SNCA irna formulations and methods of use thereof

Abstract

The disclosure relates to formulations of double stranded ribonucleic acid (dsRNAi) agents targeting a SNCA gene, as well as methods of inhibiting expression of a SNCA gene and methods of treating subjects having a SNCA-associated neurodegenerative disease or disorder, e.g., Parkinson's Disease (PD), multiple system atrophy, Lewy body dementia (LBD), among other synucleinopathies, using such dsRNAi agents formulations.

Description

[0001]Atty Docket No.: 121301-24920 SNCA IRNA FORMULATIONS AND METHODS OF USE THEREOF FIELD OF THE INVENTION The instant disclosure relates generally to formulations of SNCA-targeting RNAi agents and methods for their use. RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 708119, filed on October 16, 2024, the entire contents of which are incorporated herein by reference. BACKGROUND OF THE INVENTION HTQ GB76 SQZQ QZO[PQ_ M \^Q_eZM\`UO ZQa^[ZMX \^[`QUZ% i&_eZaOXQUZ #MX_[ ^QRQ^^QP `[as alpha-synuclein or synuclein-alpha herein), and has been linked genetically and neuropathologically to Parkinson's disease (PD) (Stefanis, L. Cold Spring Harb Perspect Med.+3 M))2,22$' i&GeZaOXQUZ U_ bUQcQP `[ O[Z`^UNa`Q `[ D8 \M`T[SQZQ_U_ UZ M ZaYNQ^ [R cMe_% Na`U` U_ SQZQ^MXXe NQXUQbQP `TM` MNQ^^MZ` _[XaNXQ [XUS[YQ^UO O[ZR[^YM`U[Z_ [R i&_eZaOXQUZ% `Q^YQPprotofibrils, are the toxic species that mediate disruption of cellular homeostasis and neuronal death, through effects on various intracellular targets, including synaptic function.:a^`TQ^Y[^Q% _QO^Q`QP i&_eZaOXQUZ U_ NQXUQbQP `[ QdQ^` PQXQ`Q^U[a_ QRRQO`_ [Z ZQUSTN[^UZS OQXX_%including seeding of aggregation, thus possibly contributing to disease propagation. Although`TQ Qd`QZ` `[ cTUOT i&_eZaOXQUZ U_ UZb[XbQP UZ MXX OM_Q_ [R D8 U_ Z[` OXQM^% `M^SQ`UZS `TQ `[dUOfunctions conferred by this protein when it is dysregulated presents a potentially valuable therapeutic strategy, not only for PD, but also for other neurodegenerative conditions, termed synucleinopathies, which all exhibit common neuropathological hallmarks as a result of alpha- synuclein accumulation, referred to as Lewy bodies (LBs) and Lewy neurites (LNs). In addition to PD, such documented or suspected SNCA-related synucleinopathies include, without limitation, multiple system atrophy, Lewy body dementia (LBD), pure autonomic failure (PAF), Pick's disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic grain disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar Page 1 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 degeneration, Alzheimer's disease, Huntington's disease, Down’s syndrome, psychosis, schizophrenia and Creutzfeldt-Jakob disease. PD and LBD are the two most prevalent examples of neurodegenerative disorders with SNCA brain pathology. PD is the most common movement disorder and is characterized by rigidity, hypokinesia, tremor and postural instability. PD is believed to affect approximately four to six million people worldwide. LBD represents 5-15 % of all dementia. In addition to forgetfulness and other dementing symptoms that often fluctuate, LBD patients typically suffer from recurrent falls and visual hallucinations. 6\M^` R^[Y `TQ ZQa^[\M`T[X[SUOMX OTMZSQ_ [N_Q^bQP UZ i&_eZaOXQUZ[\M`TUQ_% XQbQX_ [Ri&_eZaOXQUZ \^[`QUZ M^Q SQZQ^MXXe UZO^QM_QP UZ MRRQO`QP N^MUZ ^QSU[Z_ #?XaOWQZ et al., 2006).i&GeZaOXQUZ Y[Z[YQ^_% `Q`^MYQ^_ MZP RUN^UXXM^ MSS^QSM`Q_ M^Q M YMV[^ O[Y\[ZQZ` [RLewy body (LB)-like intraneuronal inclusions, glial inclusions and axonal spheroids in neurodegeneration with brain iron accumulation. Lewy-related pathology (LRP), primarilyO[Y\^U_QP [R i&_eZaOXQUZ% U_ \^Q_QZ` UZ M YMV[^U`e [R 6XfTQUYQ^h_ Ma`[\_UQ_% MZP TUSTQ^ XQbQX_[R i&_eZaOXQUZ UZ \M`UQZ`_ TMbQ NQQZ XUZWQP `[ O[SZU`UbQ PQOXUZQ #Hc[TUS Q` MX' #+)*2$Molecular Neurodegeneration). Autosomal dominant mutations in the SNCA gene including, among others, A53T, A30P, E46K, and H50Q (Zarranz et al. (2004) Ann. Neurol.55,164-173, Choi et al. (2004) FEBS Lett.576, 363-368, and Tsigelny et al. (2015) ACS Chem. Neurosci. 6, 403-416), A53T (Polymeropoulos et al. (1997) Science), as well as triplications and duplications, have been identified to run in families afflicted with associated neurodegenerative diseases. The preceding indicates that not only pathogenic mutations in SNCA, but also increases in alpha-synuclein protein, impact disease outcome. The role of SNCA mutations in disease onset is not well understood, however evidence\[UZ`_ `[ M `[dUO SMUZ&[R&RaZO`U[Z UZTQ^QZ` UZ `TQ Z[^YMX i&_eZaOXQUZ \^[`QUZ cTQZ U` QdOQQP_ Mcertain level (Stefanis et al. (2012) Cold Spring Harb Perspect Med.) and / or interacts aberrantly with cellular lipids and vesicles (reviewed in Kiechler et al. (2020) Front. Cell Dev. Biol). In apparent agreement with this, SNCA null mice, in contrast to transgenic over-expressors, displayed no overt neuropathological or behavioral phenotype (Abeliovich et al. (2000) Neuron). Posttranscriptional regulation of SNCA was also shown to occur through endogenousYUO^[ FB6_% NUZPUZS `[ `TQ ,j QZP [R `TQ SQZQ #>aZZ Q` MX' #+))2$ PNAS 106: 13052–13057;Doxakis (2010), JBC). Further, studies on the familial point mutations in SNCA demonstrated suppressed expression, especially in cases with prolonged disease onset (Markopoulou et al. (1999) Ann Neurol. 46(3):374-81 and Kobayashi et al. (2003) Brain 126(Pt 1):32-42). Similarly, Voutsinas et al. (2010) Hum Mutat. 31(6):685-91) found that over-expression of Page 2 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 even wild-type SNCA messenger RNA (mRNA) was responsible for disease onset. These dataUZPUOM`Q `TM` _a\\^Q__U[Z [R `[`MX GB76 XQbQX_ c[aXP X[cQ^ i&_eZaOXQUZ&UZPaOQP `[dUOU`e'There are no disease modifying treatments for synucleinopathies, including PD, multiple system atrophy, and Lewy body dementia, and treatment options are limited, e.g., merely palliative. For example, at present, only symptomatic treatments are available for PD patients (by substituting the loss of active dopamine in the brain) and AD patients (i.e.,OT[XUZQ_`Q^M_Q UZTUNU`[^_$' B[ZQ [R `TQ QdU_`UZS `^QM`YQZ` _`^M`QSUQ_ R[^ i&_eZaOXQUZ[\M`TUQ_ M^Qdirected against the underlying disease processes. Thus, noting the described involvement of SNCA in several neurodegenerative disorders (synucleinopathies), there remains a need for an agent that can selectively andQRRUOUQZ`Xe _UXQZOQ `TQ GB76 SQZQ #Q'S'% QXUYUZM`UZS [^ ^QPaOUZS `TQ QRRQO` [R `[dUO i&_eZaOXQUZspecies) using the cell's own RNAi machinery that has both high biological activity and in vivo stability, and that can effectively inhibit expression of a target SNCA gene. BRIEF SUMMARY OF THE INVENTION The present disclosure, at least in part, provides formulations of SNCA dsRNA agents, as well as resultant drug product formulations, associated methods, kits and other compositions. In particular, the compositions herein may be administered via parenteral (e.g., injectable) administration. The present disclosure provides RNAi agent formulations which affect the RNA- induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a Synuclein alpha(SNCA) gene. The SNCA gene may be within a cell, e.g., a cell within a subject, such as ahuman. The present disclosure also provides methods of using the RNAi agent formulations of the disclosure for inhibiting the expression of a SNCA gene or for treating a subject who would benefit from inhibiting or reducing the expression of a SNCA gene, e.g., a subject suffering or prone to suffering from a SNCA-associated neurodegenerative disease or disorder, e.g., PD, multiple system atrophy, Lewy body dementia (LBD), pure autonomic failure (PAF), Pick's disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic grain disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, Page 3 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer's disease and Huntington's disease. In one aspect, the instant disclosure provides a formulation comprising a double- stranded ribonucleic acid (dsRNA) for inhibiting expression of synuclein alpha (SNCA), wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand and the antisense strand are represented by a dsRNA listed in Table 1, and wherein the antisense strand is present at no less than equimolar amount or at about a 1% to about a 2% excess relative to the sense strand. In one embodiment, the instant disclosure provides a formulation comprising a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of synuclein alpha (SNCA), wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein (a) the sense strand comprises the nucleotide sequence and all the modifications of.q ;Y&\_&6Y&\_&;Y&7Y&6Y&6TP&;Y&IY&;R&6R&7R&6Y&6Y&6Y&IY&;Y&IY&IY&;Y&ps-Gm-ps-Am 3q #G9E =8 BC3 *$4 MZP #N$ `TQ MZ`U_QZ_Q _`^MZP O[Y\^U_Q_ `TQ ZaOXQ[`UPQsequence and all the modifications of.q JDa&\_&P7&\_&7Y&6Y&P6&7Y&P6&IY&IY&IY&;Y&PH&7Y&6R&7Y&IY&IY&;Y&7Y&Um-Cm-ps-Um-ps-Um 3q #G9E =8 BC3 +$4 cTQ^QUZ 6R U_ +q&RXa[^[MPQZ[_UZQ% 7R U_ +q&RXa[^[Oe`UPUZQ% ;R U_ +q&RXa[^[SaMZ[_UZQ% 6Y U_ +q&O&YQ`TeXMPQZ[_UZQ% IY U_ +q&O-YQ`TeXa^UPUZQ% 7Y U_ +q&O&YQ`TeXOe`UPUZQ% ;Y U_ +q&O&YQ`TeXSaMZ[_UZQ% P6 U_ +q&PQ[deMPQZ[_UZQ% P7 U_ +q&PQ[deOe`UPUZQ% PH U_ +q&PQ[de`TeYUPUZQ% 6TP U_ +q&O-TQdMPQOeXMPQZ[_UZQ% JDa U_ bUZeX\T[_\T[ZM`Q +q&O&YQ`TeXa^UPUZQ% q&q #Te\TQZ$ U_ M ,q&.q\T[_\T[PUQ_`Q^ XUZWMSQ% MZP q&\_&q U_ M ,q&.q \T[_\T[^[`TU[M`Q XUZWMSQ4 and wherein theantisense strand is present at no less than equimolar amount or at about a 1% to about a 2% excess relative to the sense strand. In one embodiment, the formulation comprises greater than 1 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 5 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 10 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 25 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 50 mg of the dsRNA agent per mL of the formulation, or the formulation comprises greater than 60 mg of the dsRNA agent per mL of the formulation. Page 4 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 In another embodiment, the formulation comprises about 50 mg to about 70 mg of the dsRNA agent per mL of the formulation. In certain embodiments, the formulation comprises about 60 mg of the dsRNA agent per mL of the formulation. In one embodiment, the formulation further comprises a sodium source, a potassium source, a magnesium source, and / or a calcium source. In one embodiment, the formulation further comprises a sodium source, a potassium source, a magnesium source, and a calcium source. In one embodiment, the formulation comprises sodium chloride, magnesium chloride, potassium chloride, and / or calcium chloride. In one embodiment, the formulation comprises sodium chloride, magnesium chloride, potassium chloride, and calcium chloride. In one embodiment, the formulation comprises sodium chloride at about 70 mM to about 100 mM. In specific embodiments, the formulation comprises sodium chloride at about 87 mM. In one embodiment, the formulation comprises potassium chloride at about 1.0 mM to about 2.5 mM. In a specific embodiment, the formulation comprises potassium chloride at about 1.7 mM In one embodiment, the formulation comprises magnesium chloride at about 0.1 mM to about 1.0 mM. In a specific embodiment, the formulation comprises magnesium chloride at about 0.46 mM. In one embodiment, the formulation comprises calcium chloride at about 8.0 mM to about 25.0 mM. In a specific embodiment, the formulation comprises calcium chloride at about 16.3 mM. In one embodiment, the formulation has a pH between about 6.0 and about 10.0. In another embodiment the pH of the formulation is between about 6.0 and about 8.0. In a specific embodiment, the pH of the formulation is about 6.8. In one embodiment, the formulation has an osmolality between about 200 and 400 mOsm / kg. In a specific embodiment, the osmolality is about 300 mOsm / kg. In one embodiment, the formulation is a pharmaceutical formulation for intrathecal administration of the dsRNA agent to a subject. In one embodiment, the subject is a mammal. In another embodiment, the subject is human. In one aspect, the instant disclosure provides a formulation for intrathecal administration comprising, (a) a dsRNA agent, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand and the antisense strand are represented Page 5 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 by a dsRNA listed in Table 1, and wherein the antisense strand is present at no less than equimolar amount or at about a 1% to about a 2% excess relative to the sense strand; (b) sodium chloride at about 70 mM to about 100 mM; (c) potassium chloride at about 1.0 mM to about 2.5 mM; (d) magnesium chloride at about 0.1 mM to about 1.0 mM; (e) calcium chloride at about 8.0 mM to about 25.0 mM; (f) a pH between about 6.0 and about 8.0; and (g) an osmolality between about 200 and 400 mOsm / kg. In one embodiment, the instant disclosure provides a formulation for intrathecal administration comprising, (a) a dsRNA agent comprising a sense strand and an antisense strand, wherein the sense strand comprises the nucleotide sequence and all the modifications of.q ;Y&\_&6Y&\_&;Y&7Y&6Y&6TP&;Y&IY&;R&6R&7R&6Y&6Y&6Y&IY&;Y&IY&IY&;Y&ps-Gm-ps-Am 3q #G9E =8 BC3 *$4 MZP `TQ MZ`U_QZ_Q _`^MZP O[Y\^U_Q_ `TQ ZaOXQ[`UPQ _Q]aQZOQand all the modifications of.q JDa&\_&P7&\_&7Y&6Y&P6&7Y&P6&IY&IY&IY&;Y&PH&7Y&6R&7Y&IY&IY&;Y&7Y&Um-Cm-ps-Um-ps-Um 3q #G9E =8 BC3 +$4 cTQ^QUZ 6R U_ +q&RXa[^[MPQZ[_UZQ% 7R U_ +q&RXa[^[Oe`UPUZQ% ;R U_ +q&RXa[^[SaMZ[_UZQ% 6Y U_ +q&O&YQ`TeXMPQZ[_UZQ% IY U_ +q&O-YQ`TeXa^UPUZQ% 7Y U_ +q&O&YQ`TeXOe`UPUZQ% ;Y U_ +q&O&YQ`TeXSaMZ[_UZQ% P6 U_ +q&PQ[deMPQZ[_UZQ% P7 U_ +q&PQ[deOe`UPUZQ% PH U_ +q&PQ[de`TeYUPUZQ% 6TP U_ +q&O-TQdMPQOeXMPQZ[_UZQ% JDa U_ bUZeX\T[_\T[ZM`Q +q&O&YQ`TeXa^UPUZQ% q&q #Te\TQZ$ U_ M ,q&.q\T[_\T[PUQ_`Q^ XUZWMSQ% MZP q&\_&q U_ M ,q&.q \T[_\T[^[`TU[M`Q XUZWMSQ4 (b) sodium chloride atabout 70 mM to about 100 mM; (c) potassium chloride at about 1.0 mM to about 2.5 mM; (d) magnesium chloride at about 0.1 mM to about 1.0 mM; (e) calcium chloride at about 8.0 mM to about 25.0 mM; (f) a pH between about 6.0 and about 8.0; and (g) an osmolality between about 200 and 400 mOsm / kg. In one embodiment, the dsRNA agent of the formulation is ALN-1747580. In another aspect, the instant disclosure provides a solid prepared by lyophilization of the any of the formulations disclosed herein. In one aspect, the instant disclosure provides a kit, comprising (a) the formulation of any one of the preceding embodiments, and (b) instructions for use, and (c) optionally, a means for administering the formulation to a subject. In one aspect, the instant disclosure provides a method of treating a subject having a disease or disorder that would benefit from a reduction in expression of synuclein alpha Page 6 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 (SNCA); or preventing development of a SNCA-associated neurodegenerative disease in a subject; or inhibiting the expression of synuclein alpha (SNCA) in a subject, the method comprising administering to the subject a therapeutically effective amount of a any of the formulations disclosed herein. In one embodiment, the subject is a human. In one embodiment, the subject meets at least one diagnostic criterion for a SNCA- associated disease or disorder. In another embodiment, the subject has a SNCA-associated disease. In another embodiment, the subject has been diagnosed with a SNCA-associated disease. In one embodiment, the SNCA-associated disease or disorder is selected from the group consisting of a synucleinopathy, such as PD, multiple system atrophy, Lewy body dementia (LBD), pure autonomic failure (PAF), Pick's disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic grain disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden- Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer's