WO2019219741A1

WO2019219741A1 - 2-hydroxypropyl-beta-cyclodextrin for use in a method of treatment of a parkinsonian condition

Info

Publication number: WO2019219741A1
Application number: PCT/EP2019/062469
Authority: WO
Inventors: Javier Martin JARAZO; Jonas WALTER; Jens Christian SCHWAMBORN
Original assignee: Université Du Luxembourg
Priority date: 2018-05-15
Filing date: 2019-05-15
Publication date: 2019-11-21
Also published as: LU100797B1

Abstract

The present invention relates to 2-hydroxypropyl-β-cyclodextrin for use in a method of treatment of a parkinsonian condition selected from the group consisting of: Parkinson's disease, Parkinsonism and Parkinson-plus syndrome as well as methods and uses based thereon. The present invention further relates to an isolated dopaminergic neuron or an isolated precursor cell thereof exposed to 2-hydroxypropyl-β-cyclodextrin as well as methods and uses based thereon.

Description

2-hydroxypropyl-beta-cyclodextrin for use in a method of treatment of a

parkinsonian condition

[001] This application contains a Sequence Listing in computer readable form, which is incorporated herein by reference.

Technical field

[002] The present invention relates to 2-hydroxypropyl- -cyclodextrin for use in a method of treatment of a parkinsonian condition selected from the group consisting of: Parkinson’s disease (PD), Parkinsonism and Parkinson-plus syndrome. The present invention further relates to an isolated dopaminergic neuron or an isolated precursor cell thereof exposed to 2-hydroxypropyl- b-cyclodextrin as well as methods and uses based thereon.

Background of the invention

[003] Neurodegenerative diseases pose a great threat to ageing populations, especially for those patients suffering from Parkinson’s disease (PD) that rely only on palliative or surgical treatments (Fahn 2015, Lozano et al., 2018). Many neurodegenerative diseases involve the loss of dopaminergic neurons, which are neurons that release dopamine from its synapses. Such diseases including PD may result not only in the loss of motor skills, but also in the development of a number of other non-motor symptoms, such as mood disturbances and cognitive disturbances (W02009109001 ). For example, Parkinson’s disease (PD) has an etiology that is not completely understood even though environmental causes, risk factors and specific point mutations have been identified as contributors to the onset of the disease (Przedborski 2017, Farrer 2006, Schapira & Tolosa 2010). Affected loci reported as risk or causative factors of PD are involved in controlling major cellular processes such as cell proliferation, membrane trafficking, mitochondria homeostasis and autophagy (Bras et al., 2015). One of the hallmarks of PD is the loss of dopaminergic in the substantia nigra pars compacts, even though other regions have also been found to be altered. These dopaminergic neurons release dopamine within the striatum, the area of the brain that regulates smooth execution of movement. As such, motor symptoms such as resting tremor and bradykinesia, a slowness in movement, predominate as the disease progresses. The loss of dopaminergic neurons in PD progresses slowly and surviving neurons can to a certain extent compensate for this loss by increasing dopamine synthesis and release. Such compensation is reasonably effective until approximately 50% of neurons have been lost, at which point the clinical symptoms present (W02009109001 ). Once diagnosed, there is some time for therapeutic intervention that will slow down or stop the progression of the disease, since the continued loss of dopaminergic neurons does not occur at a faster rate after the presentation of clinical symptoms. However, the cause of death of the dopaminergic neurons is unknown, despite a number of factors having been implicated, including oxidative stress, glutamate excitotoxicity and mitochondrial dysfunction (W02009109001 ). Individuals that present homozygous point mutations in PINK1 develop the disease at an early age denoting that an altered mitochondrial function, morphology and degradation are important processes in the pathology of PD. Homozygous point mutations of PINK1 involved in mitochondrial homeostasis, vesicle trafficking and autophagy are sufficient for triggering the disease at an early age.

[004] Accordingly, there is a need for new therapeutic interventions to prevent and/or treat diseases, conditions, states or syndromes associated with reduced dopaminergic neuron number or function (e.g., as in PD). In the course of the present invention it has been shown that patient derived neuro-precursors cells have a modified mitochondrial network morphology concomitant with an imbalanced differentiation efficiency in their transition to dopaminergic neurons. Mitophagy abnormalities during differentiation were detected in PD patients’ derived neurons related to the count and size of these events. It has been further shown that impaired dopaminergic differentiation of PD patients’ neurons was rescued by the treatment with HR-b- CD. These findings suggest that HR-b-CD modulation can reduce neuronal loss in the context of a parkinsonian condition associated with reduced dopaminergic neuron number and/or function selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome.

Summary of the invention

[005] The present invention relates to HR-b-CD of general formula I:

wherein R is hydrogen (-H) or 2-hydroxypropyl (-CH₂-CHOH-CH₃) group;

an isomer of said 2-hydroxypropyl- -cyclodextrin or a mixture of isomers thereof;

a derivative of said 2-hydroxypropyl-3-cyclodextrin or a mixture of derivatives thereof, preferably said mixture comprising: monomeric and/or homo- and/or heterodimeric form of said 2- hydroxypropyl^-cyclodextrin; a pharmaceutically acceptable salt of said 2-hydroxypropyl- -cyclodextrin or a mixture of pharmaceutically acceptable salts thereof; or

a complex of said 2-hydroxypropyl-P-cyclodextrin or a mixture of complexes thereof; for use in one or more of the following methods for improving the condition of dopaminergic neurons:

i) method for increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome;

ii) method for modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome;

iii) method for reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome;

iv) method for modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; v) method for modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome;

vi) any method of (i)-(v), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons; preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ;

vii) any method of (i)-(vi), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra, most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome.

[006] As there is a need for new therapeutic interventions to prevent and/or treat diseases, conditions, states or syndromes associated with reduced dopaminergic neuron number or function, especially in those conditions that may result in the loss of motor skills of the affected individuals (e.g., as in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome).

[007] The present application satisfies this demand by the provision of compounds, isomers, derivatives and mixtures thereof, isolated dopaminergic neurons or isolated precursor cell thereof, compositions, kits, methods and uses described herein below, characterized in the claims and illustrated by the appended Examples and Figures.

Overview of the Sequence Listing

[008] As described herein references are made to UniProtKB Accession Numbers (http://www.uniprot.org/, e.g., as available in UniProtKB Release 2018 04; published April 25, 2018).

[009] SEQ ID NO: 1 is the amino acid sequence of human PTEN-induced putative kinase 1 (PINK1 ), UniProtKB Accession Number: Q9BXM7.

[0010] SEQ ID NO: 2 is the amino acid sequence of human E3 ubiquitin-protein ligase parkin (PRKN), UniProtKB Accession Number: 060260.

[00 1] SEQ ID NO: 3 is the nucleic acid sequence of pASI NB m Rosella I.

Brief description of the drawings

[0012] Figure 1 : Overview of the samples used (A) and assessment of differentiation potential of dopaminergic neurons diagram (B).

[0013] Figure 2: Immunocytochemical (ICH) assessment of the impaired differentiation of NECSs derived from patient- and control groups of samples. Antibody-based staining of dopaminergic marker tyrosine hydroxylase (TH), general neuronal marker (neuron-specific class III b-tubulin, Tuj1 ) and Hoechst33342-based nuclear staining are shown.

[0014] Figure 3: Immunocytochemical (ICH) assessment of the impaired differentiation of NECSs derived from patient- and control groups of samples. Segmentation and quantification of the ICH-based NECSs images derived from patient- and control groups of samples showing that patient-derived NESCs have a reduced tendency of developing into TH⁺ neurons. [0015] Figure 4: Serial time points (i.e., 7, 14 and 21 days of differentiation)-based quantification of the NECSs differentiation marker.

[0016] Figure 5: Morphological assessment of mitochondria in different cell types (NESCs and neurons) allowing evaluation of the fission/fusion status of the network.

[0017] Figure 6: Assessment of the total mitochondrial volume and mitochondrion count per nuclei unit in NESCs showing that the median size of the mitochondrion is higher in NESCs- derived from patients carrying PINK1 mutations.

[0018] Figure 7: Assessment of the total mitochondrial volume and mitochondrion count per nuclei unit in TH⁺ neurons showing reduction of mitochondria area in dopaminergic neurons derived from patients.

[0019] Figure 8: Assessment of the mitochondrial degradation by mitophagy using Rosella mitophagy reporter in patient- (PINK1 , I368N substitution) and control cell lines expressing the Rosella construct bound to ATP5C1. These cell lines were generated at the hiPSCs levels and further differentiated into NESCs and subsequently to neurons.

[0020] Figure 9: Assessment of the mitochondrial degradation by mitophagy using Rosella mitophagy reporter in patient (PINK1 , I368N substitution) and control cell lines expressing the Rosella construct bound to ATP5C1. Analysis of the serial measurements the dynamic changes of the mitophagy activity during differentiation into neurons showing that that the amount of mitophagy events in patients’ neurons was significantly reduced but the mean area of the mitophagy event was bigger.

[0021] Figure 10: Assessment of the effect of the treatment with HR-b-CD showing an increase in the total volume of mitophagy (i.e., increase in the number of mitophagy events and in the total volume of mitophagy).

[0022] Figure 11 : Assessment of the effect of the treatment with HR-b-CD showing an increase the proportion of TH⁺ voxel over the total neuronal volume (PINK1 patients samples compared to HR-b-CD treated PINK1 patients samples).

[0023] Figure 12: Assessment of the effect of the treatment with HR-b-CD showing an increase the proportion of TH⁺ voxel over the total neuronal volume (PARKIN patient sample compared to HR-b-CD treated PARKIN patient sample). hiPSCs reprogrammed fibroblast from patient carrying a homozygous Parkin mutation (R275W substitution) were further differentiated into NESCs and neurons showing a significant increase in dopaminergic neurons.

[0024] Figure 13: Assessment of the improvement of several mitochondria and mitophagy properties in PD patient’s neurons after treatment with HR-b-CD. [0025] Figure 14: Mass Spectrometry-based assessment of the specific finger print of the HP- b-CD isomer mixture used showing the presence of monomeric and oligomeric forms of HR-b- CD (e.g., homo- and heterodimeric forms of HR-b-CD).

[0026] Figure 15: Mass Spectrometry-based assessment of the specific finger print of the HP- b-CD mixture used showing the relative intensity of the degree of substitution (DS) of the HR-b- CD isomer mixture used to be in the range from 2 to 10 with preference in the range from 3 to 9, with more preference in the range from 4 to 8, with most preference in the range from 5 to 7, wherein the major (e.g., dominant) isomer of the HR-b-CD mixture used has DS of 6.

