein autophagy disease is Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or Huntington's disease,40. The use of any one of claims 35-39, wherein autophagy disease is an autophagy disease related to a TECPR2 mutation in the patient.

41. The use of any one of claims 35-40, wherein the medicament is administered systemically.

42. The use of claim 41, wherein the medicament is administered subcutaneously, intraperitoneally, intramuscularly, or intravenously.

43. The use of claim 42, wherein the medicament is administered subcutaneously.

44. The use of claim 42, wherein the medicament is administered intraperitoneally.

45. The use of claim 42, wherein the medicament is administered intramuscularly.

46. The use of claim 42, wherein the medicament is administered intravenously.

47. The use of any one of claims 35-41, wherein the medicament is administered orally.

48. The use of claim 47, wherein the medicament is a capsule or a tablet.

49. The use of any one of claims 35-48, wherein the medicament is administered in combination with at least one further therapeutic agent.

50. The use of any one of claims 35-49, wherein the medicament comprises from about 0.1 mg to about 1,000 mg of the compound per kg of body weight of the patient.JEM-OOl / OIWO 40846 / 3Patent Application51. The use of claims 41-46, wherein the medicament comprises the compound in a concentration between 1 mg / ml and 500 mg / mL.

52. A method of treating an autophagy disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound, wherein the compound is dexibuprofen dimethylamino ethyl ester (mDex).

53. A method of treating an autophagy disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound, wherein the compound is dexibuprofen dimethylamino ethyl ester (mDex).

54. A method of treating a TECPR2-realted disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound, wherein the compound is dexibuprofen dimethylamino ethyl ester (mDex).

55. A method of treating a TECPR2-realted disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound, wherein the compound is dexibuprofen dimethylamino ethyl ester (mDex).

Images