disease, Huntington's disease, Down’s syndrome, psychosis, schizophrenia and Creutzfeldt-Jakob disease. In one embodiment, the formulation is administered to the subject intrathecally. In one embodiment, treating comprises amelioration or delay of at least one sign or symptom of the disease or disorder. In another embodiment, treating comprises prevention or delay of development or progression of the disease or disorder. In one embodiment, the SNCA-associated disease or disorder is characterized by one or more symptoms selected from the group consisting of tremors, slowed movement (bradykinesia), rigid muscles, impaired posture and balance, loss of automatic movements, speech changes, writing changes, visual, auditory, olfactory, or tactile hallucinations, poor regulation of body functions (autonomic nervous systems) such as dizziness, falls and bowel issues, cognitive problems such as confusion, poor attention, visual-spatial problems and memory loss, sleep difficulties such as rapid eye movement (REM) sleep behavior disorder (in which dreams are physically acted out while asleep), fluctuating attention including episodes of drowsiness, long periods of staring into space, long naps during the day or disorganized speech, depression, and apathy, orthostatic hypotension (a sudden drop in blood pressure that occurs when a person stands up, causing a person to feel dizzy and lightheaded, and the need to sit, squat, or lie down in order to prevent fainting), clumsiness or Page 7 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 incoordination, bladder control problems, contractures (chronic shortening of muscles or tendons around joints, which prevents the joints from moving freely) in the hands or limbs, Pisa syndrome (an abnormal posture in which the body appears to be leaning to one side), antecollis (in which the neck bends forward and the head drops down), and involuntary and uncontrollable sighing or gasping. In another aspect, the instant disclosure provides a method for preparing an SNCA formulation comprising annealing a sense strand and an antisense strand, wherein one of the sense strand and antisense strand contains a lipophilic modification, to form a duplex solution comprising a SNCA double stranded RNA (dsRNA); lyophilizing the duplex solution to provide a duplex composition; and dissolving the duplex composition in an injection solution, wherein the injection solution comprises a divalent cation and does not comprise a phosphate buffer, wherein the duplex composition comprises about 1-2% molar excess of antisense strand over sense strand, and wherein the sense strand and the antisense strand are represented by a dsRNA listed in Table 1. In one embodiment, the instant disclosure provides a method for preparing an SNCA formulation comprising annealing a sense strand and an antisense strand, wherein one of the sense strand and antisense strand contains a lipophilic modification, to form a duplex solution comprising a SNCA double stranded RNA (dsRNA); lyophilizing the duplex solution to provide a duplex composition; and dissolving the duplex composition in an injection solution, wherein the injection solution comprises a divalent cation and does not comprise a phosphate buffer, wherein the duplex composition comprises about 1-2% molar excess of antisense strand over sense strand, wherein the sense strand comprises the nucleotide sequence and all the modifications of.q ;Y&\_&6Y&\_&;Y&7Y&6Y&6TP&;Y&IY&;R&6R&7R&6Y&6Y&6Y&IY&;Y&IY&IY&;Y&ps-Gm-ps-Am 3q #G9E =8 BC3 *$4 wherein the antisense strand comprises the nucleotidesequence and all the modifications of.q JDa&\_&P7&\_&7Y&6Y&P6&7Y&P6&IY&IY&IY&;Y&PH&7Y&6R&7Y&IY&IY&;Y&7Y&Um-7Y&\_&IY&\_&IY ,q #G9E =8 BC3 +$% MZP cTQ^QUZ 6R U_ +q&RXa[^[MPQZ[_UZQ% 7R U_ +q&RXa[^[Oe`UPUZQ% ;R U_ +q&RXa[^[SaMZ[_UZQ% 6Y U_ +q&O&YQ`TeXMPQZ[_UZQ% IY U_ +q&O-YQ`TeXa^UPUZQ% 7Y U_ +q&O&YQ`TeXOe`UPUZQ% ;Y U_ +q&O&YQ`TeXSaMZ[_UZQ% P6 U_ +q&PQ[deMPQZ[_UZQ% P7 U_ +q&PQ[deOe`UPUZQ% PH U_ +q&PQ[de`TeYUPUZQ% 6TP U_ +q&O-Page 8 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920TQdMPQOeXMPQZ[_UZQ% JDa U_ bUZeX\T[_\T[ZM`Q +q&O&YQ`TeXa^UPUZQ% q&q #Te\TQZ$ U_ M ,q&.q\T[_\T[PUQ_`Q^ XUZWMSQ% MZP q&\_&q U_ M ,q&.q \T[_\T[^[`TU[M`Q XUZWMSQ'In one embodiment, the divalent cation is calcium, magnesium, copper, nickel, zinc, or strontium. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a schematic of the sodium salt structure of ALN-1747580. The sense strand A-3230018 (SEQ ID NO: 1) and the antisense strand A-2861285 (SEQ ID NO: 2) are shown. FIG. 2 depicts a more simplified form of the structure of ALN-1747580. The sense strand (SEQ ID NO: 1) and antisense strand (SEQ ID NO: 2) are shown with the bases involved in a base pair formation connected with a centered dot. FIG.3 depicts an exemplary chromatogram from the duplex annealing method showing the antisense strand (AS), sense strand (SS), and duplex peaks. The present disclosure is further illustrated by the following detailed description. DETAILED DESCRIPTION OF THE INVENTION The present disclosure, at least in part, provides drug product formulations, associated methods, and kits for CNS-directed delivery (e.g., via intrathecal injection) of dsRNA agents for inhibiting the expression of a synuclein-alpha (SNCA) gene. The use of these dsRNA agents enables the targeted degradation of mRNAs of a SNCA gene in mammals. Thus, methods and formulations including these RNAi agents are useful for treating a subject having a disorder that would benefit from inhibiting or reducing the expression of a SNCA gene, e.g., a SNCA- associated disease, e.g., a synucleinopathy, such as PD, multiple system atrophy, Lewy body dementia (LBD), pure autonomic failure (PAF), Pick's disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic grain disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer's disease, Huntington's disease, Down’s syndrome, psychosis, schizophrenia and Creutzfeldt-Jakob disease. Page 9 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 =Z`^MZQa^[ZMX MOOaYaXM`U[Z [R i&_eZaOXQUZ TM_ NQQZ PQ_O^UNQP M_ QU`TQ^ ^Q_aX`UZS UZ `TQformation of Lewy bodies, round eosinophilic hyaline 10-20 pm large inclusions, or Lewy neurites, elongated thread-like dystrophic axons and dendrites. In the PD brain, deposition of Lewy bodies and Lewy neurites are mostly limited to neurons connecting striatum with substantia nigra. These cells are crucial for the execution of movement and postural functions, explaining the nature of PD symptoms. In the LBD brain, widespread depositions of Lewy bodies and Lewy neurites are found both in midbrain and cortical areas. i&GeZaOXQUZ U_ M \^[`QUZ cTUOT U_ YMUZXe R[aZP UZ`^MZQa^[ZMXXe' KU`TUZ `TQ ZQa^[Z% i&synuclein is predominantly located presynaptically and it has therefore been speculated that it\XMe_ M ^[XQ UZ `TQ ^QSaXM`U[Z [R _eZM\`UO MO`UbU`e' HT^QQ YMUZ U_[R[^Y_ [R i&_eZaOXQUZ TMbQbeen identified, of which the longest and most common form comprises 140 amino acids. Oxidative stress has been implicated in a number of neurodegenerative disordersOTM^MO`Q^UfQP Ne `TQ \M`T[X[SUOMX MOOaYaXM`U[Z [R YU_R[XPQP i&_eZaOXQUZ' JM^U[a_ ^QMO`UbQoxygen species can induce peroxidation of lipids such as cellular membranes or lipoproteins and also result in the generation of highly reactive aldehydes from poly-unsaturated fatty acids (Yoritaka et al., 1996) Brain pathology indicative of Alzheimer’s disease (AD), i.e. amyloid plaques and neurofibrillary tangles, are seen in approximately 50% of cases with LBD. It is unclear whether the existence of parallel pathologies implies two different diseases or just represents a variant of each respective disorder. Sometimes the cases with co-pathology are described as having a Lewy body variant of AD (Hansen et al., 1990). FQ_QM^OT TM_ MX_[ UY\XUOM`QP M ^[XQ [R GB76 UZ 68 MZP 8[cZh_ _eZP^[YQ% M_ `TQ i&synuclein protein has been demonstrated to accumulate in the limbic region in these disorders (Crews et al., 2009). Rare dominantly inherited forms of PD and LBD can be caused by point mutations orPa\XUOM`U[Z_ [R `TQ GB76 SQZQ' HTQ \M`T[SQZUO Ya`M`U[Z_ k,)n MZP k.,o #?^aSQ^ etal., 1998) (Polymeropoulos et al., 1998) and duplication of the gene (Chartier-Harlin et al., 2004) have been described to cause familial PD, whereas one other a-synuclein mutation,l- / m #LM^^MZf et al., 2004) as well as triplication of the a-synuclein gene (Singleton etal., 2003) have been reported to cause either PD or LBD. HTQ \M`T[SQZUO O[Z_Q]aQZOQ_ [R `TQ i&_eZaOXQUZ Ya`M`U[Z_ M^Q [ZXe \M^`Xe aZPQ^_`[[P'However, in vitro PM`M TMbQ _T[cZ `TM` `TQ k,)n MZP k.,o Ya`M`U[Z_ UZO^QM_Q `TQ ^M`Q [Raggregation (Conway et al., +)))$' 6 N^[MP ^MZSQ [R PURRQ^QZ`Xe O[Y\[_QP i&_eZaOXQUZ _\QOUQ_(monomers, dimers, oligomers, including protofibrils) are involved in the aggregation process, Page 10 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 all of which may have different toxic properties. It is not clear which molecular species exert`[dUO QRRQO`_ UZ `TQ N^MUZ' <[cQbQ^% ^Q_QM^OT TM_ UZPUOM`QP `TM` [XUS[YQ^UO R[^Y_ [R i&_eZaOXQUZare particularly neurotoxic. Additional evidence for the role of oligomers is given by the[N_Q^bM`U[Z `TM` OQ^`MUZ i&_eZaOXQUZ Ya`M`U[Z_ #k,)n MZP k.,o$ OMa_UZS TQ^QPU`M^eParkinson’s disease, lead to an increased rate of oligomerization. =` U_ Z[` O[Y\XQ`QXe WZ[cZ T[c `TQ i&_eZaOXQUZ MSS^QSM`U[Z OM_OMPQ NQSUZ_' D[__UNXe%MZ MX`Q^QP O[ZR[^YM`U[Z [R Y[Z[YQ^UO i&_eZaOXQUZ UZU`UM`Q_ R[^YM`U[Z [R PUYQ^_ MZP `^UYQ^_%which continue to form higher soluble oligomers, including protofibrils, before these intermediately sized species are deposited as insoluble fibrils in Lewy bodies. It is alsoO[ZOQUbMNXQ `TM` `TQ i&_eZaOXQUZ [XUS[YQ^_% [ZOQ `TQe M^Q R[^YQP% OMZ NUZP ZQc Y[Z[YQ^_MZP([^ _YMXXQ^ YaX`UYQ^_ [R i&_eZaOXQUZ MZP TQZOQ MOOQXQ^M`Q `TQ RUN^UX R[^YM`U[Z \^[OQ__' GaOTseeding effects can possibly also occur in the extracellular space as some evidence suggests`TM` i&_eZaOXQUZ \M`T[X[Se YMe \^[\MSM`Q R^[Y ZQa^[Z `[ ZQa^[Z UZ `TQ PU_QM_QP N^MUZ'I. Definitions That the present disclosure may be more readily understood, certain terms are first defined. In addition, it should be noted that whenever a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also intended to be part of this disclosure. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element, e.g., a plurality of elements. The term "including" is used herein to mean, and is used interchangeably with, the phrase "including but not limited to". The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless context clearly indicates otherwise. The term “about” is used herein to mean within the typical ranges of tolerances in the art. For example, “about” can be understood as about 2 standard deviations from the mean. In certain embodiments, about means ±10%. In certain embodiments, about means ±5%. When about is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range. The term “at least” prior to a number or series of numbers is understood to include the number adjacent to the term “at least”, and all subsequent numbers or integers that could logically be included, as clear from context. For example, the number of nucleotides in a Page 11 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 nucleic acid molecule must be an integer. For example, “at least 18 nucleotides of a 21 nucleotide nucleic acid molecule” means that 18, 19, 20, or 21 nucleotides have the indicated property. When at least is present before a series of numbers or a range, it is understood that “at least” can modify each of the numbers in the series or range. As used herein, “no more than” or “less than” is understood as the value adjacent to the phrase and logical lower values or integers, as logical from context, to zero. For example, a duplex with an overhang of “no more than 2 nucleotides” has a 2, 1, or 0 nucleotide overhang. When “no more than” is present before a series of numbers or a range, it is understood that “no more than” can modify each of the numbers in the series or range. As used herein, ranges include both the upper and lower limit. As used herein, methods of detection can include determination that the amount of analyte present is below the level of detection of the method. In the event of a conflict between an indicated target site and the nucleotide sequence for a sense or antisense strand, the indicated sequence takes precedence. In the event of a conflict between a chemical structure and a chemical name, the chemical structure takes precedence. As used herein, “excess” is any amount of excess of one component over a second component. “excess” can be measured / estimated by non-denaturing Ion-pair reverse phase HPLC (nd-IPRP), which if not equivalent to, approximates molar excess. As such, herein the terms “molar excess” and “excess” are used interchangeably. For example, an excess of antisense strand over sense strand or an excess of sense strand over antisense strand. The molar excess can be any amount. The excess can be about a 1-2% molar excess, a 1-3% molar excess, a 1-4% molar excess, a 1-5% molar excess, a 0-5% molar excess, a 0-1% molar excess, a 2- 3% molar excess, a 3-4% molar excess, a 3-5% molar excess, a 2-4% molar excess, a 2-5% molar excess, a 0-10% molar excess, a 5-10% molar excess, a 2-6% molar excess, a 3-7% molar excess, or a 4-8% molar excess of one component over a second component (e.g., of antisense strand over sense strand or sense strand over antisense strand). The term "inorganic phosphate", as used herein, refers to the total amount of free phosphate (PO43-) in a solution and / or composition of the instant disclosure, as determined by art-recognized means, including, e.g., taking a measured amount of an aqueous sample and adding ammonium heptamolybdate reagent in a mixing tube. The tube is then stoppered and vigorously shaken. Dilute stannous chloride reagent, which has been freshly prepared from concentrated stannous chloride reagent and distilled water, to the mixture in the tube. This will produce a blue color (due to the formation of molybdenum blue) and the depth of the blue color Page 12 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 indicates the amount of phosphate in the boiler water. The absorbance of the blue solution can be measured with a colorimeter and the concentration of phosphate in the original solution can be calculated. Alternatively, a direct (but approximate) reading of phosphate concentration can be obtained by using a Lovibond comparator. In certain embodiments, the total amount of inorganic phosphate is less than 100 parts per million (ppm), or is less than 0.64 µg / L. The term “SNCA,” “e-synuclein,” “synuclein alpha,” or “alpha-synuclein,” refers to a gene associated with neurodegenerative diseases, termed “synucleinopathies,” as well as the proteins encoded by that gene. The human SNCA gene region covers approximately 114 kb. The SNCA transcript contains 13 exons, and 15 mRNA isoforms have been identified or otherwise predicted as produced. Nucleotide and amino acid sequences of SNCA may be found, for example, at GenBank Accession No. NM_007308.3 (Homo sapiens SNCA); GenBank Accession No. XM_005555421 (Macaca fascicularis SNCA); GenBank Accession No.: NM_009221 (Mus musculus SNCA); GenBank Accession No. NM_019169.2 (Rattus norvegicus SNCA); and GenBank Accession No. XM_535656.7 (Canis lupus familiaris SNCA). The term “SNCA” as used herein also refers to variations of the SNCA gene including naturally occurring sequence variants. Non-limiting examples of SNCA variants are provided, for example, in WO2022 / 072447 and WO2023 / 192977 each of which are hereby incorporated by reference in their entireties. Additional examples of SNCA sequences can be found in publicly available databases, for