[0027] Figure 16: Mass Spectrometry-based assessment of the specific finger print of the HP- b-CD isomer mixture used showing the relative intensity of the degree of substitution (DS) of the HR-b-CD mixture used (with standard deviation) to be in the range from 2 to 9 with preference in the range from 3 to 8, with more preference in the range from 4 to 7, with most preference in the range from 5 to 6, wherein the major (e.g., dominant) isomer of the HR-b-CD mixture used has DS of 6.

[0028] Figure 17: (A) Quantification of the amount of pixels stained with Hoechst belonging to live nuclei. Categorization of the pixels in either belonging to live or dead cells is based on intensity. Values for control untreated, “Patient untreated” and “Patient + Cyclodextrin” are displayed. (B) Ratio of pixels between the neuronal marker (TUBB3; also called Tuj1 ) and the dopaminergic neuron marker (TH) masked values to determine the differentiation efficiency of neuroepithelial stem cells into dopaminergic neurons. Values for control untreated, “Patient untreated” and“Patient + Cyclodextrin” are displayed.

Detailed description of the invention

[0029] The following detailed description refers to the accompanying Examples and Figures that show, by way of illustration, specific details and embodiments, in which the invention may be practised. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention. Other embodiments may be utilized such that structural, logical, and eclectic changes may be made without departing from the scope of the invention. Various aspects of the present invention described herein are not necessarily mutually exclusive, as aspects of the present invention can be combined with one or more other aspects to form new embodiments of the present invention.

[0030] Definitions

[0031] Unless otherwise specified, the terms used herein have their common general meaning as known in the art (e.g., as defined by IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997); XML on-line corrected version: http://goldbook.iupac.org (2006-) created by M. Nic, J. Jirat, B. Kosata; updates compiled by A. Jenkins. ISBN 0-9678550-9-8. https://doi.Org/10.1351/goldbook).

[0032] As used herein, the term “cyclodextrin” (used interchangeably with “cyclodextrin compound”) refers to a cyclic oligoglucoside containing 5 to about 10 glucose residues in which an enclosed tubular space allows reception of a guest molecule to form a clathrate. Preferably, a cyclodextrin of the present invention is 2- ^-cyclodextrin (used interchangeably

with “HR-b-CD”) of the general formula I

wherein R is hydrogen (-H) or 2- hydroxypropyl (-CH₂-CHOH-CH₃) group).

[0033] As used herein, the term“guest” refers to an organic or inorganic ion or molecule that occupies a cavity, cleft or pocket within the molecular structure of a host molecular entity and forms a complex with it or that is trapped in a cavity within the crystal structure of a host.

[0034] As used herein, the term“clathrate” refers to inclusion compounds in which the guest molecule is in a cage formed by the host molecule or by a lattice of host molecules.

[0035] As used herein, the term“isomer” refers to one of several species (or molecular entities) of HR-b-CD as described herein including but is not limited to those having various degree and/or pattern of hydroxypropylation (Malanga M et al., 2016).

[0036] As used herein, the term“derivative” refers to a compound that is derived from a HR-b- CD as described herein and includes but is not limited to amide, ether, ester, amino, carboxyl, acetyl, and/or alcohol derivatives of a given compound as well as isomers having various degree and/or pattern of hydroxypropylation. Preferably, a derivative of the present invention is HR-b-CD having monomeric- and/or oligomeric (e.g., homo-oligomeric and/or hetero-oligomeric) form. For example, hydroxypropyl groups can be bonded to the beta-cyclodextrins as monomers or can themselves be sequentially bonded to one or more additional hydroxypropyl groups to form hydroxypropyl oligomers which are then bonded to the beta-cyclodextrins (US2017042932).

[0037] As used herein, the term “complex" refers to a molecular entity formed by loose association involving two or more component molecular entities (e.g., ionic or uncharged), or the corresponding chemical species. The bonding between the components is normally weaker than in a covalent bond. Preferably, a complex of the present invention is a complex of HR-b-CD with a pharmaceutically acceptable complexing agent, e.g., glycyrrhizic acid.

[0038] As used herein, the term "dopaminergic neuron" refers to a neuron that releases dopamine from its synapses (e.g., W02009109001 ). Non-limiting examples of dopaminergic neurons of the present invention include dopaminergic neurons present in the ventral tegmental area of the midbrain, substantia nigra pars compacta, and arcuate nucleus of the hypothalamus. Preferably, dopaminergic neurons of the present invention are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons (e.g., tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ). Further preferably, dopaminergic neurons of the present invention are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra\ most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject (e.g., human) diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome.

[0039] As used herein, the term "human induced pluripotent stem cells” (used interchangeably with“hiPSCs") refers to human pluripotent stem cells that can be generated directly from adult human cells (Yu et al., 2007), i.e., they are obtainable without destruction of human embryos, e.g., they are obtainable from somatic fibroblasts.

[0040] As used herein, the term "human neuroepithelial stem cells” (used interchangeably with “NESCs") refers to neuroepithelial cells that can be derived from hiPSCs, i.e., they are obtainable without destruction of human embryos, e.g., they are obtainable from somatic fibroblasts.

[0041] As used herein, the term "isolated precursor cell of dopaminergic neuron” (used interchangeably with“isolated progenitor cell of dopaminergic neuron” refers to any isolated cell that can be differentiated into a dopaminergic neuron. Preferably, isolated precursor cell of dopaminergic neuron of the present invention is selected from the group consisting of: isolated hiPSCs and NESCs.

[0042] As used herein, the term“affecting the condition of dopaminergic neurons” refers to affecting (e.g., improving) one or more activities and/or functions and/or numbers of dopaminergic neurons (e.g., in a pathological condition or clinical situation) that may result in the affecting (e.g., improving) of motor skills in the affected individuals (e.g., as in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome). Dopaminergic neuron function includes, for example, the stimulation of a dopaminergic neuron, the transmission of an electrical impulse along a dopaminergic neuron, release of dopamine as a result of the electrical impulse, binding of released dopamine to dopamine receptors, and dopamine receptor signalling.

[0043] As used herein, the term“improving the condition of dopaminergic neurons” refers to improving one or more activities and/or functions and/or numbers of dopaminergic neurons (e.g., in a pathological condition or clinical situation) that may result in the improving of motor skills in the affected individuals (e.g., as in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome).

[0044] As used herein, the term“degree of substitution” (used interchangeably with“DS”) refers to the average number of substituents (e.g., at one or more hydroxyl positions by hydroxypropyl groups) on a cyclodextrin molecule (e.g., HR-b-CD of formula I). Preferably, said DS is in the range from about 3 to about 8, further preferably said DS is in the range from about 4 to about 7, most preferably said DS is in the range from about 5 to about 6. Degree of substitution (DS) is determinable by one or more of the following methods: nuclear magnetic resonance (NMR), mass spectrometry (MS), differential scanning calorimetry, microcalorimetric titration, near infrared reflectance spectroscopy (Malanga M et al., 2016; US9675634).

[0045] As used herein, the terms "effective amount" or "therapeutically effective amount," refer to an amount of an active agent (e.g., HR-b-CD) as described herein that is sufficient to achieve, or contribute towards achieving, one or more desirable clinical outcomes. An appropriate "effective" amount in any individual case may he determined using standard techniques known in the art, such as a dose escalation study.

[0046] In certain embodiments, the pharmaceutical composition comprises about 100 mg to about 2000 mg, such as about 100 to about 1800, about 100 to about 1600, about 100 to about 1500, about 100 to about 1200, about 100 to about 1000, about 100 to about 800, about 100 to about 600, about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200 to about 2000, about 200 to about 1800, about 200 to about 1600, about 200 to about 1500, about 200 to about 1200, about 200 to about 1000, about 200 to about 800, about 200 to about 600, about 200 to about 500, about 200 to about 400, about 200 to about 300, about 300 to about 2000, about 300 to about 1800, about 300 to about 1600, about 300 to about 1500, about 300 to about 1200, about 300 to about 1000, about 300 to about 800, about 300 to about 600, about 300 to about 500, about 300 to about 400, about 400 to about 2000, about 400 to about 1800, about 400 to about 1600, about 400 to about 1500, about 400 to about 1200, about 400 to about 1000, about 400 to about 800, about 400 to about 600, about 400 to about 500, about 500 to about 2000, about 500 to about 1800, about 500 to about 1600, about 500 to about 1500, about 500 to about 1200, about 500 to about 1000, about 500 to about 800, about 500 to about 600, about 600 to about 2000, about 600 to about 1800, about 600 to about 1600, about 600 to about 1500, about 600 to about 1200, about 600 to about 1000, about 600 to about 800, about 800 to about 2000, about 800 to about 1800, about 800 to about 1600, about 800 to about 1500, about 800 to about 1200, or about 800 to about 1000 mg of the pharmaceutically active ingredient. For example, the pharmaceutical composition can comprise about 100, about 200, about 300, about 400, about 500, about 600, about 800, about 1000, about 1200, about 1400, about 1500, about 1600, about 1800, or about 2000 mg of the pharmaceutically active ingredient (e.g., HR-b-cyclodextrin).

[0047] As used herein, “about” means especially +/-10%, +1-5% or +/- 3% (referring to the given numeric value), if not indicated otherwise. In each of the invention embodiments,“about” can be deleted.

[0048] As used herein,“administering” a compound can be affected or performed using any of the various methods and delivery systems known to those skilled in the art. The administering can be performed, for example, intravenously, orally, nasally, via the cerebrospinal fluid, via implant, transmucosally, transdermally, intramuscularly, intraocularly, parenterally, topically and subcutaneously. The following delivery systems, which employ a number of routinely used pharmaceutically acceptable carriers, are only representative of the many embodiments envisioned for administering compositions according to the instant methods.

[0049] The appropriate dosage, or therapeutically effective amount, will depend on the condition to be treated, the severity of the condition, prior therapy, and the patient's clinical history and response to the therapeutic agent. The proper dose can be adjusted according to the judgment of the attending physician such that it can be administered to the patient one time or over a series of administrations. The pharmaceutical composition can be administered as a sole therapeutic or in combination with additional therapies as needed.

[0050] If the pharmaceutical composition has been lyophilized, the lyophilized material is first reconstituted in an appropriate liquid prior to administration. The lyophilized material may be reconstituted in, e.g., bacteriostatic water for injection (BWFI), physiological saline, phosphate buffered saline (PBS), or the same formulation the protein had been in prior to lyophilization.

[0051] Pharmaceutical compositions for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In addition, several recent drug delivery approaches have been developed and the pharmaceutical compositions of the present invention are suitable for administration using these new methods, e. g., Inject-ease, Genject, injector pens such as Genen, and needleless devices such as MediJector and BioJector. The present pharmaceutical composition can also be adapted for yet to be discovered administration methods. See also Langer, 1990, Science, 249: 1527-1533.

[0052] The pharmaceutical composition can also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously, into the ligament or tendon, subsynovially or intramuscularly), by subsynovial injection or by intramuscular injection. Thus, for example, the formulations may be modified with suitable polymeric or hydrophobic materials (for example as a emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. [0053] The pharmaceutical compositions may also be in a variety of conventional depot forms employed for administration to provide reactive compositions. These include, for example, solid, semi-solid and liquid dosage forms, such as liquid solutions or suspensions, slurries, gels, creams, balms, emulsions, lotions, powders, sprays, foams, pastes, ointments, salves, balms and drops.

[0054] The pharmaceutical compositions may, if desired, be presented in a vial, pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. In one embodiment, the dispenser device can comprise a syringe having a single dose of the liquid formulation ready for injection. The syringe can be accompanied by instructions for administration.

[0055] The pharmaceutical composition may further comprise additional pharmaceutically acceptable components. Other pharmaceutically acceptable carriers, excipients, or stabilizers, such as those described in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980) may also be included in a HR-b-CD formulations described herein, provided that they do not adversely affect the desired characteristics of the formulation. As used herein, "pharmaceutically acceptable carrier" means any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and include: additional buffering agents; preservatives; co-solvents; antioxidants, including ascorbic acid and methionine; chelating agents such as EDTA; metal complexes (e.g., Zn-protein complexes); biodegradable polymers, such as polyesters; salt-forming counterions, such as sodium, polyhydric sugar alcohols; amino acids, such as alanine, glycine, asparagine, 2-phenylalanine and threonine; sugars or sugar alcohols, such as lactitol, stachyose, mannose, sorbose, xylose, ribose, ribitol, myoinisitose, myoinisitol, galactose, galactitol, glycerol, cyclitols (e.g., inositol), polyethylene glycol; sulfur containing reducing agents, such as glutathione, thioctic acid, sodium thioglycolate, thioglycerol, [alpha]-monothioglycerol, and sodium thio sulfate; low molecular weight proteins, such as human serum albumin, bovine serum albumin, gelatin, or other immunoglobulins; and hydrophilic polymers, such as polyvinylpyrrolidone.

[0056] The formulations described herein are useful as pharmaceutical compositions in the treatment and/or prevention of the pathological medical condition as described herein in a patient in need thereof. The term "treatment" refers to both therapeutic treatment and prophylactic or preventative measures. Treatment includes the application or administration of the formulation to the body, an isolated tissue, or cell from a patient who has a disease/disorder, a symptom of a disease/disorder, or a predisposition toward a disease/disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disease, the symptom of the disease, or the predisposition toward the disease.

[0057] The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.

[0058] The compositions of the invention can be formulated as neutral or salt forms.

[0059] Pharmaceutically acceptable salts include, but are not limited to those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.

[0060] As used herein, the term "treating" and "treatment" refers to administering to a subject a therapeutically effective amount of a pharmaceutical composition according to the invention. A “therapeutically effective amount” may refer to an amount of the pharmaceutical composition which is sufficient to treat or ameliorate a disease or disorder, to delay the onset of a disease or to provide any therapeutical benefit in the treatment or management of a disease.

[0061] As used herein, the term“prophylaxis” refers to the use of an agent for the prevention of the onset of a disease, disorder, syndrome or condition. A“prophylactically effective amount” defines an amount of the active component or pharmaceutical agent sufficient to prevent the onset or recurrence of a disease.

[0062] As used herein, the term “parkinsonian condition” refers to a clinical/pathological condition (e.g., clinical situation), disease, state (e.g., pathological state) or syndrome comprising the following symptoms: tremor, bradykinesia, rigidity, and postural instability. Preferably, said parkinsonian condition is selected from the group consisting of: Parkinson's disease, Parkinsonism and Parkinson-plus syndrome.

[0063] As used herein, the term“Parkinsonism” refers to a clinical/pathological condition (e.g., clinical situation) characterized by (e.g., consisting of) the following symptoms: tremor, bradykinesia, rigidity and postural instability. Preferably, said Parkinsonism comprises one or more of the following conditions: drug induced parkinsonism, toxin induced parkinsonism and secondary parkinsonism. Preferably, said drug induced parkinsonism is selected from the group consisting of parkinsonism induced by one or more of the following: neuroleptics, antipsychotics, lithium, metoclopramide, MDMA, tetrabenazine. Preferably, said secondary parkinsonism is selected from the group consisting of: malignant neuroleptic syndrome; drug- induced secondary parkinsonism, secondary parkinsonism due to other external agents; post- encephalitic parkinsonism; vascular parkinsonism; syphilitic parkinsonism.

[0064] As used herein, the term“Parkinson’s disease” refers to a clinical/pathological condition (e.g., clinical situation) characterized by (e.g., consisting of) the following symptoms: tremor, bradykinesia, rigidity, postural instability and cognitive impairment. Preferably, said Parkinson’s disease comprises one or more of the following: Parkinsonism, Hemiparkinsonism; Paralysis agitans; idiopathic Parkinson’s disease; primary Parkinson’s disease, Parkinson's disease dementia.

[0065] As used herein, the term “Parkinson-plus syndrome” refers to a clinical/pathological condition (e.g., clinical situation) characterized by the following symptoms: tremor, bradykinesia, rigidity, postural instability with additional symptoms that distinguish it from Parkinson's disease. Preferably, said Parkinson-plus syndrome is selected from the group consisting of: atypical parkinsonism; multiple system atrophy (MSA); progressive supranuclear palsy (PSP); corticobasal degeneration (CBD); dementia with Lewy bodies (DLB); Pick's disease; olivopontocerebellar atrophy.

[0066] The term“polypeptide” is equally used herein with the term "protein". Proteins (including fragments thereof, preferably biologically active fragments, and peptides, usually having less than 30 amino acids) comprise one or more amino acids coupled to each other via a covalent peptide bond (resulting in a chain of amino acids). The term "polypeptide" as used herein describes a group of molecules, which, for example, consist of more than 30 amino acids. Polypeptides may further form multimers such as dimers, trimers and higher oligomers, i.e. consisting of more than one polypeptide molecule. Polypeptide molecules forming such dimers, trimers etc. may be identical or non-identical. The corresponding higher order structures of such multimers are, consequently, termed homo- or heterodimers, homo- or heterotrimers etc. The terms "polypeptide" and "protein" also refer to naturally modified polypeptides/proteins wherein the modification is effected e.g. by post-translational modifications like glycosylation, acetylation, phosphorylation and the like. Such modifications are well known in the art.

[0067] The term "amino acid" or "amino acid residue" typically refers to an amino acid having its art recognized definition such as an amino acid selected from the group consisting of: alanine (Ala or A); arginine (Arg or R); asparagine (Asn or N); aspartic acid (Asp or D); cysteine (Cys or C); glutamine (Gin or Q); glutamic acid (Glu or E); glycine (Gly or G); histidine (His or H); isoleucine (He or I): leucine (Leu or L); lysine (Lys or K); methionine (Met or M); phenylalanine (Phe or F); proline (Pro or P); serine (Ser or S); threonine (Thr or T); tryptophan (Trp or W); tyrosine (Tyr or Y); and valine (Val or V), although modified, synthetic, or rare amino acids may be used as desired. Generally, amino acids can be grouped as having a nonpolar side chain (e.g., Ala, Cys, He, Leu, Met, Phe, Pro, Val); a negatively charged side chain (e.g., Asp, Glu); a positively charged sidechain (e.g., Arg, His, Lys); or an uncharged polar side chain (e.g., Asn, Cys, Gin, Gly, His, Met, Phe, Ser, Thr, Trp, and Tyr).

[0068] The term "position" when used in accordance with the present invention means the position of an amino acid within an amino acid sequence depicted herein.

[0069] The term“substitution” means replacement of the amino acid occupying a position with a different amino acid or termination signal. For example, for an amino acid substitution, the following nomenclature is used: original amino acid, position, substituted amino acid. Accordingly, for example, the substitution of arginine at position 275 with tryptophan is designated as "Arg275Trp" or "R275W".

[0070] The term "subject" is intended to include living organisms. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In preferred embodiments of the invention, the subject is a human.

[0071] Those "in need of treatment" include those already with the disorder, as well as those in which the disorder is to be prevented.

[0072] Embodiments

[0073] In some aspects, the present invention relates to a cyclodextrin compound, wherein said cyclodextrin compound is 2-hydroxypropyl^-cyclodextrin (HR-b-CD, e.g., wherein said HR-b- CD is a derivative of beta-cyclodextrin (e.g., a soluble derivative), preferably said HR-b-CD is of

the general formula

wherein R is hydrogen (-H) or 2-hydroxypropyl (-CH₂-

CHOH-CH₃) group).

[0074] In some aspects, the present invention relates to an isomer or derivative of 2- hydroxypropyl^-cyclodextrin or a mixture of isomers or derivative thereof (e.g., an isomer or derivative with various degrees and/or pattern of hydroxypropylation), wherein said isomer or derivative or mixture thereof is characterized by a degree of substitution (DS) in the range from about 2 to about 10, wherein said DS is the average number of substituents on a cyclodextrin molecule (e.g., of formula I), preferably said DS is in the range from about 3 to about 8, further preferably said DS is in the range from about 4 to about 7, most preferably said DS is in the range from about 5 to about 6.

[0075] In some aspects, the present invention relates to an isomer or derivative of 2- hydroxypropyl^-cyclodextrin or a mixture of isomers or derivatives thereof (e.g., an isomer or derivative with various degrees and/or pattern of hydroxypropylation), wherein said isomer or derivative or mixture thereof is characterized by the presence of the major isomer having a degree of substitution (DS) of 6.

[0076] In some aspects, the present invention relates to an isomer or derivative of 2- hydroxypropyl^-cyclodextrin or a mixture of isomers or derivatives thereof (e.g., an isomer or derivative with various degrees and/or pattern of hydroxypropylation), wherein a degree of substitution (DS) is determinable by one or more of the following methods: nuclear magnetic resonance (NMR), mass spectrometry (MS), differential scanning calorimetry, microcalorimetric titration, near infrared reflectance spectroscopy.

[0077] In some aspects, the present invention relates to an isomer or derivative of 2- hydroxypropyl-3-cyclodextrin or a mixture of isomers or derivatives thereof (e.g., with various degrees and/or pattern of hydroxypropylation),

[0078] In some aspects, the present invention relates to a derivative of 2-hydroxypropyl-3- cyclodextrin (e.g., an oligomeric derivative of 2-hydroxypropyl- -cyclodextrin, e.g., monomeric and/or homo-oligomeric and/or hetero-oligomeric derivative of 2-hydroxypropyl-3-cyclodextrin) or a mixture of derivatives thereof, preferably said mixture comprising: monomeric and/or homo- and/or hetero-dimeric form of derivative of 2-hydroxypropyl- -cyclodextrin.

[0079] In some aspects, the present invention relates to a pharmaceutically acceptable salt of 2-hydroxypropyl- -cyclodextrin or a mixture of pharmaceutically acceptable salts thereof.