example, GenBank, OMIM, UniProt, NCBI dbSNP (see, e.g., www.ncbi.nlm.nih.gov / gene / 6622), and the Macaca genome project web site (macaque.genomics.org.cn / page / species / index.jsp). Additional information on SNCA can be found, for example, at www.ncbi.nlm.nih.gov / gene / 6622. The entire contents of each of the foregoing GenBank Accession numbers and the Gene database numbers are incorporated herein by reference as of the date of filing this application. HT^QQ \^[`QUZ U_[R[^Y_ [R i&_eZaOXQUZ TMbQ NQQZ PQ_O^UNQP UZ IZUD^[`' HTQ X[ZSQ_` i&synuclein isoform is an approximately 14 kDa protein (Isoform 1 UniProt, P37840 of 140MYUZ[ MOUP_$' C`TQ^ i&_eZaOXQUZ U_[R[^Y_ UZ IZUD^[` UZOXaPQ3 =_[R[^Y +&-% D,01-)&+ [R **+amino acids; and Isoform 2-5, P37840-3 of 126 amino acids. The 140 amino acid e-Synuclein protein is encoded by 5 exon pairs mapping to chromosome loci 4q21.3-q22. The e-synuclein protein has an N-terminal region composed of incomplete KXKEGV motifs, an extremely hydrophobic NAC domain and a highly acidic C-terminal domain. At physiological conditions, Page 13 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 SNCA is believed to be an intrinsically disordered monomer or helically folded tetramer. e- Synuclein composes 1% of all proteins in the cytosol of brain cells, and is predominantly expressed in the neocortex, hippocampus, substantia nigra, thalamus, and cerebellum. e- Synuclein is also expressed in lower amounts in the in heart, skeletal muscle and pancreas. Although the function of SNCA is not well understood, evidence suggests it plays an important role in maintaining an adequate supply of synaptic vesicles in presynaptic terminals. e- Synuclein is implicated in the regulation of dopamine release and transport, fibrillization of microtubule associated protein tau, and the regulation of a neuroprotective phenotype in non- dopaminergic neurons by regulating the inhibition of both p53 expression and transactivation of proapoptotic genes, leading to decreased caspase-3 activation. The primary mechanism by which e-synuclein induces neurodegenerative diseases such as Parkinson’s, Lewy body dementia, and multiple system atrophy, appears to be elevated levels of the e-synuclein protein resulting in e-synuclein fibrillary aggregates. As used herein, “target sequence” refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a SNCA gene, including mRNA that is a product of RNA processing of a primary transcription product. In one embodiment, the target portion of the sequence will be at least long enough to serve as a substrate for RNAi-directed cleavage at or near that portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a SNCA gene. In one embodiment, the target sequence is within the protein coding region of the SNCA gene. In another embodiment, the target sequence is within the 3’ UTR of the SNCA gene. The target sequence may be from about 9-36 nucleotides in length, e.g., about 15-30 nucleotides in length. For example, the target sequence can be from about 15-30 nucleotides, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18- 30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19- 28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20- 26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides in length. In some embodiments, the target sequence is about 19 to about 30 nucleotides in length. In other embodiments, the target sequence is about 19 to about 25 nucleotides in length. In still other embodiments, the target sequence is about 19 to about 23 nucleotides in length. In some embodiments, the target sequence is about 21 to about 23 nucleotides in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure. Page 14 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 As used herein, the term “strand comprising a sequence” refers to an oligonucleotide comprising a chain of nucleotides that is described by the sequence referred to using the standard nucleotide nomenclature. “G,” “C,” “A,” “T”, and “U” each generally stand for a nucleotide that contains guanine, cytosine, adenine, thymidine, and uracil as a base, respectively in the context of a modified or unmodified nucleotide. However, it will be understood that the term “ribonucleotide” or “nucleotide” can also refer to a modified nucleotide, as further detailed below, or a surrogate replacement moiety. The skilled person is well aware that guanine, cytosine, adenine, thymidine, and uracil can be replaced by other moieties without substantially altering the base pairing properties of an oligonucleotide comprising a nucleotide bearing such replacement moiety. For example, without limitation, a nucleotide comprising inosine as its base can base pair with nucleotides containing adenine, cytosine, or uracil. Hence, nucleotides containing uracil, guanine, or adenine can be replaced in the nucleotide sequences of dsRNA featured in the disclosure by a nucleotide containing, for example, inosine. In another example, adenine and cytosine anywhere in the oligonucleotide can be replaced with guanine and uracil, respectively to form G-U Wobble base pairing with the target mRNA. Sequences containing such replacement moieties are suitable for the compositions and methods featured in the disclosure. The oligonucleotides used in the formulations and methods of the disclosure is a double-stranded RNA and is referred to herein as a “double stranded RNAi agent,” “double stranded RNA (dsRNA) molecule,” “dsRNA agent,” “dsRNA”, “RNAi”, “iRNA”, or “iRNA agent”. The term “dsRNA” refers to a complex of one or more (e.g., two) ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary nucleic acid portions (e.g., strands), referred to as having “sense” and “antisense” orientations with respect to a target RNA, i.e., a SNCA gene. In some embodiments of the disclosure, a double stranded RNA (dsRNA) triggers the degradation of a target RNA, e.g., an mRNA, through a post-transcriptional gene-silencing mechanism referred to herein as RNA interference or RNAi. In one embodiment, the dsRNA contains two separate strands that form the duplex structure. In another embodiment, the dsRNA is a single oligonucleotide having two separate portions that form the duplex structure, the two portions being part of a hairpin or dumbbell type structure. Hairpin and dumbbell type oligomeric compounds may have a duplex region equal to, or at least, 14, 15, 15, 16, 17, 18, 19, 29, 21, 22, 23, 24, or 25 nucleotide pairs. In some embodiments, the duplex region can be equal to or less than 200, 100, or 50, in length. In some embodiments, ranges for the duplex region are 15-30, 17 to 23, 19 to Page 15 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 23, and 19 to 21 nucleotides pairs in length. In some embodiments, the hairpin oligomeric compounds can have a single strand overhang or terminal unpaired region, in some embodiments at the 3', and in some embodiments on the antisense side of the hairpin. In some embodiments, the overhangs are 1-4, more generally 2-3 nucleotides in length. The hairpin oligomeric compounds that can induce RNA interference are also referred to as "shRNA" herein. In general, a dsRNA molecule can include ribonucleotides, but as described in detail herein, each or both strands can also include one or more non-ribonucleotides, e.g., a deoxyribonucleotide, a modified nucleotide. In addition, as used in this specification, an “RNAi agent” may include ribonucleotides with chemical modifications; an RNAi agent may include substantial modifications at multiple nucleotides. As used herein, the term “modified nucleotide” refers to a nucleotide having, independently, a modified sugar moiety, a modified internucleotide linkage, or a modified nucleobase. Thus, the term modified nucleotide encompasses substitutions, additions or removal of, e.g., a functional group or atom, to internucleoside linkages, sugar moieties, or nucleobases. The modifications suitable for use in the agents of the disclosure include all types of modifications disclosed herein or known in the art. Any such modifications, as used in a siRNA type molecule, are encompassed by “RNAi agent” for the purposes of this specification and claims. In certain embodiments of the instant disclosure, inclusion of a deoxy-nucleotide – which is acknowledged as a naturally occurring form of nucleotide – if present within an RNAi agent can be considered to constitute a modified nucleotide. As used herein, the term "2'-deoxynucleotide" refers to a 2'-deoxyribonucleotide, or to a 2'-deoxy nucleotide including a ribose analog. In certain embodiments, a "2'- deoxynucleotide" refers to a 2'-deoxyribonucleotide. It is understood that, when present within an RNAi agent, a 2’-deoxy modification is considered a modified nucleotide. In one embodiment, an RNAi agent of the disclosure is a dsRNA agent, each strand of which comprises 19-23 nucleotides that interacts with a SNCA RNA sequence to direct the cleavage of the target RNA. Without wishing to be bound by theory, long double stranded RNA introduced into cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev.15: 485). Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pair short interfering RNAs with characteristic two base 3’ overhangs (Bernstein, et al., (2001) Nature 409: 363). The siRNAs are then incorporated into an RNA- induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, Page 16 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001) Cell 107: 309). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001) Genes Dev.15: 188). In one embodiment, an RNAi agent of the disclosure is a dsRNA of 24- 30 nucleotides that interacts with a SNCA RNA sequence to direct the cleavage of the target RNA. The term “antisense strand” or "guide strand" refers to the strand of an RNAi agent, e.g., a dsRNA, which includes a region that is substantially complementary to a target sequence, e.g., a SNCA mRNA. As used herein, the term “region of complementarity” refers to the region on the antisense strand that is substantially complementary to a sequence, for example a target sequence, e.g., a SNCA nucleotide sequence, as defined herein. Where the region of complementarity is not fully complementary to the target sequence, the mismatches can be in the internal or terminal regions of the molecule. Generally, the most tolerated mismatches are in the terminal regions, e.g., within 5, 4, 3, or 2 nucleotides of the 5’- or 3’-terminus of the RNAi agent. In some embodiments, a double stranded RNA agent of the disclosure includes a nucleotide mismatch in the antisense strand. The term “sense strand” or "passenger strand" as used herein, refers to the strand of an RNAi agent that includes a region that is substantially complementary to a region of the antisense strand as that term is defined herein. As used herein, and unless otherwise indicated, the term “complementary,” when used to describe a first nucleotide sequence in relation to a second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize and form a duplex structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence, as will be understood by the skilled person. Such conditions can, for example, be stringent conditions, where stringent conditions can include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50oC or 70oC for 12-16 hours followed by washing (see, e.g., “Molecular Cloning: A Laboratory Manual, Sambrook, et al. (1989) Cold Spring Harbor Laboratory Press). Other conditions, such as physiologically relevant conditions as can be encountered inside an organism, can apply. The skilled person will be able to determine the set of conditions most appropriate for a test of complementarity of two sequences in accordance with the ultimate application of the hybridized nucleotides. Page 17 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 Complementary sequences within an RNAi agent, e.g., within a dsRNA as described herein, include base-pairing of the oligonucleotide or polynucleotide comprising a first nucleotide sequence to an oligonucleotide or polynucleotide comprising a second nucleotide sequence over the entire length of one or both nucleotide sequences. Such sequences can be referred to as “fully complementary” with respect to each other herein. However, where a first sequence is referred to as “substantially complementary” with respect to a second sequence herein, the two sequences can be fully complementary, or they can form one or more, but generally not more than 5, 4, 3 or 2 mismatched base pairs upon hybridization for a duplex up to 30 base pairs, while retaining the ability to hybridize under the conditions most relevant to their ultimate application, e.g., inhibition of gene expression via a RISC pathway. However, where two oligonucleotides are designed to form, upon hybridization, one or more single stranded overhangs, such overhangs shall not be regarded as mismatches with regard to the determination of complementarity. For example, a dsRNA comprising one oligonucleotide 21 nucleotides in length and another oligonucleotide 23 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 21 nucleotides that is fully complementary to the shorter oligonucleotide, can yet be referred to as “fully complementary” for the purposes described herein. “Complementary” sequences, as used herein, can also include, or be formed entirely from, non-Watson-Crick base pairs or base pairs formed from non-natural and modified nucleotides, in so far as the above requirements with respect to their ability to hybridize are fulfilled. Such non-Watson-Crick base pairs include, but are not limited to, G:U Wobble or Hoogstein base pairing. The terms “complementary,” “fully complementary” and “substantially complementary” herein can be used with respect to the base matching between the sense strand and the antisense strand of a dsRNA, or between the antisense strand of an RNAi agent and a target sequence, as will be understood from the context of their use. As used herein, a polynucleotide that is “substantially complementary to at least part of” a messenger RNA (mRNA) refers to a polynucleotide that is substantially complementary to a contiguous portion of the mRNA of interest (e.g., an mRNA encoding SNCA). Forexample, a polynucleotide is complementary to at least a part of a SNCA mRNA if the sequenceis substantially complementary to a non-interrupted portion of an mRNA encoding SNCA.Accordingly, in some embodiments, the antisense strand polynucleotides disclosed herein are fully complementary to the target SNCA sequence. Page 18 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 In one embodiment, at least partial suppression of the expression of a SNCA gene, is assessed by a reduction of the amount of SNCA mRNA which can be isolated from or detected in a first cell or group of cells in which a SNCA gene is transcribed and which has or have been treated such that the expression of a SNCA gene is inhibited, as compared to a second cell or group of cells substantially identical to the first cell or group of cells but which has or have not been so treated (control cells). The degree of inhibition may be expressed in terms of: The phrase “contacting a cell with an RNAi agent,” such as a dsRNA, as used herein, includes contacting a cell by any possible means. Contacting a cell with an RNAi agent includes contacting a cell in vitro with the RNAi agent or contacting a cell in vivo with the RNAi agent. The contacting may be done directly or indirectly. Thus, for example, the RNAi agent may be put into physical contact with the cell by the individual performing the method, or alternatively, the RNAi agent may be put into a situation that will permit or cause it to subsequently come into contact with the cell. Contacting a cell in vitro may be done, for example, by incubating the cell