[0080] In some aspects, the present invention relates to a complex of 2-hydroxypropyl^- cyclodextrin (e.g., with a pharmaceutically acceptable complexing agent, e.g., glycyrrhizic acid) or a mixture of complexes thereof.

[0081] In some aspects, the present invention relates to 2-hydroxypropyl^-cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof for use in one or more of the following methods for affecting (e.g., improving) the condition (e.g., pathological condition) or function of dopaminergic neurons (e.g., any pathological condition susceptible of being improved or prevented by said affecting of dopaminergic neurons, e.g., said condition is associated with reduced dopaminergic neuron function in the subject (e.g., human), preferably said condition is not Niemann Pick disease (e.g., Niemann-Pick Disease type C1 ), Alzheimer's disease or cancer: (i) method for increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (ii) method for modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (iii) method for reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (iv) method for increasing survival of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (v) method for modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (vi) method for modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (vii) any method of (i)-(vi), wherein said dopaminergic neurons are tyrosine hydroxylase positive (i.e., TH⁺) dopaminergic neurons; preferably said tyrosine hydroxylase is the tyrosine 3- monooxygenase having UniProtKB Accession Number: P07101 ; (viii) any method of (i)-(vii), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra, most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject (e.g., human) diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome.

[0082] In some aspects, the present invention relates to 2-hydroxypropyl^-cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof for use in one or more of the methods as described herein, wherein said use is not the use as one or more of the following: (i) an excipient; (ii) a solubilizer; (iii) a stabilizer; (iv) a vehicle (e.g., a delivery vehicle); or (v) carrier (e.g., carrier for L-DOPA).

[0083] In some aspects, the present invention relates to 2-hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof having a biological and/or pharmacological activity (e.g., 2-hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof is an active pharmaceutical agent). [0084] In some aspects, the present invention relates to an isolated dopaminergic neuron or an isolated precursor cell thereof exposed to 2-hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, preferably said isolated dopaminergic neuron is obtainable from human induced pluripotent stem cells (hiPSCs) or human neuroepithelial stem cells (NESCs), further preferably said precursor cell is selected from the group consisting of: human induced pluripotent stem cells (hiPSCs) and human neuroepithelial stem cells (NESCs), wherein said hiPSCs and NESCs are obtainable without destruction of human embryos, most preferably said hiPSCs and NESCs are obtainable from somatic fibroblasts.

[0085] In some aspects, the present invention relates to an isolated dopaminergic neuron or an isolated precursor cell thereof exposed to 2-hydroxypropyl-3-cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, for use in one or more of the following methods for affecting (e.g., improving) the condition (e.g., pathological condition) or function of dopaminergic neurons (e.g., any pathological condition susceptible of being improved or prevented by said affecting of dopaminergic neurons, e.g., said condition is associated with reduced dopaminergic neuron function in the subject (e.g., human)): (i) method for increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (ii) method for modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease,

Parkinsonism and Parkinson-plus syndrome; (iii) method for reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (iv) method for increasing survival of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (v) method for modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease,

Parkinsonism and Parkinson-plus syndrome; (vi) method for modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (vii) any method of (i)-(vi), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons; preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ; (viii) any method of (i)-(vii), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra ; most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject (e.g., human) diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome.

[0086] In some aspects, the present invention relates to 2-hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or an isolated dopaminergic neuron or precursor cell thereof, for use in one or more of the methods as described herein, wherein said method is a method of treatment, amelioration, prophylaxis or diagnostics of a parkinsonian condition, wherein said parkinsonian condition is selected from the group consisting of: Parkinson’s disease; Parkinsonism; Parkinson-plus syndrome.

[0087] In some aspects, the present invention relates to a composition or kit comprising 2- hydroxypropyl^-cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or an isolated dopaminergic neuron or precursor cell thereof as described herein.

[0088] In some aspects, the present invention relates to a composition or kit as described herein, for use in one or more of the following methods for affecting (e.g., improving) the condition (e.g., pathological condition) or function of dopaminergic neurons (e.g., any pathological condition susceptible of being improved or prevented by said affecting of dopaminergic neurons, e.g., said condition is associated with reduced dopaminergic neuron function in the subject (e.g., human)): (i) method for increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (ii) method for modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (iii) method for reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (iv) method for increasing survival of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (v) method for modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (vi) method for modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (vii) any method of (i)-(vi), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons; preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ; (viii) any method of (i)-(vii), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject (e.g., human) diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson's disease, Parkinsonism and Parkinson-plus syndrome.

[0089] In some aspects, the present invention relates to the composition or kit as described herein, wherein said composition or kit is a pharmaceutical or diagnostic composition or kit.

[0090] In some aspects, the present invention relates to the composition or kit as described herein, wherein the concentration of 2-hydroxypropyl-p-cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof in said composition or kit is in the range from about 10nM to about 100pM, preferably in the range from about 100nM to about 200nM.

[0091] In some aspects, the present invention relates to the composition or kit as described herein, wherein the concentration of 2-hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof in said composition or kit is in the range from about 100 mg to about 2000 mg (e.g., from about 100 mg to about 1800 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 g to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 100 mg to about 200 mg).

[0092] In some aspects, the cyclodextrin of the present invention is administered to a subject at a dose of about 2500 mg/kg bi-weekly (about 700 mg/kg/d), the same dose used for HR-b- cyclodextrin in two children with NPC for over a year, with no discemable side effects for a targeted concentration of 0.1 -1 .0 mM. In other aspects, the dose will be adjusted over time to the highest dose not causing renal or hemolysis in the patient.

[0093] In some aspects, the cyclodextrin of the present invention is administered to a subject at a dose of at least 100 mg, at least 200 mg, at least 500 mg, at least 1000 mg, at least 2000 mg, at least 5000 mg, or at least 10,000 mg.

[0094] In some aspects, cyclodextrin of the present invention is administered to the subject at a dose in the range of from about 1 to about 10,000 mg, from about 1 to about 7,500 mg, from about 1 to about 5,000 mg, from about 1 to about 2,500 mg, from about 1 to about 1 ,000 mg, from about 1 to about 500 mg, from about 1 to about 200 mg, from about 200 to about 10,000 mg, from about 200 to about 4,000 mg, from about 200 mg to about 2,000 mg, from about 200 to about 1 ,000 mg, or from about 200 to about 500 mg per day. In some such aspects, each of the dosages described above is mg/kg/day.

[0095] In some aspects, the present invention relates to the composition or kit as described herein, further comprising a pharmaceutically acceptable carrier and/or an antiparkinsonian agent, preferably said antiparkinsonian agent is one or more of the following: L-DOPA, Deprenyl, Apomorphine, an anticholinergic agent, further preferably said anticholinergic agent is selected from the group consisting of: benzhexol and orphenadrine.

[0096] In some aspects, the present invention relates to a method for affecting (e.g., improving) the condition (e.g., pathological condition) or function of dopaminergic neurons in a sample or subject (e.g., human) in need thereof (e.g., any pathological condition susceptible of being improved or prevented by said affecting of dopaminergic neurons, preferably said condition is not Niemann Pick disease (e.g., Niemann-Pick Disease type C1 ), Alzheimer's disease or cancer; wherein said affecting the condition of dopaminergic neurons comprising one or more of the following: (i) increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (ii) modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (iii) reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (iv) method for increasing survival of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (v) modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (vi) modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (vii) any one of (i)-(vi), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons; preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ; (viii) any one of (i)-(vii), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject (e.g., human) diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; said method for affecting (e.g., improving) the condition (e.g., pathological condition) or function of dopaminergic neurons comprising: (a) providing 2-hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the composition or kit, or the isolated dopaminergic neuron or precursor cell thereof, as described herein; to said sample or subject (e.g., human); (b) administering a therapeutically effective amount of 2- hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or composition or kit, or the isolated dopaminergic neuron or precursor cell thereof, as described herein; to said sample or subject (e.g., human).

[0097] In some aspects, the present invention relates to a method as described herein, wherein said therapeutically effective amount of 2-hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof is in the range from about 100 mg to about 2000 mg (e.g., from about 100 mg to about 1800 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 100 mg to about 200 mg).

[0098] In some aspects, the present invention relates to a method for producing an isolated dopaminergic neuron or an isolated precursor cell thereof (e.g., as described herein), said method comprising: (i) providing: (a) 2-hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the composition or kit (e.g., as described herein); (b) an isolated dopaminergic neuron or a precursor cell thereof (e.g., as described herein); (ii) adding an effective amount of (a) to (b), preferably said adding is carried out to a final concentration of (a) in the range from about 10nM to about 100pM, further preferably in the range from about 100nM to about 200nM.

[0099] In some aspects, the present invention relates to a method for producing an isolated dopaminergic neuron or an isolated precursor cell thereof as described herein, wherein said effective amount of said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof is in the range from about 100 mg to about 2000 mg (e.g., from about 100 mg to about 1800 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 100 mg to about 200 mg).

[00100] In some aspects, the present invention relates to a use of 2-hydroxypropyl^- cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the composition or kit, or the isolated dopaminergic neuron or precursor cell thereof, as described herein, for affecting (e.g., improving) the condition (e.g., pathological condition) or function of dopaminergic neurons in one or more of the following ways: (i) for increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (ii) for modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (iii) for reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (iv) for increasing survival of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (v) for modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (vi) for modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; (vii) for any use of (i)-(vi), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons; preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ; (viii) for any use of (i)-(vii), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject (e.g., human) diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome.

[00101] In some aspects, the present invention relates to a method or use of 2- hydroxypropyl^-cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the composition or kit, or the isolated dopaminergic neuron or precursor cell thereof, as described herein, wherein a final concentration of 2-hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, in said method or use is: (i) in the range from about 10nM to about 100pM, further preferably in the range from about 100nM to about 200nM; or (ii) in the range from about 100 mg to about 2000 mg (e.g., from about 100 mg to about 1800 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 100 mg to about 200 mg).

[00102] In some aspects, the present invention relates to a method or use of 2- hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the composition or kit, or the isolated dopaminergic neuron or precursor cell thereof, as described herein, wherein said method or use is an in vitro, ex vivo or in vivo method or use.