with the RNAi agent. Contacting a cell in vivo may be done, for example, by injecting the RNAi agent into or near the tissue where the cell is located, or by injecting the RNAi agent into another area, e.g., the central nervous system (CNS), optionally via intrathecal, intravitreal or other injection, or to the bloodstream or the subcutaneous space, such that the agent will subsequently reach the tissue where the cell to be contacted is located. For example, the RNAi agent may contain or be coupled to a ligand, e.g., a lipophilic moiety or moieties as described below and further detailed, e.g., in PCT / US2019 / 031170, which is incorporated herein by reference, that directs or otherwise stabilizes the RNAi agent at a site of interest, e.g., the CNS. In some embodiments, the RNAi agent may contain or be coupled to a ligand, e.g., one or more GalNAc derivatives as described below, that directs or otherwise stabilizes the RNAi agent at a site of interest, e.g., the liver. In other embodiments, the RNAi agent may contain or be coupled to a lipophilic moiety or moieties and one or more GalNAc derivatives. Combinations of in vitro and in vivo methods of contacting are also possible. For example, a cell may also be contacted in vitro with an RNAi agent and subsequently transplanted into a subject. In one embodiment, contacting a cell with an RNAi agent includes “introducing” or “delivering the RNAi agent into the cell” by facilitating or effecting uptake or absorption into the cell. Absorption or uptake of an RNAi agent can occur through unaided diffusive or active Page 19 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 cellular processes, or by auxiliary agents or devices. Introducing an RNAi agent into a cell may be in vitro or in vivo. For example, for in vivo introduction, an RNAi agent can be injected into a tissue site or administered systemically. In vitro introduction into a cell includes methods known in the art such as electroporation and lipofection. Further approaches are described herein below or are known in the art. The term “artificial cerebrospinal fluid (aCSF)" refers to a solution prepared with a composition representative of human cerebrospinal fluid (hCSF) that closely matches the electrolyte concentrations of hCSF, and may include glucose. Exemplary ion concentrations, as prepared in high purity water, include (in mM): Na+150; K+3.0; Ca2+1.4; Mg2+0.8; P 1.0; Cl- 155 (for example, Tocris Bioscience™ ACSF, Cat. No.3525, available from Thermo Fisher Scientific, Hampton, NH, USA). An exemplary aCSF formulation includes 127 mM NaCl; 1.0 mM KCl; 1.2 mM KH2PO4; 26 mM NaHCO3; 10 mM D-glucose; 2.4 mM CaCl2; and 1.3 mM MgCl2, with the pH and oxygen level stabilized by bubbling with carbogen (95% O2and 5% CO2). A solution is considered "isotonic to aCSF" when its effective osmole concentration is the same as that of aCSF. For example, the solutions on either side of a cell membrane are isotonic if the concentration of solutes outside the cell is equal to the concentration of solutes inside the cell. As used herein, a “subject” is an animal, such as a mammal, including a primate (such as a human, a non-human primate, e.g., a monkey, and a chimpanzee), or a non-primate (such as a a rat, or a mouse). In a preferred embodiment, the subject is a human, such as a human being treated or assessed for a disease, disorder, or condition that would benefit from reduction in SNCA expression; a human at risk for a disease, disorder, or condition that would benefit from reduction in SNCA expression; a human having a disease, disorder, or condition that would benefit from reduction in SNCA expression; or human being treated for a disease, disorder, or condition that would benefit from reduction in SNCA expression as described herein. As used herein, the term "SNCA-associated disease,” “SNCA-associated disease or disorder”, or SNCA-associated disease, disorder, or condition” are used interchangeably to refer to a disease, disorder, or condition that is caused by, or associated with, SNCA gene expression or SNCA protein production. The term "SNCA-associated disease” includes a disease, disorder or condition that would benefit from a decrease in SNCA gene expression or protein activity. In one embodiment, a SNCA-associated disease, disorder, or condition is an SNCA-associated neurodegenerative disease. Page 20 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 As used herein, the terms “treating” or “treatment” refer to a beneficial or desired result including, but not limited to, alleviation or amelioration of one or more signs or symptoms associated with SNCA gene expression or SNCA protein production, e.g., SNCA-associated neurodegenerative disease, e.g., synucleinopathies, such as PD, multiple system atrophy, Lewy body dementia (LBD), pure autonomic failure (PAF), Pick's disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic grain disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer's disease, Huntington's disease, Down’s syndrome, psychosis, schizophrenia and Creutzfeldt-Jakob disease, decreased expression or activity of SNCA in regions of increased neuronal dysfunction or death, in subjects having such neurodegenerative diseases. “Treatment” can also mean prolonging survival as compared to expected survival in the absence of treatment. The term “lower” in the context of the level of SNCA in a subject or a disease marker or symptom refers to a statistically significant decrease in such level. The decrease can be, for example, at least 10%, 15%, 20%, 25%, 30%, %, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more. In certain embodiments, a decrease is at least 20%. In certain embodiments, the decrease is at least 50% in a disease marker, e.g., protein or gene expression level. “Lower” in the context of the level of SNCA in a subject is optionally down to a level accepted as within the range of normal for an individual without such disorder. In certain embodiments, “lower” is the decrease in the difference between the level of a marker or symptom for a subject suffering from a disease and a level accepted within the range of normal for an individual, e.g., the level of decrease in speed of movement (bradykinesia) and ability to regulate posture and balance in an individual having Parkinson’s and an individual not having Parkinson’s or having symptoms that are within the range of normal. As used herein, “prevention” or “preventing,” when used in reference to a disease or disorder, that would benefit from a reduction in expression of a SNCA gene or production of SNCA protein, e.g., in a subject susceptible to a SNCA-associated disorder due to, e.g., genetic factors or age, wherein the subject does not yet meet the diagnostic criteria for the SNCA- associated disorder. As used herein, prevention can be understood as administration of an agent to a subject who does not yet meet the diagnostic criteria for the SNCA-associated disorder to delay or reduce the likelihood that the subject will develop the SNCA-associated disorder. As the agent is a pharmaceutical agent, it is understood that administration typically would be Page 21 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 under the direction of a health care professional capable of identifying a subject who does not yet meet the diagnostic criteria for a SNCA-associated disorder as being susceptible to developing a SNCA-associated disorder. The term “synucleinopathies” refers to a group of neurodegenerative disorders characterized by fibrillary aggregates of e-synuclein protein that tend to accumulate in the cytoplasm of selective populations of neurons and glia. Synucleinopathies are therefore a class of SNCA-associated neurodegenerative diseases and disorders, which include Parkinson's disease (PD), Lewy body dementia (LBD), pure autonomic failure (PAF), and multiple system atrophy (MSA), among other neurodegenerative diseases. Clinically, synucleinopathies are characterized by a chronic and progressive decline in motor, cognitive, behavioral, and autonomic functions, depending on the distribution of the lesions in the brain. Because of clinical overlap, differential diagnosis is sometimes very difficult. Parkinsonism is the predominant symptom of PD, but it can be indistinguishable from the parkinsonism of LBD and MSA. Autonomic dysfunction, which is an isolated finding in PAF, may be present in PD and LBD, but is usually more prominent and appears earlier in MSA. LBD could be the same disease as PD but with widespread cortical pathological states, leading to dementia, fluctuating cognition, and the characteristic visual hallucinations. The likelihood of developing a synucleinopathy, e.g., PD, LBD, etc., is reduced, for example, when an individual having one or more risk factors for PD or for LBD (or other synucleinopathy) either fails to develop PD or LBD (or other synucleinopathy) or develops PD or LBD (or other synucleinopathy) with less severity relative to a population having the same risk factors and not receiving treatment as described herein. The failure to develop a SNCA- associated disorder, e.g., PD or LBD (or other synucleinopathy), or a delay in the time to develop PD or LBD (or other synucleinopathy) by months or years is considered effective prevention. Prevention may require administration of more than one dose of the iRNA agent. Provided with appropriate methods to identify subjects at risk to develop any of the SNCA- associated diseases above, the iRNA agents provided herein can be used as pharmaceutical agents for or in methods of prevention of SNCA-associated diseases. Risk factors for various SNCA-associated diseases are discussed herein. As used herein, the term “Parkinson’s disease” or “PD” refers to a progressive nervous system disorder that affects movement. The main pathological characteristics of PD are cell death in the brain's basal ganglia (affecting up to 70% of the dopamine secreting neurons in the substantia nigra pars compacta by the end of life) and the presence of Lewy bodies Page 22 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 (accumulations of the SNCA-encoded e-synuclein protein) in many of the remaining neurons. Symptoms start gradually, sometimes with a barely noticeable tremor in just one hand, or stiffness or slowing of movement. Other early symptoms include lack of facial expression, lack of arm movement while walking, and slurring during speech. Parkinson's disease symptoms worsen over time. The average onset of PD is age 60, and later onset is associated with greater symptom severity. Clinical features include, but are not limited to, more severe tremors, slowed movement (bradykinesia), rigid muscles, impaired posture and balance, loss of automatic movements, speech changes, and eventually, dementia, hallucinations, and wheelchair confinement. As used herein, the term “Lewy body dementia (LBD)” refers to a type of progressive dementia that leads to a decline in thinking, reasoning and independent function caused by the aggregation of e-synuclein protein within diseased brain neurons, known as Lewy bodies and Lewy neurites. Aggregates of e-synuclein protein lead to sub-optimal functioning and eventual death of the affected neurons. Symptoms include visual, auditory, olfactory, or tactile hallucinations, signs of Parkinson's disease (parkinsonian signs), poor regulation of body functions (autonomic nervous system) such as dizziness, falls and bowel issues, cognitive problems such as confusion, poor attention, visual-spatial problems and memory loss, sleep difficulties such as rapid eye movement (REM) sleep behavior disorder (in which dreams are physically acted out while asleep), fluctuating attention including episodes of drowsiness, long periods of staring into space, long naps during the day or disorganized speech, depression, and apathy. In one embodiment, a SNCA-associated disease or disorder (synucleinopathy) is one of Parkinson’s disease, Lewy body dementia, multiple system atrophy (MSA), and pure autonomic failure (PAF). "Therapeutically effective amount," as used herein, is intended to include the amount of an RNAi agent that, when administered to a subject having a SNCA-associated disease, is sufficient to effect treatment of the disease (e.g., by diminishing, ameliorating, or maintaining the existing disease or one or more symptoms of disease). The "therapeutically effective amount" may vary depending on the RNAi agent, how the agent is administered, the disease and its severity and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the subject to be treated. Page 23 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 “Prophylactically effective amount,” as used herein, is intended to include the amount of an RNAi agent that, when administered to a subject having a SNCA-associated disorder, is sufficient to prevent or ameliorate the disease or one or more symptoms of the disease. Ameliorating the disease includes slowing the course of the disease or reducing the severity of later-developing disease. The "prophylactically effective amount" may vary depending on the RNAi agent, how the agent is administered, the degree of risk of disease, and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated. A "therapeutically-effective amount" or “prophylactically effective amount” also includes an amount of an RNAi agent that produces some desired local or systemic effect at a reasonable benefit / risk ratio applicable to any treatment. An RNAi agent employed in the methods of the present disclosure may be administered in a sufficient amount to produce a reasonable benefit / risk ratio applicable to such treatment. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human subjects and animal subjects without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. As used herein, the phrase "pharmaceutically acceptable salt" refers to both pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC-(CH2)n-COOH where n is 0-4, and the like. Non- toxic pharmaceutical base addition salts include salts of bases such as lithium, sodium, potassium, calcium, magnesium, ammonium, and the like. In certain embodiments, the pharmaceutically acceptable salt is a sodium salt. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts. The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject being treated. Some examples of Page 24 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium state, sodium lauryl sulfate and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids (23) serum component, such as serum albumin, HDL and LDL; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. The term “sample,” as used herein, includes a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Examples of biological fluids include blood, serum and serosal fluids, plasma, cerebrospinal fluid, ocular fluids, lymph, urine, saliva, and the like. Tissue samples may include samples from tissues, organs or localized regions. For example, samples may be derived from particular organs, parts of organs, or fluids or cells within those organs. In certain embodiments, samples may be derived from the brain (e.g., whole brain or certain segments of brain, e.g., striatum, or certain types of cells in the brain, such as, e.g., neurons and glial cells (astrocytes, oligodendrocytes, microglial cells)). In other embodiments, a “sample derived from a subject” refers to liver tissue (or subcomponents thereof) derived from the subject. In some embodiments, a “sample derived from a subject” refers to blood drawn from the subject or plasma or serum derived therefrom. In further embodiments, a “sample derived from a subject” refers to brain tissue (or subcomponents thereof) or retinal tissue (or subcomponents thereof) derived from the subject. It will be understood that, although the sequences provided herein are described as modified or conjugated sequences, the RNA of the RNAi agent of the disclosure e.g., a dsRNAof the disclosure, may comprise any one of the sequences provided herein that is un-modified,un-conjugated, or modified or conjugated differently than described therein. That is, the modified sequences provided herein do not require the indicated hexadecyl lipophilic moiety, Page 25 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 or any ligand. A lipophilic ligand can be included in any of the positions provided in the instant application. II. dsRNA Agents of the Disclosure Described herein are formulations of dsRNA agents which inhibit the expression of a SNCA gene. Non-limiting examples of dsRNA agents that target the SNCA gene are provided in WO2022 / 072447 and WO2023 / 192977; each of which are hereby incorporated by reference in their entireties. The exemplified RNAs described herein identify a site(s) in an SNCA transcript that is susceptible to RISC-mediated cleavage. As such, the present disclosure further features RNAi agents that target within this site(s). As used herein, a RNAi agent is said to target within a particular site of an RNA transcript if the RNAi agent promotes cleavage of the transcript anywhere within that particular site. Such a RNAi agent will generally include at least about 15 contiguous nucleotides from one of the sequences provided herein coupled to additional nucleotide sequences taken from the region contiguous to the selected sequence in an SNCA gene. A RNAi agent as described herein can contain one or more mismatches to the target sequence. In one embodiment, a RNAi agent as described herein contains no more than 3 mismatches. In certain embodiments, if the antisense strand of the RNAi agent contains mismatches to the target sequence, the mismatch can optionally be restricted to be within the last 5 nucleotides from either the 5’- or 3’-end of the region of complementarity. For example, in such embodiments, for a 23 nucleotide RNAi agent, the strand which is complementary to a region of a SNCA gene, generally does not contain any mismatch within the central 13 nucleotides. The methods described herein or methods known in the art can be used to determine whether a RNAi agent containing a mismatch to a target sequence is effective in inhibiting the expression of an SNCA gene. Consideration of the efficacy of RNAi agents with mismatches in inhibiting expression of an SNCA gene is important, especially if the particular region of complementarity in an SNCA gene is known to have polymorphic sequence variation within the population. In one aspect, a dsRNA of the disclosure includes at least two nucleotide sequences, a sense sequence and an antisense sequence. In one aspect, the dsRNA agent is ALN-1747580, or a pharmaceutically acceptable salt thereof, such as a sodium, potassium, or magnesium salt. In preferred embodiments, Page 26 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 ALN-1747580 is in sodium salt form. The drug substance ALN-1747580 , is a small interfering ribonucleic acid (siRNA) comprised of a chemically synthesized double stranded oligonucleotide. The sense strand (A-3230018) contains 21 nucleosides and the antisense_`^MZP #6&+1 / *+1.$ O[Z`MUZ_ +,' HTQ ZaOXQ[_UPQ_ UZ QMOT _`^MZP M^Q O[ZZQO`QP `T^[aST ,q&.qphosphodiester or 3’-5’ phosphorothioate linkages, thus forming the sugar-phosphate backbone of the oligonucleotide. The majority of nucleotides in ALN-1747580 are either 2’-< #PQ[de^UN[ZaOXQ[`UPQ_$% +q&C&YQ`TeX ZaOXQ[`UPQ_ #+h&CAQ$ [^ +h&: Y[PURUQPribonucleotides. There is one vinyl phosphonate (VP) modified 2’-OMe uridine at the 5’-end of the antisense strand, A-2861285, and one 2’-hexadecyl modified adenosine (Ahd) near the 5’ end of the sense strand, A-3230018. In certain embodiments, ALN-1747580 is ALN- 1747580 is schematically presented in FIG.1. The molecular formula of the sodium salt form of ALN-1747580 is C470H573F4N160O292P43S8Na44. The formula weight of the sodium form is 15,811.45 Da. The molecular formula of the H-form of ALN-1747580 is C470H617F4N160O292P43S8. The formula weight of the H-form is 14,844.24 Da. The ALN-1747580 drug substance may be named using the following accepted oligonucleotide nomenclature: A-3230018, sense strand:.q #+q&O&YQ`TeX$`TU[SaMZeXeX&#,q&.q$&#+q&O&YQ`TeX$`TU[MPQZeXeX &#,q&.q$&#+q&O-YQ`TeX$SaMZeXeX&#,q&.q$&#+q&O&YQ`TeX$Oe`UPeXeX&#,q&.q$&#+q&O&YQ`TeX$MPQZeXeX&#,q&.q$&#+q&O-TQdMPQOeX$MPQZeXeX&#,q&.q$&#+q&O&YQ`TeX$SaMZeXeX &#,q&.q$&#+q&O&YQ`TeX$a^UPeXeX&#,q&.q$&#+q&RXa[^[$SaMZeXeX&#,q&.q$&#+q&RXa[^[$MPQZeXeX&#,q&.q$&#+q&RXa[^[$Oe`UPeXeX&#,h&.h$& #+q&O-YQ`TeX$MPQZeXeX&#,q&.q$&#+q&OYQ`TeX$ MPQZeXeX&#,q&.q$&#+q&O&YQ`TeX$MPQZeXeX&#,q&.q$&#+q&O-YQ`TeX$a^PeXeX&#,q&.q$&#+q&O- YQ`TeX$SaMZeXeX&#,q&.q$&#+q&C&YQ`TeX$a^PeXeX #,q&.q$&#+q&C&YQ`TeX$a^PeXeX&#,q&.q$&#+q&CYQ`TeX$ `TU[SaMZeXeX&#,q&.q$&#+q&C&YQ`TeX$`TU[SaMZeXeX&#,q&.q$#+q&C&YQ`TeX$MPQZUZQ% +) _[PUaY _MX` ,q4 (SEQ ID NO: 1).The sense strand, A-3230018, is base-paired with the antisense strand A-2861285. A-2861285, antisense strand:.q #JUZeX\T[_\T[ZM`Q&+q&C&YQ`TeX$`TU[a^UPeXeX&#,q&.q$ &#+q&PQ[de$`TU[Oe`UPeXeX&#,q&.q$&#+q&CYQ`TeX$ Oe`UPeXeX&#,q&.q$&#+q&C&YQ`TeX$MPQZeXeX &#,q&.q$&#+q&PQ[de$MPQZeXeX&#,q&.q$&#+q&CYQ`TeX$Oe`UPeXeX&#,q&.q$ #+q&PQ[de$MPQZeXeX&#,q&.q$&#+q&C&YQ`TeX$a^UPeXeX&#,q&.q$&#+q&CYQ`TeX$ a^UPeXeX&#,q&.q$&#+q&C YQ`TeX$a^UPeXeX&#,q&.q$&#+q&C&YQ`TeX$SaMZeXeX&#,q&.q$&#+q&PQ[de$`TeYUPeXeX&#,q&.q$&#+q&C&YQ`TeX$Oe`UPeXeX&#,q&.q$&#+q&RXa[^[$MPQZeXeX&#,q&.q$&#+q&C&YQ`TeX$Oe`UPeXeX&#,q&.q$&#+q&C&YQ`TeX$a^UPeXeX&#,q&.q$&# +q&C&YQ`TeX$a^UPeXeX&#,q&.q$&#+q&CYQ`TeX$SaMZeXeX&#,q&.q$&#+q&C&YQ`TeX$ Oe`UPeXeX&#,q&.q.q$&# +q&C&YQ`TeX$a^UPeXeX&#,q&.q$&#+q&Page 27 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920CYQ`TeX$`TU[Oe`UPeXeX&#,q&.q$&#+q&C&YQ`TeX$`TU[a^UPeXeX&#,q&.q$&#+q&C&YQ`TeX$a^UPUZQ% +-_[PUaY _MX` ,q #G9E =8 BC3 +$'Alternatively, the ALN-1747580 drug substance may be described using the following abbreviated format for each single strand: A-3230018, sense strand .q ;Y&\_&6Y&\_&;Y&7Y&6Y&6TP&;Y&IY&;R&6R&7R&6Y&6Y&6Y&IY&;Y&IY&IY&;Y&\_&;Y&\_&6Y ,q #G9E =8 BC3 *$base-paired with: A-2861285, antisense strand .q JDa&\_&P7&\_&7Y&6Y&P6&7Y&P6&IY&IY&IY&;Y&PH&7Y&6R&7Y&IY&IY&;Y&7Y&IY&7Y&\_&IY&\_&IY ,q #G9E =8 BC3 +$6R 5 +q&RXa[^[MPQZ[_UZQ7R 5 +q&RXa[^[Oe`UPUZQ;R 5 +q&RXa[^[SaMZ[_UZQ6Y 5 +q&O-methyladenosineIY 5 +q&O-methyluridine7Y 5 +q&O-methylcytidine;Y 5 +q&O-methylguanosineP6 5 +q&PQ[deMPQZ[_UZQP75 +q&PQ[deOe`UPUZQPH 5 +q&PQ[de`TeYUPUZQ6TP 5 +q&O-hexadecyladenosineJDa 5 bUZeX\T[_\T[ZM`Q +q&O-methyluridineq&q #Te\TQZ$ 5 ,q&.q \T[_\T[PUQ_`Q^ XUZWMSQq&\_&q 5 ,q&.q \T[_\T[^[`TU[M`Q XUZWMSQ'The ALN-1747580 drug substance may also be named using a convention in which the ribonucleosides are designated by three-letter symbols: A-3230018, sense strand 5’ Guom-ps-Adom-ps-Guom-Cydm-Adom-Ahd-Guom-Urdm-Guof-Adof-Cydf- Adom-Adom-Adom- Urdm-Guom-Urdm-Urdm-Guom-ps-Guom-ps-Adom 3’ (SEQ ID NO: 1) base-paired with: A-2861285, antisense strand Page 28 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 5’ VPu-ps-dCyd-ps-Cydm-Adom-dAdo-Cydm-dAdom-Urdm-Urdm-Urdm-Guom- dTym-Cydm-Adof-Cydm-Urdm-Urdm-Gydm-Cydm-Urdm-Cydm-ps-Urdm-ps-Urdm 3’ (SEQ ID NO: 2) 6P[R 5 +q&RXa[^[MPQZ[_UZQ7ePR 5 +q&RXa[^[Oe`UPUZQGuof= 2’-fluoroguanosine 6P[Y 5 +q&O-methyladenosineI^PY 5 +q&O-methyluridine7ePY 5 +q&O-methylcytidine;a[Y 5 +q&O-methylguanosineP6P[ 5 +q&PQ[deMPQZ[_UZQdCyd = 2’-deoxycytidine dTym = 2’-deoxythymidine Ahd = 2’-O-hexadecyladenosine VPu = vinylphosphonate 2’-O-methyluridine #Te\TQZ$ 5 ,q&.q \T[_\T[PUQ_`Q^ XUZWMSQq&\_&q 5 ,q&.q \T[_\T[^[`TU[M`Q XUZWMSQ'The molecular formula of the sodium salt form of the sense strand, A-3230018, is C237H592F3N89O134P20S4Na20. The molecular weight of the sodium form of the sense strand is 7,795.91 Da. The molecular formula of the H-form of the sense strand is C237H312F3N89O134P20S4. The molecular weight of the free acid is 7,356.27 Da. The molecular formula of the sodium salt form of the antisense strand, A-2861285, is C233H281F1N71O158P23S4Na24. The molecular weight of the sodium form of the antisense strand is 8,051.54 Da. The molecular formula of the H-form of the sense strand is C233H305F1N71O158P23S4. The molecular weight of the free acid is 7,487.97 Da. A simplified form of the structure of ALN-1747580 is presented in FIG.2 with the bases involved in a base pair formation connected with a centered dot. In one embodiment, the dsRNA agent is selected from Table 1, including the sodium salts thereof. In another example, the dsRNA is one of, or the sodium salt of, ALN-1804698, ALN-1804699, ALN-1747575, ALN-1747576, ALN-1804700, ALN-1747577, ALN- 1747578, ALN-1747579, ALN-1747580, ALN-1747581, ALN-1804701, ALN-1747582, ALN-1804702, ALN-1804703, ALN-1804704, ALN-1747583, ALN-1804705, ALN- 1804706, ALN-1804707, ALN-1804708, ALN-1804709, ALN-1747591, ALN-1747585, Page 29 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 ALN-1804710, ALN-1804711, ALN-1747586, ALN-1804712, ALN-1747587, ALN- 1804713, ALN-1804714, ALN-1747588, ALN-1804715, ALN-1804716, ALN-1804717, ALN-1804718, ALN-1804719, ALN-1804720, ALN-1804721, ALN-1804722, ALN- 1804723, ALN-1804724, ALN-1804725, or ALN-1804726. Optionally, the dsRNA agent is ALN-1747580, ALN-1747583, or ALN-1747585, or the sodium salt thereof. The abbreviations of nucleotide monomers used in the nucleic acid sequence representation herein are provided in Table 2. Page 30 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 02942-103121:.o Ntekco D yttA c n V e u Q : qeED IO 11 8 SN1 52 3 4 5 6 7 8 9 01 21 31 41 51 61 S dna a aas a aaa a aaa aasgs s assusgsa s s sassaausus sart sgsgs c ssasc sasgsuss s usgsscsa cgau u u uSa aua uuc c c a cucu gu u g u uguu u uau gueua cc uua u)us c auaea aucuga uca uac ad uaauau unag u uuaun h u u uaggccc a ae a a ueaga acs auc cag uu uaUfu(i g a gc atg gufa a u af ff f fa uf fff f f f fq uAn efuA A AG A GC U AfAG Gf ff f fA Af ff ff f f fS gAAfa A G AoA G AAfG AfGG Uf ff fA Uf f f fff f f fd g U A CniGCAGl fG A GA UU Gg G Aaf a acu uca aa u ua auOC a aag cfc g a cu) )g a)a a) )) ) ) ))) ) ) )Ue)sd dded dd d d ddd C d d dsd h hhh hn h h h hhh h h huhnceeCA UC A C CC U GU( (A( ( ( (U G( ( (g(( ( (GS((Scu gu gg gag a g ga c agaa c a ac c ag gd u g uu gu g 1g g ugagau u aug ue usi sss s sss s sg s s s ss.vs a a a caufu uic gua c ggs s6ss s ssu s s ss s s sss a9a cda a a c au u u g u g u 5 go 96 M 40 3 5 8 9 5 6 0 7 8 9 1 1 2 2 3. 8x - - - - - - - - - - - - - - - -e 8 8 8 9 9 7 7 0 7 7 7 8 0 8 0 015\el5 5 5 6 6 5 5 7 5 5 5 5 7 5 7 7N N N N N N N N N N N N N N N Nm 17 7 7 4 4 7 7 4 7 7 7 7 4 7 4 4pelL L L L L L L L L L L L L L L La E4 4 4 0 0 4 4 0 4 4 4 4 0 4 0 0ub A A A A A A A A A A A A A A A A N 7 7 7 8 8 7 7 8 7 7 7 7 8 7 8 8 M Da 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 T Page 31 of 79ME1\58469596.v1 Atty Docket No.: 121301-24920 02942-103121:.o Ntekco D yttA C U A U G A A G U U 97fo 23 e gaP 1 .v6959648 5\1E M Page 32 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 02942-103121:.o Ntekco D yttA gsgsasgsgsu uggsgscscsa gu ususcsu u asucscsc sg g ga sa suagagasuausu u u u e u g ccfuuc cg cafuucu aag g g ggfacgaane Gaccu Cauccf fu Ucuuf fu gfg uafcf9 qufe UAf7 C a aaA U aGfuaAaAaCg G f S u o c u A d Ccu C o d T 3 c d TuagaT ddd G uu aaa ad 3 gil ac u O)uu ccac)u gaa a cugug)ae nc an u g g esg d g A A n uuA T TaganT dd Ad g d T P d d e(u uaT(a uauA(g u siC A G d G Gd T Td u Ad T tdagdacdaudnau T a d udasa asaas susus scuaA CAssA G GC Csff fdd d d dd dss s s ss sAA Gss suu u u uu uuu u PP P P PP PPP P V V V V V V V V V V :Q 6 7 8 9 0 1 2 3 4 5DOEI3 3 3 3 4 4 4 4 4 4NS aa assasa aaa a ass ss s suu scs csug c gg usss s ss sagsugauauu u uuuc a aacugu uac a auaacu uaaaea aauu ccaua a auucuuugncuaauguug ceaa aa auga uuuf ffga g ua c ufff ff f fqeA UAf ffUU CG U CAf f ff f ffSG AGf ffCAoG AU AGfff ff ffg U UU CiU UlAA UUcua cauggfu uffOaa ggg a c)) ))) ) )CAA)))ddeddd d dsddd hh hhh h h hhnheUGGUU G A(((( ( (A (GCS((( auuuc cgua cacgggguca cg 1c aac uas sss ssac sas .vs s augu a acs su 6sussc sss a9c asu u usgc a5 g 9647 8 9 0 1 2 3 4 5 6 8x - - - - - - - - - -e 1 1 1 2 2 2 2 2 2 25\el7 7 7 7 7 7 7 7 7 7N N N N N N N N N Nm 14 4 4 4 4 4 4 4 4 4p L L L L L L L L L La E0 0 0 0 0 0 0 0 0 0u A A A A A A A A A A N 8 8 8 8 8 8 8 8 8 8 M D 1 1 1 1 1 1 1 1 1 1 Page 33 of 79ME1\58469596.v1 Atty Docket No.: 121301-24920 Table 2. Abbreviations of nucleotide monomers used in nucleic acid sequence representation: It will be understood that these monomers, when present in an oligonucleotide, are mutually linked by 5'-3'-phosphodiester bonds; and it is understood that when the nucleotide contains a 2’-fluoro modification, then the fluoro replaces the hydroxy at that position in the parent nucleotide (i.e., it is a 2’-deoxy-2’-fluoronucleotide). It will also be understood that the abbreviations correspond to nucleotides which omit the 3’-phosphate when found at the 3’-terminal position (i.e., they are 3’-OH). Page 34 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 Page 35 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 In one aspect, the dsRNA agent is ALN-1747583. In one aspect, the dsRNA agent is the sodium salt of ALN-1747583. In one aspect, the dsRNA agent is ALN-1747585. In one aspect, the dsRNA agent is the sodium salt of ALN-1747585. III. Preparation of dsRNA Agents of the Disclosure A dsRNA can be synthesized by standard methods known in the art as further discussed below, e.g., by use of an automated DNA synthesizer, such as are commercially available from, for example, Biosearch, Applied Biosystems, Inc. RNAi agents of the disclosure may be prepared using a two-step procedure. First, the individual strands of the double stranded RNA molecule are prepared separately. Then, the component strands are annealed. The individual strands of the siRNA compound can be prepared using solution-phase or solid-phase organic synthesis or both. Organic synthesis offers the advantage that the oligonucleotide strands comprising unnatural or modified nucleotides can be easily prepared. Single-stranded oligonucleotides of the disclosure can be prepared using solution-phase or solid-phase organic synthesis or both. An siRNA can be produced, e.g., in bulk, by a variety of methods. Exemplary methods include: organic synthesis and RNA cleavage, e.g., in vitro cleavage. An siRNA can be made by separately synthesizing a single stranded RNA molecule, or each respective strand of a double-stranded RNA molecule, after which the component strands can then be annealed. A large bioreactor, e.g., the OligoPilot II from Pharmacia Biotec AB (Uppsala Sweden), can be used to produce a large amount of a particular RNA strand for a given siRNA. The OligoPilotII reactor can efficiently couple a nucleotide using only a 1.5 molar excess of a phosphoramidite nucleotide. To make an RNA strand, ribonucleotides amidites are used. Standard cycles of monomer addition can be used to synthesize the 21 to 23 nucleotide strand for the siRNA. Typically, the two complementary strands are produced separately and then annealed, e.g., after release from the solid support and deprotection. Organic synthesis can be used to produce a discrete siRNA species. The complementary of the species to a SNCA gene can be precisely specified. For example, the species may be complementary to a region that includes a polymorphism, e.g., a single nucleotide polymorphism. Further the location of the polymorphism can be precisely defined. In some embodiments, the polymorphism is located in an internal region, e.g., at least 4, 5, 7, or 9 nucleotides from one or both of the termini. Page 36 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 In one embodiment, RNA generated is carefully purified to remove ends. iRNA is cleaved in vitro into siRNAs, for example, using a Dicer or comparable RNAse III-based activity. For example, the dsiRNA can be incubated in an in vitro extract from Drosophila or using purified components, e.g., a purified RNAse or RISC (RNA-induced silencing complex). See, e.g.,Ketting et al. Genes Dev 2001 Oct 15;15(20): 2654-9 and Hammond Science 2001 Aug10;293(5532): 1146-50. dsiRNA cleavage generally produces a plurality of siRNA species, each being a particular 21 to 23 nt fragment of a source dsiRNA molecule. For example, siRNAs that include sequences complementary to overlapping regions and adjacent regions of a source dsiRNA molecule may be present. Regardless of the method of synthesis, the siRNA preparation can be prepared in a solution (e.g., an aqueous or organic solution) that is appropriate for formulation. For example, the siRNA preparation can be precipitated and re-dissolved in pure double-distilled water, and lyophilized. The dried siRNA can then be resuspended in a solution appropriate for the intended formulation process. An exemplary manufacturing process is detailed in the examples provided herein for ALN-1747580. IV. Formulations of the Disclosure In order to administer dsRNAs to a subject via parenteral administration, the dsRNA must be formulated into a suitable aqueous solution. In the course of research into preparing such formulations, it has been surprisingly discovered that dsRNAs having at least one lipophilic modification must be formulated in a particular way to avoid long-term stability problems. In particular, formulation of dsRNAs in the presence of a bivalent cation (e.g., calcium, magnesium, copper, nickel, zinc, or strontium) can result in problematic precipitation issues where the stoichiometry of the individual strands of a dsRNA in the formulation should be controlled to prevent precipitation of lipophilic molecules in the aqueous solution. Exemplary dsRNA formulations and methods of formulating dsRNAs that may be used in the formulations and methods provided herein are provided in PCT / US2024 / 024374, which is herein incorporated by reference in its entirety. In addition to stoichiometry control of the sense and antisense duplexes, the formulations provided herein may also be substantially free of inorganic phosphate. In some embodiments, the formulations provided herein are substantially free of inorganic and also have the addition of a divalent cation (such as calcium). Page 37 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 Certain compositions of the disclosure therefore carry an excess of a non-lipophile- modified strand of a dsRNA relative to a lipophile-modified strand of the dsRNA. Some compositions are also substantially free of sources of inorganic phosphate. It is contemplated in certain embodiments that mitigation against particulate formation in nucleic acid formulations of the disclosure can be achieved by reducing sources of inorganic phosphate in such compositions, e.g., to 100 ppm or less, to 50 ppm or less, or to 10 ppm or less. In embodiments, the compositions of the disclosure are employed for delivery of nucleic acid agents, e.g., iRNA agents, including dsRNAs as specifically exemplified herein. The level of nucleic acid agent in a composition of the instant disclosure can range, e.g., from about 5 mg / mL to about 300 mg / mL. In a related embodiment, the composition includes a nucleic acid agent at about 10 mg / mL to about 200 mg / mL. In a further embodiment, the composition includes a nucleic acid agent at about 20 mg / mL to about 100 mg / mL. In one embodiment, the composition includes a nucleic acid agent at about 40 mg / mL to about 80 mg / mL. In one embodiment, the composition includes a nucleic acid agent at about 50 mg / mL to about 70 mg / mL. Optionally, the composition includes a nucleic acid agent at about 60 mg / mL. Compositions of the present disclosure may comprise a number of salts that provide sources of physiologically relevant ionic species, such as Na+, K+, Mg2+, Cl-, or Ca2+. These may include, without limitation, sodium chloride, potassium chloride, magnesium chloride, and calcium chloride. The compositions may further comprise other trace elements and their salts, including, but not limited to, selenium, copper, chromium, iodine, fluoride, zinc, manganese, molybdenum, and iron. Sodium ions are included in relatively large concentrations in the formulations of the instant disclosure, at least in part in view of their role in normal physiological functioning. Na+is the major cation of the extracellular fluid. It plays an important role in many physiological processes, including the regulation of blood volume, blood pressure, osmotic equilibrium, and pH, as well as the generation of nerve impulses. Potassium ions are the major cation of intracellular fluid, and, with the sodium ions of the extracellular fluid, K+is a primary generator of the electrical potential across cellular membranes. Accordingly, it plays a significant role in normal functioning, and is relevant to such body functions as neurotransmission, muscle contraction, and heart function. Calcium ions are likewise important to many physiological processes. In particular, Ca2+ions are one of the most widespread second messengers used in signal transduction. In endothelial cells, Ca2+ions may regulate several signaling pathways which cause smooth Page 38 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 muscles surrounding blood vessels to relax. Dysfunction within Ca2+-activated pathways can lead to an increase in tone caused by unregulated smooth muscle contraction. This type of dysfunction can be seen in cardiovascular diseases, hypertension, and diabetes. Inclusion of Ca2+ions in the compositions of the instant disclosure also has been identified to mitigate against certain adverse events (e.g., tremors, twitches, other neurological issues) seen in subjects administered calcium-free or low calcium nucleic acid formulations via intrathecal injection. Magnesium ions are used in relatively large concentrations in normal metabolism. It is recognized that deficiency of magnesium is rare unless it is accompanied by severe losses in other electrolytes such as in vomiting and diarrhea. It is however frequently recognized as deficient in the modern diet with symptoms such as muscle tremors and weakness. This mineral is important in many enzymatic reactions and will stabilize excitable membranes. Administered intravenously, magnesium may produce an anesthetic action and this is indirect evidence of its action on the vascular wall endothelial component to stabilize and normalize the surface of the vascular wall. In some embodiments, a composition of the present disclosure includes a sodium ion (Na+) source (e.g., provided as sodium chloride) at a concentration between 0.1 mM and 1 M. In a related embodiment, a Na+source is present at a concentration between about 40 mM and about 300 mM. Optionally, a Na+source is present at a concentration between about 70 mM and about 200 mM. In a related embodiment, a Na+source is present at a concentration between about 70 mM and about 100 mM. In a related embodiment, a Na+source is present at a concentration between about 80 mM and about 120 mM. In a related embodiment, a Na+source is present at a concentration between about 80 mM and about 110 mM. In a related embodiment, a Na+source is present at a concentration between about 85 mM and about 100 mM. In a related embodiment, a Na+source is present at a concentration between about 90 mM and about 100 mM. In an alternative embodiment, a Na+source is present at a concentration between about 90 mM and about 105 mM, optionally between about 95 mM and about 100 mM. In a related embodiment, a Na+source is present at a concentration of about 97 mM to about 98 mM. In a related embodiment, a Na+source is present at a concentration between about 78 mM and about 96 mM. In a related embodiment, a Na+source is present at a concentration between about 83 mM and about 91 mM. In one embodiment, a Na+source is present at a concentration of about 87 mM. In one embodiment, a Na+source is present at a concentration of 87 mM. Page 39 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 In certain embodiments, a composition of the present disclosure includes a calcium ion (Ca2+) source (e.g., provided as calcium chloride) at a concentration between 0.1 mM and 1 M. In some embodiments, a Ca2+source is present at a concentration between about 0.1 mM and about 200 mM. In a further embodiment, a Ca2+source is present at a concentration between about 0.5 mM and about 100 mM. Optionally, a Ca2+source is present at a concentration between about 0.8 mM and about 50 mM. In some embodiments, a Ca2+source is present at a concentration between about 1 mM and about 25 mM. In some embodiments, a Ca2+source is present at a concentration between about 2 mM and about 20 mM. In some embodiments, a Ca2+source is present at a concentration between about 8 mM and about 20 mM. In some embodiments, a Ca2+source is present at a concentration between about 8 mM and about 25 mM. In some embodiments, a Ca2+source is present at a concentration between about 5 mM and about 15 mM. Alternatively, a Ca2+source is present at a concentration between about 10 mM and about 18 mM. In some embodiments, a Ca2+source is present at a concentration between about 12 mM and about 18 mM. In some embodiments, a Ca2+source is present at a concentration between about 15 mM and about 17 mM. In some embodiments, a Ca2+source is present at a concentration between about 15.5 mM and about 16.5 mM. In some embodiments, a Ca2+source is present at a concentration between about 14.7 mM and about 17.9 mM. In some embodiments, a Ca2+source is present at a concentration between about 15.5 mM and about 17.1 mM. Optionally, a Ca2+source is present at a concentration of about 15.5 mM, about 15.75 mM, about 16.0 mM, about 16.25 mM, about 16.3 mM, about 16.5 mM, or about 16.75 mM. In certain embodiments, a Ca2+source is present at a concentration of about 16.3 mM. In certain embodiments, a Ca2+source is present at a concentration of 16.3 mM. In some embodiments, a composition of the present disclosure comprises a potassium ion (K+) source (e.g., provided as potassium chloride) at a concentration between 0.0 mM and 1 M. In some embodiments, a K+source is present at a concentration between about 0.1 mM and about 100 mM. In a further embodiment, a K+source is present at a concentration between about 0.2 mM and about 40 mM. In a further embodiment, a K+source is present at a concentration between about 0.5 mM and about 20 mM. In some embodiments, a K+source is present at a concentration between about 1 mM and about 5 mM. In some embodiments, a K+source is present at a concentration between about 1 mM and about 4 mM. In some embodiments, a K+source is present at a concentration between about 1 mM and about 3 mM. In some embodiments, a K+source is present at a concentration between about 1.0 mM and about 2.5 mM. In some embodiments, a K+source is present at a concentration between about Page 40 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 1.5 mM and about 2.5 mM. In some embodiments, a K+source is present at a concentration between about 1.5 mM and about 2.2 mM. In some embodiments, a K+source is present at a concentration between about 1.5 mM and about 1.9 mM. In some embodiments, a K+source is present at a concentration between about 1.6 mM and about 1.8 mM. Optionally, a K+source is present at a concentration of about 1.0 mM, about 1.1 mM, about 1.2 mM, about 1.3 mM, about 1.4 mM, about 1.5 mM, about 1.6 mM, about 1.7 mM, about 1.8 mM, about 1.9 mM, about 2.0 mM, about 2.1 mM, about 2.2 mM, about 2.3 mM, about 2.4 mM, about 2.5 mM, about 2.6 mM, about 2.7 mM, about 2.8 mM, about 2.9 mM, or about 3.0 mM,. In certain embodiments, a K+source is present at a concentration of about 1.7 mM. In certain embodiments, a K+source is present at a concentration of 1.7 mM. In certain embodiments, a composition of the present disclosure comprises a magnesium ion (Mg2+) source (e.g., provided as magnesium chloride) at a concentration between 0.0 mM and 1 M. In some embodiments, a Mg2+source is present at a concentration between about 0.01 mM and about 100 mM. In a further embodiment, a Mg2+source is present at a concentration between about 0.1 mM and about 40 mM. In a further embodiment, a Mg2+source is present at a concentration between about 0.2 mM and about 20 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.3 mM and about 5 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.3 mM and about 4 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.3 mM and about 3 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.3 mM and about 2 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.3 mM and about 1 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.1 mM and about 1 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.3 mM and about 0.7 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.3 mM and about 0.6 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.4 mM and about 0.6 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.4 mM and about 0.5 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.44 mM and about 0.48 mM. Optionally, a Mg2+source is present at a concentration of about 0.3 mM, about 0.4 mM, about 0.5 mM, about 0.6 mM, about 0.7 mM, about 0.8 mM, or about 0.9 mM,. In certain embodiments, a Mg2+source is present at a concentration of about 0.5 mM. In a further embodiment, a Mg2+source is present at a concentration of 0.5 mM. In certain embodiments, a Mg2+source is present at a concentration of about 0.4 mM. In a further embodiment, a Mg2+source is present at a Page 41 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 concentration of 0.4 mM. In certain embodiments, a Mg2+source is present at a concentration of about 0.4 mM. Alternatively, a Mg2+source is present at a concentration of 0.46 mM. In some embodiments, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent of greater than about 2:1. In certain embodiments, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent of greater than about 2.5:1. In further embodiments, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent of greater than about 3:1. In other embodiments, a composition of the disclosure has a molar ratio of divalent cation source-to- nucleic acid agent of greater than about 3.5:1. In further related embodiments, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent of greater than about 4:1. In certain related embodiments, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent between about 2:1 and about 10:1. Optionally, a composition of the disclosure has a molar ratio of divalent cation source-to- nucleic acid agent between about 3:1 and about 10:1. Optionally, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent between about 3:1 and about 9:1. Optionally, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent between about 3:1 and about 8:1. Optionally, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent between about 3:1 and about 7:1. Optionally, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent between about 3:1 and about 6:1. Optionally, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent between about 3:1 and about 5:1. In some embodiments of the solutions provided herein, the pH of the solution is between 4 and 10, optionally between 6 and 10. In related embodiments, the pH of the solution is between about 6.5 and about 8.0. In some embodiments, the pH of the solution is between about 6.1 and about 7.5. In some embodiments, the pH of the solution is between about 6.5 and about 7.1. In a further embodiment, the pH of the solution is 6.5-7.8. In certain