[00103] In some aspects, the present invention relates to 2-hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, as described herein, wherein said parkinsonian condition is characterized (e.g., caused) by a dysregulation (e.g., malfunction) of one or more of the following proteins (or variants thereof, e.g., isomeric (e.g., splice forms thereof) and/or processed forms (e.g., mature forms) thereof,): PTEN-induced putative kinase 1 (PINK1 ) (e.g., having EC: 2.7.1 1.1 activity, e.g., UniProtKB Accession Number: Q9BXM7); Parkin RBR E3 ubiquitin protein ligase (PRKN or PARK2) (e.g., having EC:2.3.2.31 activity, e.g., UniProtKB Accession Number: 060260); Synuclein alpha (SNCA) (e.g., UniProtKB Accession Number: P37840); Parkinson protein 7 (PARK7/DJ-1 ) (e.g., UniProtKB Accession Number: Q99497); Leucine-rich repeat kinase 2 (LRRK2) (e.g., UniProtKB Accession Number: Q5S007); Phospholipase A2, group VI (PLA2G6) (e.g., UniProtKB Accession Number: 060733); F-box protein 7 (FBX07) (e.g., UniProtKB Accession Number: Q9Y3I1 ); Vacuolar protein sorting 35 homolog (VPS35) (e.g., UniProtKB Accession Number: Q96QK1 ); ATPase type 13A2 (ATP13A2) (e.g., UniProtKB Accession Number: Q9NQ11 ); DnaJ (Hsp40) homolog, subfamily C, member 6 (DNAJC6) (e.g., UniProtKB Accession Number: 075061 ); Synaptojanin 1 (SYNJ1 ) (e.g., UniProtKB Accession Number: 043426); Glucosidase, beta, acid (GBA) (e.g., UniProtKB Accession Number: P04062); Ataxin- 2 (e.g., UniProtKB Accession Number: Q99700); Ataxin-3 (e.g., UniProtKB Accession Number: P54252); GTP cyclohydrolase 1 (e.g., UniProtKB Accession Number: P30793); Granulins (e.g., UniProtKB Accession Number: P28799); Microtubule-associated protein tau (e.g., UniProtKB Accession Number: P10636); Guanine nucleotide exchange C9orf72 (e.g., UniProtKB Accession Number: Q96LT7); Macrophage colony-stimulating factor 1 receptor (e.g., UniProtKB Accession Number: P07333); Negative elongation factor C/D (e.g., UniProtKB Accession Number: Q8IXH7); Neural cell adhesion molecule L1 (e.g., UniProtKB Accession Number: P32004); Ras-related protein Rab-39 (e.g., UniProtKB Accession Number: Q96DA2).

[00104] In some aspects, the present invention relates to 2-hydroxypropyl^-cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, as described herein, wherein said parkinsonian condition is characterized (e.g., caused) by the presence of one or more of the following mutations in one or more of the following proteins: (i) LRRK2 (e.g., UniProtKB Accession Number: Q5S007) comprising one or more of the following point mutations: R1 14C, R1441G, R1441 H, Y1699C, G2019S and I2020T; (ii) SNCA (e.g., UniProtKB Accession Number: P37840) comprising one or more of the following point mutations: A18T, A29S, A30P, E46K, H50Q, G51 D and A53T; (ii) DJ-1 (e.g., UniProtKB Accession Number: Q99497) comprising one or more of the following point mutations: M26I, E64D, D149A and L166P.

[00105] In some aspects, the present invention relates to 2-hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, as described herein, wherein said parkinsonian condition is characterized (e.g., caused) by the presence of one or more of the following: (i) one or more mutations (e.g., causative mutations, e.g., homozygous or heterozygous point mutation, preferably homozygous point mutation) in a mitochondrial serine/threonine-protein kinase (e.g., in PTEN-INDUCED PUTATIVE KINASE 1 or PINK1 , e.g., having EC: 2.7.11.1 activity); preferably said one or more mutations is one or more loss of function mutations (e.g., a following point mutation of PINK1 : Q456X or Q456^* or Gln456Ter, i.e., a substitution of glutamine (Gin or Q) at position 456 resulting in termination signal (ter)); and/or at least I368N point mutation (i.e., a substitution of isoleucine (lie or I) at position 368 to asparagine (Asn or N)); further preferably said PINK1 having SEQ ID NO: 1 (or UniProtKB Accession Number: Q9BXM7); most preferably said PINK1 having SEQ ID NO: 1 (or UniProtKB Accession Number: Q9BXM7) and comprises at least Q456X and/or I368N mutation; (ii) one or more mutation (e.g., causative mutations, e.g., homozygous or heterozygous point mutation, preferably homozygous point mutation) in a E3 ubiquitin-protein ligase parkin (PRKN); preferably a R275W point mutation (i.e., a substitution of arginine (Arg or R) at position 275 to tryptophan (Trp or W)); further preferably said PRKN having SEQ ID NO: 2 (or UniProtKB Accession Number: 060260); most preferably said PRKN having SEQ ID NO: 2 (or UniProtKB Accession Number: 060260) and comprises at least R275W mutation.

[00106] In some aspects, the present invention relates to 2-hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, as described herein, for use in: (i) increasing (e.g., said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use is capable of increasing) locomotor activity; and/or (ii) improving (e.g., said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use is capable of improving); of emotional state in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome.

[00107] In some aspects, the present invention relates to 2-hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, as described herein, wherein said Parkinson’s disease refers to one or more of the following:

Parkinsonism, Hemiparkinsonism; Paralysis agitans; idiopathic Parkinson’s disease; primary Parkinson’s disease, Parkinson's disease dementia.

[00108] In some aspects, the present invention relates to 2-hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, as described herein, wherein said Parkinsonism refers to one or more of the following: drug induced parkinsonism, toxin induced parkinsonism and secondary parkinsonism. Preferably, said drug induced parkinsonism is selected from the group consisting of parkinsonism induced by one or more of the following: neuroleptics, antipsychotics, lithium, metoclopramide, MDMA, tetrabenazine. Preferably, said secondary parkinsonism is selected from the group consisting of: malignant neuroleptic syndrome; drug-induced secondary parkinsonism, secondary parkinsonism due to other external agents; post-encephalitic parkinsonism; vascular parkinsonism; syphilitic parkinsonism.

[00109] In some aspects, the present invention relates to 2-hydroxypropyl- -cyclodextrin, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, as described herein, wherein said Parkinson-plus syndrome refers to one or more of the following: atypical parkinsonism; multiple system atrophy (MSA); progressive supranuclear palsy (PSP); corticobasal degeneration (CBD); dementia with Lewy bodies (DLB); Pick's disease; olivopontocerebellar atrophy.

[00110] In some aspects, the present invention relates to articles of manufacture and kits containing the compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition as described herein, which can be used, for instance, for the therapeutic or non- therapeutic applications described above. The article of manufacture comprises a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which includes an active agent that is effective for therapeutic or non-therapeutic applications, such as described above. The active agent in the composition is the compound for use of the present invention. The label on the container indicates that the composition is used for a specific therapy or non-therapeutic application and may also indicate directions for either in vivo or in vitro use, such as those described above.

[00111] The kit of the present invention will typically comprise the container described above and one or more other containers comprising materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.

[00112] The invention is also characterized by the following items:

1. A cyclodextrin compound, wherein said cyclodextrin compound is 2-hydroxypropyl-3- cyclodextrin (HR-b-CD, e.g., wherein said HR-b-CD is a derivative of beta-cyclodextrin (e.g., a soluble derivative), preferably said HR-b-CD is of the general formula I:

wherein R is hydrogen (-H) or 2-hydroxypropyl (-CH₂-CHOH-CH₃) group); an isomer of said cyclodextrin compound or a mixture of isomers thereof (e.g., with various degrees and/or pattern of hydroxypropylation); a derivative of said cyclodextrin compound (e.g., an oligomer of said cyclodextrin compound, e.g., monomer and/or homo-oligomer and/or hetero-oligomer) or a mixture of derivatives thereof, preferably said mixture comprising: monomeric and/or homo- and/or hetero-dimeric form of said compound; a pharmaceutically acceptable salt of said cyclodextrin compound or a mixture of pharmaceutically acceptable salts thereof; or a complex of said cyclodextrin compound (e.g., with a pharmaceutically acceptable complexing agent, e.g., glycyrrhizic acid) or a mixture of complexes thereof; for use in one or more of the following methods for affecting (e.g., improving) the condition (e.g., pathological condition) or function of dopaminergic neurons (e.g., any pathological condition susceptible of being improved or prevented by said affecting of dopaminergic neurons, e.g., said condition is associated with reduced dopaminergic neuron function in the subject (e.g., human)), preferably said condition is not Niemann Pick disease (e.g., Niemann-Pick Disease type C1 ), Alzheimer's disease or cancer: i) method for increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; ii) method for modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iii) method for reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iv) method for increasing survival of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; v) method for modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vi) method for modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vii) any one of (i)-(vi), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons (e.g., having EC: 1.14.16.2 activity); preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ; viii) any one of (i)-(vii), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra ; most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject (e.g., human) diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome. The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof for use according to item 1 , wherein said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof has a biological and/or pharmacological activity (e.g., said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof is an active pharmaceutical agent). The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof for use according to any one of the preceding items, wherein said use in one or more methods for affecting (e.g., improving) the condition (e.g., pathological condition) or function of dopaminergic neurons (e.g., any pathological condition susceptible of being improved or prevented by said affecting of dopaminergic neurons, e.g., said condition is associated with reduced dopaminergic neuron function in the subject (e.g., human)) is not the use as one or more of the following: i) an excipient; ii) a solubilizer; iii) a stabilizer; iv) a vehicle (e.g., a delivery vehicle); or v) carrier (e.g., carrier for L-DOPA). The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof for use according to any one of the preceding items, wherein said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof is characterized by a degree of substitution (DS) in the range from about 2 to about 10, wherein said DS is the average number of substituents on a cyclodextrin molecule (e.g., of formula I), preferably said DS is in the range from about 3 to about 8, further preferably said DS is in the range from about 4 to about 7, most preferably said DS is in the range from about 5 to about 6. The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof for use according to any one of the preceding items, wherein said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof is characterized by the presence of the major isomer having DS of 6. The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof for use according to any one of the preceding items, wherein said degree of substitution (DS) is determinable by one or more of the following methods: nuclear magnetic resonance (NMR), mass spectrometry (MS), differential scanning calorimetry, microcalorimetric titration, near infrared reflectance spectroscopy. An isolated dopaminergic neuron or an isolated precursor cell thereof exposed to the compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof according to any one of the preceding items, preferably said isolated dopaminergic neuron is obtainable from human induced pluripotent stem cells (hiPSCs) or human neuroepithelial stem cells (NESCs), further preferably said precursor cell is selected from the group consisting of: human induced pluripotent stem cells (hiPSCs) and human neuroepithelial stem cells (NESCs), wherein said hiPSCs and NESCs are obtainable without destruction of human embryos, most preferably said hiPSCs and NESCs are obtainable from somatic fibroblasts. The isolated dopaminergic neuron or precursor cell thereof according to item 7 for use in one or more of the following methods for affecting (e.g., improving) the condition (e.g., pathological condition) or function of dopaminergic neurons (e.g., any pathological condition susceptible of being improved or prevented by said affecting of dopaminergic neurons, e.g., said condition is associated with reduced dopaminergic neuron function in the subject (e.g., human)): i) method for increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; ii) method for modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iii) method for reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iv) method for increasing survival of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; v) method for modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vi) method for modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vii) any one of (i)-(vi), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons (e.g., having EC: 1.14.16.2 activity); preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ; viii) any one of (i)-(vii), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra, most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject (e.g., human) diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome. The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, according to any one of the preceding items, wherein said method is the method of treatment, amelioration, prophylaxis or diagnostics of a parkinsonian condition, wherein said parkinsonian condition is selected from the group consisting of: Parkinson’s disease; Parkinsonism; Parkinson-plus syndrome. A composition or kit comprising the compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, according to any one of the preceding items, for use in one or more of the following methods for affecting (e.g., improving) the condition (e.g., pathological condition) or function of dopaminergic neurons (e.g., any pathological condition susceptible of being improved or prevented by said affecting of dopaminergic neurons, e.g., said condition is associated with reduced dopaminergic neuron function in the subject (e.g., human)): i) method for increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; ii) method for modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iii) method for reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iv) method for increasing survival of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; v) method for modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vi) method for modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vii) any method of (i)-(vi), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons (e.g., having EC: 1.14.16.2 activity); preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ; viii) any method of (i)-(vii), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra\ most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject (e.g., human) diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome. The composition or kit for use according to item 10, wherein said composition or kit is a pharmaceutical or diagnostic composition or kit. The composition or kit for use according to items 10 or 1 1 , wherein the concentration of said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof in said composition or kit is in the range from about 10nM to about 100pM, preferably in the range from about 100nM to about 200nM. The composition or kit for use according to any one of items 10-12, wherein the concentration of said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof in said composition or kit is in the range from about 100 mg to about 2000 mg (e.g., from about 100 mg to about 1800 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 100 mg to about 200 mg). The pharmaceutical composition or kit for use according to any one of items 10-13, further comprising a pharmaceutically acceptable carrier and/or an antiparkinsonian agent, preferably said antiparkinsonian agent is one or more of the following: L-DOPA, Deprenyl, Apomorphine, an anticholinergic agent, further preferably said anticholinergic agent is selected from the group consisting of: benzhexol and orphenadrine. A method for affecting (e.g., improving) the condition (e.g., pathological condition) or function of dopaminergic neurons in a sample or subject (e.g., human) in need thereof (e.g., any pathological condition susceptible of being improved or prevented by said affecting of dopaminergic neurons, preferably said condition is not Niemann Pick disease (e.g., Niemann-Pick Disease type C1 ), Alzheimer's disease or cancer; wherein said affecting the condition of dopaminergic neurons comprising one or more of the following: i) increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; ii) modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iii) reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iv) method for increasing survival of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; v) modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vi) modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vii) any one of (i)-(vi), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons (e.g., having EC: 1.14.16.2 activity); preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ; viii) any one of (i)-(vii), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra ; most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject (e.g., human) diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome. said method for affecting (e.g., improving) the condition (e.g., pathological condition) or function of dopaminergic neurons comprising: a) providing the compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the composition or kit, or the isolated dopaminergic neuron or precursor cell thereof, according to any one of the preceding items; to said sample or subject (e.g., human); b) administering a therapeutically effective amount of said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or composition or kit, or the isolated dopaminergic neuron or precursor cell thereof, according to any one of the preceding items; to said sample or subject (e.g., human). The method according to item 15, wherein said therapeutically effective amount of said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof is in the range from about 100 g to about 2000 mg (e.g., from about 100 mg to about 1800 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 100 mg to about 200 mg). A method for producing the isolated dopaminergic neuron or an isolated precursor cell thereof (e.g., according to any one of the preceding items), said method comprising: i) providing: a) the compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the composition or kit, according to any one of the preceding items; b) an isolated dopaminergic neuron or a precursor cell thereof; ii) adding an effective amount of (a) to (b), preferably said adding is carried out to a final concentration of (a) in the range from about 10nM to about 100mM, further preferably in the range from about 100nM to about 200nM. The method for producing the isolated dopaminergic neuron or an isolated precursor cell thereof according to item 17, wherein said effective amount of said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof is in the range from about 100 mg to about 2000 mg (e.g., from about 100 mg to about 1800 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 100 mg to about 200 mg). Use of the compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the composition or kit, or the isolated dopaminergic neuron or precursor cell thereof, according to any one of the preceding items, for affecting (e.g., improving) the condition (e.g., pathological condition) or function of dopaminergic neurons in one or more of the following ways: i) for increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; ii) for modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iii) for reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iv) for increasing survival of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; v) for modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vi) for modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vii) for any one of (i)-(vi), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons (e.g., having EC: 1.14.16.2 activity); preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ; viii) for any one of (i)-(vii), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra ; most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject (e.g., human) diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome. The method or use according to any one of the preceding items, wherein a final concentration of the compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, according to any one of the preceding items in said method or use is: i) in the range from about 10nM to about 100mM, further preferably in the range from about 100nM to about 200nM; or ii) in the range from about 100 mg to about 2000 mg (e.g., from about 100 mg to about 1800 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 100 mg to about 200 mg). The method or use according to any one of the preceding items, wherein said method or use is an in vitro, ex vivo or in vivo method or use. The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, according to any one of the preceding items, wherein said parkinsonian condition is characterized (e.g., caused) by a dysregulation (e.g., malfunction) of one or more of the following proteins: i) PTEN-induced putative kinase 1 (PINK1 ) (e.g., having EC: 2.7.1 1.1 activity, e.g., UniProtKB Accession Number: Q9BXM7); ii) Parkin RBR E3 ubiquitin protein ligase (PRKN or PARK2) (e.g., having EC:2.3.2.31 activity, e.g., UniProtKB Accession Number: 060260); iii) Synuclein alpha (SNCA) (e.g., UniProtKB Accession Number: P37840); iv) Parkinson protein 7 (PARK7/DJ-1 ) (e.g., UniProtKB Accession Number: Q99497); v) Leucine-rich repeat kinase 2 (LRRK2) (e.g., UniProtKB Accession Number:

Q5S007); vi) Phospholipase A2, group VI (PLA2G6) (e.g., UniProtKB Accession Number:

060733); vii) F-box protein 7 (FBX07) (e.g., UniProtKB Accession Number: Q9Y3I1 ); viii) Vacuolar protein sorting 35 homolog (VPS35) (e.g., UniProtKB Accession Number:

Q96QK1 ); ix) ATPase type 13A2 (ATP13A2) (e.g., UniProtKB Accession Number: Q9NQ1 1 ); x) DnaJ (Hsp40) homolog, subfamily C, member 6 (DNAJC6) (e.g., UniProtKB Accession Number: 075061 ); xi) Synaptojanin 1 (SYNJ1 ) (e.g., UniProtKB Accession Number: 043426); xii) Glucosidase, beta, acid (GBA) (e.g., UniProtKB Accession Number: P04062); xiii) Ataxin-2 (e.g., UniProtKB Accession Number: Q99700); xiv) Ataxin-3 (e.g., UniProtKB Accession Number: P54252); xv) GTP cyclohydrolase 1 (e.g., UniProtKB Accession Number: P30793); xvi) Granulins (e.g., UniProtKB Accession Number: P28799); xvii) Microtubule-associated protein tau (e.g., UniProtKB Accession Number: P10636); xviii) Guanine nucleotide exchange C9orf72 (e.g., UniProtKB Accession Number:

Q96LT7); xix) Macrophage colony-stimulating factor 1 receptor (e.g., UniProtKB Accession Number: P07333); xx) Negative elongation factor C/D (e.g., UniProtKB Accession Number: Q8IXH7); xxi) Neural cell adhesion molecule L1 (e.g., UniProtKB Accession Number: P32004); xxii) Ras-related protein Rab-39 (e.g., UniProtKB Accession Number: Q96DA2). The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, according to any one of the preceding items, wherein said parkinsonian condition is characterized (e.g., caused) by the presence of one or more of the following mutations in one or more of the following proteins: i) LRRK2 (e.g., UniProtKB Accession Number: Q5S007) comprising one or more of the following point mutations or substitutions: R1 14C, R1441 G, R1441 H, Y1699C, G2019S and I2020T; ii) SNCA (e.g., UniProtKB Accession Number: P37840) comprising one or more of the following point mutations or substitutions: A18T, A29S, A30P, E46K, H50Q, G51 D and A53T; iii) DJ-1 (e.g., UniProtKB Accession Number: Q99497) comprising one or more of the following point mutations or substitutions: M26I, E64D, D149A and L166P. The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, according to any one of the preceding items, wherein said parkinsonian condition is characterized (e.g., caused) by the presence of one or more of the following: i) one or more mutations (e.g., causative mutations, e.g., homozygous or heterozygous point mutation, preferably homozygous point mutation) in a mitochondrial serine/threonine-protein kinase (e.g., having EC: 2.7.1 1 .1 activity, e.g., in PTEN-INDUCED PUTATIVE KINASE 1 or PINK1 ); preferably said one or more mutations is one or more loss of function mutations or substitutions (e.g., a following point mutation or substitution of PINK1 : Q456X or Q456* or Gln456Ter, i.e., a substitution of glutamine (Gin or Q) at position 456 resulting in termination signal (ter)); and/or at least I368N point mutation or substitution (i.e., a substitution of isoleucine (lie or I) at position 368 to asparagine (Asn or N)); further preferably said PINK1 having SEQ ID NO: 1 (or UniProtKB Accession Number: Q9BXM7); most preferably said PINK1 having SEQ ID NO: 1 (or UniProtKB Accession Number: Q9BXM7) and comprises at least Q456X and/or I368N mutation; ii) one or more mutation (e.g., causative mutations, e.g., homozygous or heterozygous point mutation, preferably homozygous point mutation) in a E3 ubiquitin-protein ligase parkin (PRKN); preferably a R275W point mutation or substitution (i.e., a substitution of arginine (Arg or R) at position 275 to tryptophan (Trp or W)); further preferably said PRKN having SEQ ID NO: 2 (or UniProtKB Accession Number: 060260); most preferably said PRKN having SEQ ID NO: 2 (or UniProtKB Accession Number: 060260) and comprises at least R275W mutation. The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, according to any one of the preceding items, for use in i) increasing (e.g., said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use is capable of increasing) locomotor activity; and/or ii) improving (e.g., said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use is capable of improving) of emotional state in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome. The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, according to any one of the preceding items, wherein said Parkinson's disease is selected from the group consisting of: Hemiparkinsonism; Paralysis agitans; idiopathic Parkinson’s disease; primary Parkinson’s disease, Parkinson's disease dementia. The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, according to any one of the preceding items, wherein said Parkinsonism is selected from the group consisting of: drug induced parkinsonism, toxin induced parkinsonism and secondary parkinsonism; preferably said drug induced parkinsonism is induced by one or more of the following: neuroleptics, antipsychotics, lithium, metoclopramide, MDMA, tetrabenazine; further preferably said secondary parkinsonism is selected from the group consisting of: malignant neuroleptic syndrome; drug-induced secondary parkinsonism, secondary parkinsonism due to other external agents; post-encephalitic parkinsonism; vascular parkinsonism; syphilitic parkinsonism. The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, according to any one of the preceding items, wherein said Parkinson-plus syndrome is selected from the group consisting of: atypical parkinsonism; multiple system atrophy (MSA); progressive supranuclear palsy (PSP); corticobasal degeneration (CBD); dementia with Lewy bodies (DLB); Pick's disease; olivopontocerebellar atrophy. The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, according to any one of the preceding items, wherein said affecting (e.g., improving) the condition of dopaminergic neurons is characterized by at least 5% (e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%) of one or more of the following: i) increasing of the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; ii) increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson's disease, Parkinsonism and Parkinson-plus syndrome; iii) reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iv) increasing survival of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; v) increasing of a total volume and/or number and/or size of mitochondria of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vi) increasing the amount of mitophagy events in dopaminergic neurons and/or increasing the total volume of mitophagy in dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vii) any one of (i)-(vi), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons; preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ; viii) any one of (i)-(vii), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra\ most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome.