embodiments of the solutions provided herein, the pH of the solution is 6.7-7.5. In some embodiments, the pH of the solution is 6.8-7.2. In further embodiments, the pH of the solution is about 6.8. In some embodiments of the compositions provided herein, an aqueous solution of the disclosure has an osmolality between about 100 and 500 mOsm / kg. In a further embodiment, an aqueous solution of the disclosure has an osmolality between about 200 and 400 mOsm / kg. In some embodiments, an aqueous solution of the disclosure has an osmolality between about 270 and 330 mOsm / kg. In some embodiments, an aqueous solution of the disclosure has an Page 42 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 osmolality between about 285 and 315 mOsm / kg. In certain embodiments, an aqueous solution of the disclosure has an osmolality of about 300 mOsm / kg. In a specific embodiment, an aqueous solution of the disclosure has an osmolality of 301 mOsm / kg. In certain embodiments, the compositions (i.e., aqueous compositions) provided herein can be stored for at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least one week, at least two weeks, at least three weeks, or at least one month at 25 °C without measurable precipitation of solutes and / or measurable loss of the capability to produce knockdown of a target gene in a subject administered such a solution via intrathecal injection. In some embodiments, the compositions provided herein can be stored for at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least one week, at least two weeks, at least three weeks, or at least one month at 2-8 °C without measurable precipitation of solutes and / or measurable loss of the capability of the capability to produce knockdown of a target gene in a subject administered such a solution via intrathecal injection. V. Pharmaceutical Compositions / Formulations The present disclosure provides pharmaceutical compositions and formulations which include the RNAi agents described herein (e.g., ALN-1747580); however, it is expressly contemplated that the formulations of the instant disclosure can be employed for delivery of any SNCA RNAi agent. In one embodiment, provided herein are pharmaceutical compositions containing an RNAi agent, as described herein, and a pharmaceutically acceptable carrier. The pharmaceutical compositions containing the RNAi agent are useful for treating a disease or disorder associated with the expression or activity of a gene (e.g., SNCA.) to treat a disorder such as, for example, a SNCA-associated disease. The pharmaceutical compositions of the disclosure may be administered in dosages sufficient to inhibit expression of a SNCA gene. In general, a suitable dose of an RNAi agent of the disclosure will be in the range of about 0.001 to about 200.0 milligrams per kilogram body weight of the recipient, generally in the range of about 1 to 50 mg per kilogram body weight. Such pharmaceutical compositions are formulated based on the mode of delivery. The formulations / pharmaceutical compositions disclosed herein are primarily formulated for injection, and in certain applications, for direct delivery into the CNS, e.g., by intrathecal or Page 43 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 intravitreal routes of injection, optionally by infusion into the brain (e.g., striatum), such as by continuous pump infusion. However, certain compositions of the instant disclosure can also be formulated for systemic administration via parenteral delivery, e.g., by intravenous (IV), intramuscular (IM), or for subcutaneous (subQ) delivery. In certain embodiments, the pharmaceutical compositions of the disclosure are substantially free of inorganic phosphate. In some embodiments, the molar ratio of a divalent ion source-to-nucleic acid therapeutic of the disclosure within a formulation is greater than about 2:1. In certain embodiments, the pharmaceutical compositions of the disclosure are pyrogen free or non-pyrogenic. The skilled artisan will appreciate that certain factors can influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a composition can include a single treatment or a series of treatments. The pharmaceutical compositions of the present disclosure are primarily formulated for CNS delivery, administered via an intracranial route, e.g., by intrathecal, intraparenchymal, or intraventricular administration. The RNAi agent formulations can be delivered in a manner to target a particular tissue of the CNS (e.g., neuronal, glial or vascular tissue of the brain), or both a non-CNS organ (e.g., the liver) and the CNS. Other formulations amenable to the present disclosure (if made substantially free of sources of inorganic phosphate) are described in United States provisional application serial Nos. 61 / 018,616, filed January 2, 2008; 61 / 018,611, filed January 2, 2008; 61 / 039,748, filed March 26, 2008; 61 / 047,087, filed April 22, 2008 and 61 / 051,528, filed May 8, 2008. PCT application number PCT / US2007 / 080331, filed October 3, 2007, also describes formulations that are amenable to the present disclosure (if made substantially free of sources of inorganic phosphate). The formulations of the instant disclosure are contemplated to function with inclusion of a wide variety of additional components, provided that such additional components do not detract from efficacy / drug product functionality. Examples of such additional components include, without limitation, fats, oils, waxes, fatty acids, fatty alcohols, fatty esters, humectants, hydrophilic colloids, preservatives and antioxidants (Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, Page 44 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 p.335; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199), as well as glucose and other sugars / carbon sources. Compositions and formulations suitable for parenteral administration include, but are not limited to, such suitable for intraparenchymal (into the brain, e.g., intracerebrovascular), intrathecal (e.g., lumbar puncture (LP) or intracisterna magna (ICM) injection), intradiscal, periganglionic, and / or intraventricular administration, and can include sterile aqueous solutions which can also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. In certain embodiments herein, compositions and formulations suitable for parenteral administration do not include buffering components (e.g., phosphate salts). Pharmaceutical formulations of the present disclosure include, but are not limited to, solutions and emulsions. These compositions can be generated from a variety of components that include, but are not limited to, preformed liquids. The pharmaceutical formulations of the present disclosure, which can conveniently be presented in unit dosage form, can be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. The compositions of the present disclosure can be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions can further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol or dextran. The suspension can also contain stabilizers. Excipients In contrast to a carrier compound, a “pharmaceutical carrier” or “excipient” is a pharmaceutically acceptable solvent, suspending agent or any other pharmacologically inert vehicle for delivering one or more nucleic acids to an animal. The excipient can be liquid or solid and is selected, with the planned manner of administration in mind, so as to provide for the desired bulk, consistency, etc., when combined with a nucleic acid and the other components of a given pharmaceutical composition. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, Page 45 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like. Suitable pharmaceutically acceptable excipients include, but are not limited to, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like. Other Components The formulations of the present disclosure can additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions can contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present disclosure, and for the current disclosure should not provide an appreciable source of inorganic phosphate. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., preservatives, stabilizers, emulsifiers, salts for influencing osmotic pressure, colorings, flavorings or aromatic substances and the like which do not deleteriously interact with the nucleic acid(s) of the formulation. Aqueous suspensions can contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol or dextran. The suspension can also contain stabilizers. In some embodiments, pharmaceutical compositions contemplated by the disclosure include (a) one or more RNAi agents and (b) one or more agents which function by a non- RNAi mechanism and which are useful in treating a disease or disorder, e.g., a SNCA- associated neurodegenerative disease or disorder. Examples of such agents include, but are not limited to dopamine agonists and promoters, among others, including carbidopa-levodopa, levodopa, entacopone, tolcapone, opicapone, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, rivastigmine, donepezil, galantamine and memantine. In addition to their administration, as discussed above, the RNAi agent compositions featured in the disclosure can be administered in combination with other known agents effective in treatment of a disease or disorder. In any event, the administering physician can adjust the amount and timing of RNAi agent administration on the basis of results observed using standard measures of efficacy known in the art or described herein. Page 46 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 The present disclosure also provides a method for preparing a formulation comprising annealing a sense strand and an antisense strand, wherein one of the sense strand and antisense strand contains a lipophilic modification, to form a duplex solution comprising a double stranded RNA (dsRNA); lyophilizing the duplex solution to provide a duplex composition; and dissolving the duplex composition in an injection solution, wherein the injection solution comprises a divalent cation source (e.g., calcium) and does not comprise a phosphate buffer; and the duplex composition comprises 0 – 5% molar excess (e.g., about 1 – 2 % molar excess) of antisense strand over sense strand. A “duplex solution” is meant any solution comprising double stranded RNA (dsRNA). By “duplex composition” is meant any composition comprising a dsRNA. In some embodiments, the duplex composition is prepared by lyophilization. In one embodiment, the duplex composition is a lyophilized powder. An “injection solution” is any solution used for dissolving a duplex composition. In some embodiments, the injection solution comprises a divalent cation source. The divalent cation source is calcium, magnesium, copper, nickel, zinc, or strontium, optionally wherein the divalent ion source is calcium. In one embodiment, the injection solution does not comprise a phosphate buffer. In some embodiments, the duplex composition comprises the antisense strand at no less than equimolar amount relative to the sense strand. In some embodiments, the duplex composition comprises about a 1-2% molar excess, a 1-3% molar excess, a 1-4% molar excess, a 1-5% molar excess, a 0-5% molar excess, a 0-1% molar excess, a 2-3% molar excess, a 3-4% molar excess, a 3-5% molar excess, a 2-4% molar excess, a 2-5% molar excess of antisense strand over sense strand. In one embodiment, the duplex composition comprises about a 1-2% molar excess of antisense strand over sense strand. In another embodiment, the excess of antisense strand over sense strand is less than 1%. VI. Delivery of dsRNA Agents The delivery of an RNAi agent (or other nucleic acid therapeutic agent) composition of the disclosure to a cell e.g., a cell within a subject, such as a human subject (e.g., a subject in need thereof, such as a subject having a SNCA-associated disorder, can be achieved in a number of different ways. For example, delivery may be performed by contacting a cell with an RNAi agent composition of the disclosure either in vitro or in vivo. In vivo delivery may also be performed directly by administering a composition comprising an RNAi agent, e.g., a dsRNA, to a subject. Alternatively, in vivo delivery may be performed indirectly by administering one or more vectors that encode and direct the expression of the RNAi agent. Page 47 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 In general, methods of delivering a nucleic acid molecule (in vitro or in vivo) can be adapted for use with an RNAi agent composition of the disclosure (see e.g., Akhtar S. and Julian RL., (1992) Trends Cell. Biol.2(5): 139-144 and WO94 / 02595, which are incorporated herein by reference in their entireties). For in vivo delivery, factors to consider for delivering an RNAi agent composition include, for example, biological stability of the delivered agent, prevention of non-specific effects, and accumulation of the delivered agent in the target tissue. The non-specific effects of an RNAi agent can be minimized by local administration, for example, by direct injection or implantation into a tissue or topically administering the preparation. Local administration to a treatment site maximizes local concentration of the agent, limits the exposure of the agent to systemic tissues that can otherwise be harmed by the agent or that can degrade the agent, and permits a lower total dose of the RNAi agent to be administered. Several studies have shown successful knockdown of gene products when an RNAi agent is administered locally. For example, intraocular delivery of a VEGF dsRNA by intravitreal injection in cynomolgus monkeys (Tolentino, MJ. et al., (2004) Retina 24: 132- 138) and subretinal injections in mice (Reich, SJ. et al. (2003) Mol. Vis.9: 210-216) were both shown to prevent neovascularization in an experimental model of age-related macular degeneration. In addition, direct intratumoral injection of a dsRNA in mice reduces tumor volume (Pille, J. et al. (2005) Mol. Ther. 11: 267-274) and can prolong survival of tumor- bearing mice (Kim, WJ. et al., (2006) Mol. Ther.14: 343-350; Li, S. et al., (2007) Mol. Ther. 15: 515-523). RNA interference has also shown success with local delivery to the CNS by direct injection (Dorn, G. et al., (2004) Nucleic Acids 32: e49; Tan, PH. et al. (2005) Gene Ther.12: 59-66; Makimura, H. et a.l (2002) BMC Neurosci.3: 18; Shishkina, GT., et al. (2004) Neuroscience 129: 521-528; Thakker, ER., et al. (2004) Proc. Natl. Acad. Sci. U.S.A. 101: 17270-17275; Akaneya,Y., et al. (2005) J. Neurophysiol. 