Examples of the invention

[00113] In order that the invention may be readily understood and put into practical effect, some aspects of the invention are described by way of the following non-limiting examples.

[00114] Supplementary methods:

[00115] hiPSCs culture, NESCs derivation, neurons differentiation:

Human iPSCs were cultured in Matrigel (Corning, 354277) coated plates using Essential 8 (E8) medium (Thermo Fisher, A1517001 ) under 5% C0₂ in air mixture. Passages were performed using Accutase (Sigma, A6964) depending on confluency and plated in the same conditions supplemented overnight with 10mM ROCK inhibitor Y-27632 (Merck Milipore, 688000). Human NESCs were generated as described elsewhere (e.g., Reinhardt et al., 2013) and maintained with N2B27 media supplemented with 3mM CHIR-99021 (Axon Medchem, CT 99021 ), 0.75mM purmorphamine (PMA, Enzo Life Science, ALX-420-045-M005) and 150mM ascorbic acid (Sigma, A4544) (e.g., Monzel et al., 2017). Neuronal differentiation was induced by culturing NESCs in N2B27 supplemented with 10 ng/ml hBDNF (Peprotech, 450-02), 10 ng/ml hGDNF (Peprotech, 450-10), 500 mM dbcAMP (Sigma, D0627), 200 mM ascorbic acid, 1 ng/ml TGF-33 (Peprotech, 100-36E), and 1 mM PMA for 6 days. Afterwards, the same media without PMA was used for the duration of the correspondent experiment. Media changes during differentiation were done every third day. For imaging experiments, cells were seeded in a Cell Carrier Ultra (PerkinElmer, 6055300) 96 well plate.

[00116] Immunocytochemistry:

Fixation was done using 4% PFA in 1xPBS, pH 7.4, for 15min at RT. After 3x 1xPBS washing steps, cells were permeabilized using 0.5% Triton-X100 in 1xPBS for 15 min at RT. Blocking was performed by incubating cells in 5% Normal Goat Serum (Thermo Fisher, 10000C), and 0.1 % Tween20 in 1xPBS (blocking buffer) for 1 hour at RT. Incubation with the first antibodies was done overnight at 4°C in blocking buffer. Incubation with the secondary antibodies was done after 3x 1xPBS washing steps, for 2h at RT in blocking buffer with 1 :1000 Hoechst33342. Cells were washed 3x with 1xPBS, covered with 1xPBS and imaged directly after.

[00117] Rosella mitophagy reporter:

The pH sensor fluorescent protein pHluorin was fused to DsRed and the entire open reading frame of the mitochondrial sequence of ATP5C1 as described in (Sargsyan et al., 2015). The entire cassette was introduced into the AAVS1 safe-harbour locus as previously described using the targeting donor (Addgene 22075) and TALE nucleases (Addgene 35431 and 35432) as described in (Hockemeyer et al., 2009). In particular, the Rosella template used is based on that one published in Rosado et al. 2007 as shown in SEQ ID NO. 3. This sequence has a yeast mitochondrial targeting. This sequence was modified in the construct used with the ATP synthase subunit gamma (ATP5C1 ) full-length ORF minus the terminal stop codon which was joined in-frame to 5’ of the Rosella ORF (Sargsyan et al 2015).

Human iPSCs were electroporated with a Lonza 4D nucleofector system subunit X (Lonza, AAF-1002X) according to manufacturer instructions, using a P3 primary cells kit (Lonza, V4XP- 3024) and pulse CB-150.

[00118] Compound treatment:

Titration and evaluation of the compound treatment was performed using Cell Carrier Ultra plates seeding NESCs at a density of 30000 cells/well. Compounds were added and on every media change at a concentration of 10QnM and kept in culture throughout the entire differentiation process.

[00119] Image acquisition: Cell carrier Ultra plates were imaged in an automated manner using an OPERA QEHS spinning disk microscope (PerkinElmer). Depending on the experiment images were acquired with a 10x air objective (for Prescan and Differentiation efficiency) or a 63x water immersion objective (mitochondria morphology and mitophagy). Imaging of live cells (mitophagy assessment) was performed under normal incubation conditions (37°C, 80% humidity and 5% C02 in air). Both fluorescence (pHluorin and DsRed) were acquired at the same time using two cameras using bandpass filters (520/35 and 600/40 respectively). For 3D evaluation Z stacks were performed with an interval of 3.2 pm (acquisition of the entire height of the microfluidic chip) or 400nm for the images acquired with the 63x objective.

[00120] Mass Spectrometry:

Ion mobility - MS experiments were performed using an Agilent 6560 Ion Mobility - QTOF MS equipped with a Dual Agilent Jet Stream ESI source (Agilent Technologies). First, three stock solutions of 2-Hydroxpropyl-B-cyclodextrin (c = 1 mg/mL, Sigma, H107) were prepared in 1 M ammonium hydroxide solution. Then, samples were diluted in 50:50 (v/v) ACN:H2O+0.1 % formic acid to a final concentration of 10 pg/mL. Samples were directly infused into the ion source for 2 min using a flow rate of 200 pL/min. Nitrogen was used as drying gas at a temperature of 300 °C, a drying gas flow of 5 L/min, a sheath gas temperature of 350 °C, and a sheath gas flow rate of 11 L/min. The nebulizer gas pressure was set to 35 psig, the MS capillary voltage was 3.5 kV, the nozzle voltage was 1 kV, and the fragmentor was set to 400 V. Data was acquired in a mass range from m/z 100 to 3200. The Instrument was operated in IM- QTOF mode and tuned in high resolution mode (sheer position: 5) and Extended Dynamic Range (2GHz). Ions were trapped for 20,000 ps and released every 60 ms with a trap release time of 150 ps. The drift tube was operated with an absolute entrance voltage of 1700 V and an exit voltage of 250 V with a drift tube pressure of 3.94 Torr and a temperature of 31 °C using nitrogen as the collision gas. The acquisition settings were adjusted to yield 32 ion mobility transients/frame corresponding to 0.5 frames/sec. External mass calibration as well as Single Field Calibration was performed before measurement of each set of samples and according to the manufacture instructions. All data were acquired with Agilent Mass Hunter LC/MS Data Acquisition (version B.08.00) and analyzed with Agilent Mass Hunter IM-MS Browser (version B.08.00), where all acquisition frames were extracted from a total time frame of approx. 1.8 min.

[00121] Example 1 :

One of the hallmarks of PD is the loss of dopaminergic in the substantia nigra pars compacta, even though other regions have also been reported to be altered (Goedert et al., 2012; Poewe et al., 2017). To evaluate if these impaired functions could alter the differentiation potential of dopaminergic neurons, hiPSCs derived from 3 patients carrying a mutation in PINK1 (Q456X substitution in SEQ ID NO: 1 ) and 3 control (age and gender matched, Table 1 ) were further differentiated into a neuro-precursor state (neuroepithelial stem cells, NESCs) as a starting point in their transition into dopaminergic neurons (Fig. 1 ).

Table 1 : Overview of the samples used

An early time point of differentiation (14 days after initiation of differentiation) was selected for evaluating if patients’ cells present an impaired differentiation, ICH assessment was carried out by using a dopaminergic marker tyrosine hydroxylase (TH) in respect to a general neuronal marker (neuron-specific class III b-tubulin, Tuj1 ). An automated image analysis algorithm was developed for segmenting and quantifying the proportion of voxels (tridimensional pixels) having a colocalization of TH and Tuj1 , as well as for quantifying the nuclear volume (Fig. 2). While having the same differentiation into neurons, patients’ derived NESCs have a reduced tendency of developing TH+ neurons (Fig. 3). Serial time points (7, 14 and 21 days of differentiation) were used to complement these results and a reduced differentiation capacity of patient derived cells was observed across the different time points (Fig. 4).

[00122] Example 2:

In this example mitochondrial network status was evaluated due to the close relation between PINK1 function and mitochondrial homeostasis (Pickrell et al., 2015). Morphological assessment of mitochondria was carried in different cell types (NESCs and neurons, Figs. 5-7) and features denoting their volume, shape and degree of ramification were extracted with an automated algorithm for pattern recognition, allowing the evaluation of the fission/fusion status of the network (Fig. 5). In the case of NESCs, the total mitochondrial volume as well as mitochondrion count per nuclei unit are significantly increased in case of the patients (Fig. 6). More interestingly, the median size of the mitochondrion is higher in individuals carrying PINK1 mutations (Fig. 6). The same reduction of mitochondria area was observed in patient dopaminergic neurons (Fig. 7).

[00123] Example 3:

To further understand the mitochondrial dynamics in these cells stable patient (PINK1 , I368N) and control cell lines expressing the Rosella construct bound to ATP5C1 to evaluate mitochondrial degradation by mitophagy were generated (Figs. 8-9) (Sargsyan et al., 2015). These cells were generated at the hiPSCs levels and further differentiated into NESCs and subsequently to neurons. Through serial measurements the dynamic changes of the mitophagy activity during differentiation into neurons were analyzed observing that the amount of mitophagy events in patients' neurons was significantly reduced, but the mean area of the mitophagy event was bigger (Fig. 9). This can be explained by a lag in fission in the transition between NESCs and neurons in the early stages. PINK1 mutation influence in the mitophagy capacity described herein highlights the importance of an active PINK1 mitochondrial quality control, especially during the functional and morphological changes occurring during neuronal development.

[00124] Given the altered mitochondria morphology and activity, and the impaired mitophagy capacity in patient cells, the influence of the treatment with HIR-b-CD was further evaluated. Treatment with HIR-b-CD was able to increase the proportion of TH+ voxel over the total neuronal volume (Fig. 11 ). This significant increase was observed with a rise in the number of mitophagy events as well as with an increase in the total volume of mitophagy (Fig. 10). An improvement of several mitochondria and mitophagy properties were also observed after treatment with HR-b-CD in PD patient’s neurons (Fig. 13). To assess the effectiveness of FHP-b- CD in the context of another PD causing mutation, hiPSCs reprogrammed fibroblast from patient carrying a homozygous Parkin mutation (R275W) were further differentiated into NESCs and neurons, observing also a significant increase in dopaminergic neurons (Fig. 12). Specific finger print of the HR-b-CD mixture used (Figs. 14-16) was also determined, highlighting the importance of characterizing the complex composition of cyclodextrins for efficacy studies and clinical trials and for comparing treatment results between different neurodegenerative diseases (Yergey et al., 2017).

[00125] The data obtained in the course of the present invention suggest that a loss of function mutation in PINK1 normally involved in regulating mitochondria function and morphology by quarantining damaged mitochondria before their degradation as well as triggering the process of mitophagy, is relevant in the process of dopaminergic neurons differentiation. An altered mitochondria turnover, due to an imbalanced fission/fusion status of the network unable to separate the altered part of the mitochondria that needs to be degraded, and due to a reduced mitophagy activity during differentiation, was also observed in patient cells. These phenomena occurred simultaneously with an altered dopaminergic differentiation efficiency in patient cells. Treatment with HR-b-CD solved the dopaminergic neuronal loss phenotype observed in the context of PD causative mutations.

[00126] Example 4:

The effect of 2-hydroxypropyl-B-cyclodextrin has been tested in a more complex 3D culture, namely midbrain organoids, for modelling the onset of the disease in a more physiological state rather than regular 2D cultures. Organoids provide a minimal representation with spatial archi- tecture organization similar to the organ studied. To generate midbrain-specific organoids, hu- man neuroepithelial stem cells (hNESCs) were seeded per well in an ultra-low adhesion 96-well round bottom plate at 3,000 cells per well and kept under normal maintenance conditions for 7 days. To induce differentiation of the hNESCs, cells were subjected to differentiation media and kept under static culture conditions with media changes every third day for 30 days. Organoids were fixed, sectioned and stained following standard protocols. Nuclear staining (Floechst), neuronal marker (TUBB3, also called Tuj1 ) and dopaminergic neuron marker (TH) were used for extracting the necessary features to evaluate the effect of 2-hydroxypropyl-B-cyclodextrin treatment. An automated image analysis algorithm was used to extract the features analyzed. Quantification of the nuclei pixels belonging to live or dead cells were based on a higher signal intensity due to chromatin compaction of pyknotic nuclei (Fig. 17a). Quantification of dopamin- ergic differentiation efficiency was performed by stablishing a ratio between the neuronal mark- er (TUBB3, also called Tuj1 ) and the dopaminergic neuron marker (TH) masked values (Fig 17b). A reduction in cell death in patient organoids treated with 2-hydroxypropyl^-cyclodextrin was observed, as well as an increase in the differentiation efficiency to dopaminergic neurons.

References

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Claims

WHAT IS CLAIMED IS

1. A cyclodextrin compound, wherein said cyclodextrin compound is 2-hydroxypropyl^- cyclodextrin (HR-b-CD) of general formula I,

, wherein R is hydrogen (-H) or 2-hydroxypropyl (-CH₂-CHOH-CH₃) group; an isomer of said cyclodextrin compound or a mixture of isomers thereof; a derivative of said cyclodextrin compound or a mixture of derivatives thereof, preferably said mixture comprising: monomeric and/or homo- and/or heterodimeric form of said compound; a pharmaceutically acceptable salt of said cyclodextrin compound or a mixture of pharmaceutically acceptable salts thereof; or a complex of said cyclodextrin compound or a mixture of complexes thereof; for use in one or more of the following methods for improving the condition of dopaminergic neurons: i) method for increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; ii) method for modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iii) method for reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iv) method for modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; v) method for modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vi) any one of (i)-(v), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons; preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ; vii) any one of (i)-(vi), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra ; most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome.

2. The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof for use according to claim 1 , wherein said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof is characterized by a degree of substitution (DS) in the range from about 2 to about 10, wherein said DS is the average number of substituents on a cyclodextrin molecule of formula I, preferably said DS is in the range from about 3 to about 8, further preferably said DS is in the range from about 4 to about 7, most preferably said DS is in the range from about 5 to about 6.

3. An isolated dopaminergic neuron or an isolated precursor cell thereof exposed to the compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof according to claim 1 or 2, preferably said isolated dopaminergic neuron is obtainable from human induced pluripotent stem cells (hiPSCs) or human neuroepithelial stem cells (NESCs), further preferably said precursor cell is selected from the group consisting of: human induced pluripotent stem cells (hiPSCs) and human neuroepithelial stem cells (NESCs), wherein said hiPSCs and NESCs are obtainable without destruction of human embryos, most preferably said hiPSCs and NESCs are obtainable from somatic fibroblasts.

4. The isolated dopaminergic neuron or precursor cell thereof according to claim 3 for use in one or more of the following methods for improving the condition of dopaminergic neurons: i) method for increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; ii) method for modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iii) method for reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iv) method for modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; v) method for modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vi) any one of (i)-(v), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons; preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ; vii) any one of (i)-(vi), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra, most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome.

5. The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, according to any one of the preceding claims, wherein said method is the method of treatment, amelioration, prophylaxis or diagnostics of a parkinsonian condition, wherein said parkinsonian condition is selected from the group consisting of: Parkinson’s disease; Parkinsonism; Parkinson-plus syndrome.

6. A composition or kit comprising the compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, according to any one of the preceding claims, for use in one or more of the following methods for improving the condition of dopaminergic neurons: i) method for increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; ii) method for modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iii) method for reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iv) method for modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; v) method for modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vi) any method of (i)-(v), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons; preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ; vii) any method of (i)-(vi), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra\ most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome.

7. The composition or kit for use according to claim 6, wherein said composition or kit is a pharmaceutical or diagnostic composition or kit.

8. The composition or kit for use according to claim 6 or 7, wherein the concentration of said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof in said composition or kit is in the range from about 10nM to about 100mM, preferably in the range from about 100nM to about 200nM.

9. The pharmaceutical composition or kit for use according to any one of claims 6-8, further comprising a pharmaceutically acceptable carrier and/or an antiparkinsonian agent, preferably said antiparkinsonian agent is one or more of the following: L-DOPA, Deprenyl, Apomorphine, an anticholinergic agent, further preferably said anticholinergic agent is selected from the group consisting of: benzhexol and orphenadrine.

0. A method for improving the condition of dopaminergic neurons in a sample or subject in need thereof, wherein said improving the condition of dopaminergic neurons comprising one or more of the following: i) increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; ii) modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iii) reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iv) modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; v) modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; vi) any one of (i)-(v), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons; preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ; vii) any one of (i)-(vi), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra ; most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome. said method for improving the condition of dopaminergic neurons comprising: a) providing the compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the composition or kit, or the isolated dopaminergic neuron or precursor cell thereof, according to any one of the preceding claims; to said sample or subject; b) administering a therapeutically effective amount of said compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or composition or kit, or the isolated dopaminergic neuron or precursor cell thereof, according to any one of the preceding claims; to said sample or subject.

1 1. A method for producing the isolated dopaminergic neuron or an isolated precursor cell thereof according to any one of the preceding claims, said method comprising: i) providing: a) the compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the composition or kit, according to any one of the preceding claims; b) an isolated dopaminergic neuron or a precursor cell thereof; ii) adding an effective amount of (a) to (b), preferably said adding is carried out to a final concentration of (a) in the range from about 10nM to about 100mM, further preferably in the range from about 100nM to about 200nM.

12. Use of the compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the composition or kit, or the isolated dopaminergic neuron or precursor cell thereof, according to any one of the preceding claims, for improving the condition of dopaminergic neurons in one or more of the following ways: i) for increasing the number of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; ii) for modulating differentiation of dopaminergic neurons, preferably said differentiation is the differentiation of dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) or neuroepithelial stem cells (NESCs); further preferably said modulating is increasing of the differentiation efficiency of said dopaminergic neurons; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iii) for reducing cell death of dopaminergic neurons; preferably in a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome; iv) for modulating mitochondrial morphology and/or mitochondrial function and/or mitochondrial turnover of dopaminergic neurons, preferably said modulating of the mitochondrial morphology comprises changing of a total volume and/or number and/or size of mitochondria in said dopaminergic neurons, further preferably said changing is increasing; most preferably in a parkinsonian condition selected from the group consisting of: Parkinson's disease, Parkinsonism and Parkinson-plus syndrome; v) for modulating mitophagy of dopaminergic neurons, preferably said modulating is increasing the amount of mitophagy events in said dopaminergic neurons and/or increasing the total volume of mitophagy in said dopaminergic neurons; further preferably in a parkinsonian condition selected from the group consisting of: Parkinson's disease, Parkinsonism and Parkinson-plus syndrome; vi) for any one of (i)-(v), wherein said dopaminergic neurons are tyrosine hydroxylase positive (TH⁺) dopaminergic neurons; preferably said tyrosine hydroxylase is the tyrosine 3-monooxygenase having UniProtKB Accession Number: P07101 ; vii) for any one of (i)-(vi), wherein said dopaminergic neurons are obtainable from the mammalian midbrain region, preferably said midbrain region is a substantia nigra, further preferably said midbrain region is pars compacta portion of substantia nigra ; most preferably said dopaminergic neurons are obtainable from said midbrain region of a subject diagnosed with a parkinsonian condition selected from the group consisting of: Parkinson’s disease, Parkinsonism and Parkinson-plus syndrome.

13. The method or use according to any one of the preceding claims, wherein a final concentration of the compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, according to any one of the preceding claims in said method or use is in the range from about 10nM to about 100pM, further preferably in the range from about 100nM to about 200nM.

14. The method or use according to any one of the preceding claims, wherein said method or use is an in vitro, ex vivo or in vivo method or use.

15. The compound, isomer, derivative, pharmaceutically accepted salt, complex or mixtures thereof, or the isolated dopaminergic neuron or precursor cell thereof, or the composition or kit, or the method or use, according to any one of the preceding claims, wherein said parkinsonian condition is characterized by the presence of one or more of the following: i) one or more mutations in a mitochondrial serine/threonine-protein kinase (PINK1 ), preferably said mutation is a loss of function mutation, further preferably said PINK1 having UniProtKB Accession Number: Q9BXM7, most preferably said PINK1 having UniProtKB Accession Number: Q9BXM7 comprises at least Q456X and/or I368N mutation; and/or ii) one or more mutation in a E3 ubiquitin-protein ligase parkin (PRKN), preferably said PRKN having UniProtKB Accession Number: 060260, further preferably said PRKN having UniProtKB Accession Number: 060260 comprises at least R275W mutation.