93: 594-602) and to the lungs by intranasal administration (Howard, KA. et al., (2006) Mol. Ther.14: 476-484; Zhang, X. et al., (2004) J. Biol. Chem.279: 10677-10684; Bitko, V. et al., (2005) Nat. Med.11: 50-55). Certain aspects of the instant disclosure relate to a method of reducing the expression of a target gene in a cell or subject, involving contacting said cell or subject with the double- stranded RNAi agent composition of the disclosure. In one embodiment, the cell is an extrahepatic cell, optionally a CNS cell. Another aspect of the disclosure relates to a method of reducing the expression of a target gene in a subject, involving administering to the subject the double-stranded RNAi agent composition of the disclosure. Page 48 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 Another aspect of the disclosure relates to a method of treating a subject having a target gene-associated disorder, involving administering to the subject a therapeutically effective amount of the double-stranded RNAi agent-containing composition of the disclosure, thereby treating the subject. In one embodiment, the double-stranded RNAi agent is administered intrathecally. By intrathecal administration of the double-stranded RNAi agent, the method can reduce the expression of a target gene in a brain (e.g., striatum) or spine tissue, for instance, cortex, cerebellum, cervical spine, lumbar spine, and thoracic spine. For ease of exposition the formulations, compositions and methods in this section are discussed largely with regard to modified siRNA compounds. It may be understood, however, that these formulations, compositions and methods can be practiced with other siRNA compounds, e.g., unmodified siRNA compounds, and such practice is within the disclosure. The RNAi agent compositions of the disclosure can be further incorporated into pharmaceutical compositions suitable for parenteral administration. Such compositions typically include one or more species of RNAi agent and a pharmaceutically acceptable carrier. As used herein the language “pharmaceutically acceptable carrier” is intended to include any and all solvents, antibacterial and antifungal agents, isotonic agents, and the like, compatible with pharmaceutical administration, but in certain aspects, excluding such agents comprising inorganic phosphate (e.g., excluding phosphate-buffered saline (PBS) as an isotonic solution in certain embodiments). The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. While the primary route of administration for the pharmaceutical compositions of the present disclosure is via parenteral administration, such as intrathecal injection, the pharmaceutical compositions of the present disclosure may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Parenteral administration includes intravenous drip, subcutaneous, intraperitoneal or intramuscular injection, or intrathecal or intraventricular administration. Compositions for intrathecal or intraventricular administration may include sterile aqueous solutions (though excluding agents comprising inorganic phosphate in certain aspects) which may also contain diluents and other suitable additives. Formulations for parenteral administration may include sterile aqueous solutions which may also contain diluents and other suitable additives. Intraventricular injection may be Page 49 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 facilitated by an intraventricular catheter, for example, attached to a reservoir. For intravenous use, the total concentration of solutes may be controlled to render the preparation isotonic. In one embodiment, the administration of the dsRNA compound, e.g., a double- stranded siRNA compound, or ssiRNA compound, composition is parenteral, e.g., intravenous (e.g., as a bolus or as a diffusible infusion), intradermal, intraperitoneal, intramuscular, intrathecal, intraventricular, intracranial, subcutaneous or ocular injection. Administration can be provided by the subject or by another person, e.g., a health care provider. Selected modes of delivery are discussed in more detail below. Intrathecal Administration In certain embodiments, a nucleic acid agent formulation (e.g., a double-stranded RNAi agent composition) is delivered by intrathecal injection (i.e., injection into the spinal fluid which bathes the brain and spinal cord tissue). Intrathecal injection of nucleic acid (e.g., RNAi) agents into the spinal fluid can be performed as a bolus injection or via minipumps which can be implanted beneath the skin, providing a regular and constant delivery of nucleic acid into the spinal fluid. The circulation of the spinal fluid occurs from the choroid plexus, where it is produced, down around the spinal cord and dorsal root ganglia and subsequently up past the cerebellum and over the cortex to the arachnoid granulations, where the fluid can exit the CNS, that, depending upon size, stability, and solubility of the compounds injected, allows molecules delivered intrathecally potentially to hit targets throughout the entire CNS. In some embodiments, the intrathecal administration is via a pump. The pump may be a surgically implanted osmotic pump. In one embodiment, the osmotic pump is implanted into the subarachnoid space of the spinal canal to facilitate intrathecal administration. In some embodiments, the intrathecal administration is via an intrathecal delivery system for a pharmaceutical including a reservoir containing a volume of the pharmaceutical agent, and a pump configured to deliver a portion of the pharmaceutical agent contained in the reservoir. More details about this intrathecal delivery system may be found in WO 2015 / 116658, which is incorporated by reference in its entirety. The amount of intrathecally injected nucleic acid agents (e.g., RNAi agents) may vary from one target gene to another target gene and the appropriate amount that has to be applied may also be determined individually for each target gene. In embodiments, this amount rangesR^[Y *) pS `[ *)) YS(Y@ [R UZVQO`M`Q% [\`U[ZMXXe .) pS `[ *.) YS(Y@ [R UZVQO`M`Q% Y[^Qoptionally 20 mg to 100 mg / mL of injectate. Page 50 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 VII. Methods for Inhibiting SNCA Expression The present disclosure also provides methods of inhibiting expression of a SNCA gene in a cell. The methods include contacting a cell with an RNAi agent, e.g., double stranded RNAi agent, in an amount effective to inhibit expression of SNCA in the cell, thereby inhibiting expression of SNCA in the cell. In certain embodiments of the disclosure, SNCA is inhibited preferentially in CNS (e.g., brain) cells. In other embodiments of the disclosure, SNCA is inhibited preferentially in the liver (e.g., hepatocytes). In certain embodiments of the disclosure, SNCA is inhibited in CNS (e.g., brain) cells and in liver (e.g., hepatocytes) cells. Contacting of a cell with an RNAi agent, e.g., a double stranded RNAi agent, may be done in vitro or in vivo. Contacting a cell in vivo with the RNAi agent includes contacting a cell or group of cells within a subject, e.g., a human subject, with the RNAi agent. Combinations of in vitro and in vivo methods of contacting a cell are also possible. Contacting a cell may be direct or indirect, as discussed above. Furthermore, contacting a cell may be accomplished via a targeting ligand, including any ligand described herein or known in the art. In some embodiments, the targeting ligand is a carbohydrate moiety, e.g., a GalNAc ligand, or any other ligand that directs the RNAi agent to a site of interest. The term “inhibiting,” as used herein, is used interchangeably with “reducing,” “silencing,” “downregulating,” “suppressing” and other similar terms, and includes any level of inhibition. In certain embodiments, a level of inhibition, e.g., for an RNAi agent of the instant disclosure, can be assessed in cell culture conditions, e.g., wherein cells in cell culture are transfected via LipofectamineTM-mediated transfection at a concentration in the vicinity of a cell of 10 nM or less, 1 nM or less, etc. Knockdown of a given RNAi agent can be determined via comparison of pre-treated levels in cell culture versus post-treated levels in cell culture, optionally also comparing against cells treated in parallel with a scrambled or other form of control RNAi agent. Knockdown in cell culture of, e.g., optionally 50% or more, can thereby be identified as indicative of “inhibiting” or “reducing”, “downregulating” or “suppressing”, etc. having occurred. It is expressly contemplated that assessment of targeted mRNA or encoded protein levels (and therefore an extent of “inhibiting”, etc. caused by an RNAi agent of the disclosure) can also be assessed in in vivo systems for the RNAi agents of the instant disclosure, under properly controlled conditions as described in the art. The phrase “inhibiting expression of a SNCA gene” or “inhibiting expression of SNCA,” as used herein, includes inhibition of expression of any SNCA gene (such as, e.g., a mouse SNCA gene, a rat SNCA gene, a monkey SNCA gene, or a human SNCA gene) as well as variants or mutants of a SNCA gene that encode a SNCA protein. Thus, the SNCA gene Page 51 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 may be a wild-type SNCA gene, a mutant SNCA gene, or a transgenic SNCA gene in the context of a genetically manipulated cell, group of cells, or organism. “Inhibiting expression of a SNCA gene” includes any level of inhibition of a SNCA gene, e.g., at least partial suppression of the expression of a SNCA gene, such as an inhibition by at least 20%. In certain embodiments, inhibition is by at least 30%, at least 40%, optionally at least 50%, at least about 60%, at least 70%, at least about 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%; or to below the level of detection of the assay method. The expression of a SNCA gene may be assessed based on the level of any variable associated with SNCA gene expression, e.g., SNCA mRNA level or SNCA protein level, or, for example, the level of neuroinflammation, e.g., microglial and astrocyte activation, and SNCA deposition in areas of the brain associated with neuronal cell death and / or levels of SNCA mRNA / protein within exosomes (neuronal or otherwise). Inhibition may be assessed by a decrease in an absolute or relative level of one or more of these variables compared with a control level. The control level may be any type of control level that is utilized in the art, e.g., a pre-dose baseline level, or a level determined from a similar subject, cell, or sample that is untreated or treated with a control (such as, e.g., buffer only control or inactive agent control). In some embodiments of the methods of the disclosure, expression of a SNCA gene is inhibited by at least 20%, 30%, 40%, optionally at least 50%, 60%, 70%, 80%, 85%, 90%, or 95%, or to below the level of detection of the assay. In certain embodiments, the methods include a clinically relevant inhibition of expression of SNCA, e.g. as demonstrated by a clinically relevant outcome after treatment of a subject with an agent to reduce the expression of SNCA. Inhibition of the expression of a SNCA gene may be manifested by a reduction of the amount of mRNA expressed by a first cell or group of cells (such cells may be present, for example, in a sample derived from a subject) in which a SNCA gene is transcribed and which has or have been treated (e.g., by contacting the cell or cells with an RNAi agent of the disclosure, or by administering an RNAi agent of the disclosure to a subject in which the cells are or were present) such that the expression of a SNCA gene is inhibited, as compared to a second cell or group of cells substantially identical to the first cell or group of cells but which has not or have not been so treated (control cell(s) not treated with an RNAi agent or not treated with an RNAi agent targeted to the gene of interest). The degree of inhibition may be expressed in terms of: Page 52 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 (mRNAincontrolcells) - (mRNAin treated cells) ^100 % (mRNAincontrol cells) In other embodiments, inhibition of the expression of a SNCA gene may be assessed in terms of a reduction of a parameter that is functionally linked to a SNCA gene expression, e.g., SNCA protein expression. SNCA gene silencing may be determined in any cell expressing SNCA, either endogenous or heterologous from an expression construct, and by any assay known in the art. Inhibition of the expression of a SNCA protein may be manifested by a reduction in the level of the SNCA protein that is expressed by a cell or group of cells (e.g., the level of protein expressed in a sample derived from a subject). As explained above, for the assessment of mRNA suppression, the inhibition of protein expression levels in a treated cell or group of cells may similarly be expressed as a percentage of the level of protein in a control cell or group of cells. A control cell or group of cells that may be used to assess the inhibition of the expression of a SNCA gene includes a cell or group of cells that has not yet been contacted with an RNAi agent of the disclosure. For example, the control cell or group of cells may be derived from an individual subject (e.g., a human or animal subject) prior to treatment of the subject with an RNAi agent. The level of SNCA mRNA that is expressed by a cell or group of cells may be determined using any method known in the art for assessing mRNA expression. In one embodiment, the level of expression of SNCA in a sample is determined by detecting a transcribed polynucleotide, or portion thereof, e.g., mRNA of the SNCA gene. RNA may be extracted from cells using RNA extraction techniques including, for example, using acid phenol / guanidine isothiocyanate extraction (RNAzol B; Biogenesis), RNeasyTMRNA preparation kits (Qiagen®) or PAXgene (PreAnalytix, Switzerland). Typical assay formats utilizing ribonucleic acid hybridization include nuclear run-on assays, RT-PCR, RNase protection assays, northern blotting, in situ hybridization, and microarray analysis. Circulating SNCA mRNA may be detected using methods the described in WO2012 / 177906, the entire contents of which are hereby incorporated herein by reference. In some embodiments, the level of expression of SNCA is determined using a nucleic acid probe. The term “probe”, as used herein, refers to any molecule that is capable of selectively binding to a specific SNCA nucleic acid or protein, or fragment thereof. Probes can be synthesized by one of skill in the art, or derived from appropriate biological preparations. Probes may be specifically designed to be labeled. Examples of molecules that can be utilized Page 53 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 as probes include, but are not limited to, RNA, DNA, proteins, antibodies, and organic molecules. Isolated mRNA can be used in hybridization or amplification assays that include, but are not limited to, Southern or northern analyses, polymerase chain reaction (PCR) analyses and probe arrays. One method for the determination of mRNA levels involves contacting the isolated mRNA with a nucleic acid molecule (probe) that can hybridize to SNCA mRNA. In one embodiment, the mRNA is immobilized on a solid surface and contacted with a probe, for example by running the isolated mRNA on an agarose gel and transferring the mRNA from the gel to a membrane, such as nitrocellulose. In an alternative embodiment, the probe(s) are immobilized on a solid surface and the mRNA is contacted with the probe(s), for example, in an Affymetrix®gene chip array. A skilled artisan can readily adapt known mRNA detection methods for use in determining the level of SNCA mRNA. An alternative method for determining the level of expression of SNCA in a sample involves the process of nucleic acid amplification or reverse transcriptase (to prepare cDNA) of for example mRNA in the sample, e.g., by RT-PCR (the experimental embodiment set forth in Mullis, 1987, US Patent No. 4,683,202), ligase chain reaction (Barany (1991) Proc. Natl. Acad. Sci. USA 88: 189-193), self-sustained sequence replication (Guatelli et al. (1990) Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (Kwoh et al. (1989) Proc. Natl. Acad. Sci. USA 86: 1173-1177), Q-Beta Replicase (Lizardi et al. (1988) Bio / Technology 6: 1197), rolling circle replication (Lizardi et al., US Patent No.5,854,033) or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers. In particular aspects of the disclosure, the level of expression of SNCA is determined by quantitative fluorogenic RT-PCR (i.e., the TaqManTMSystem), by a Dual-Glo® Luciferase assay, or by other art-recognized method for measurement of SNCA expression or mRNA level. The expression level of SNCA mRNA may be monitored using a membrane blot (such as used in hybridization analysis such as northern, Southern, dot, and the like), or microwells, sample tubes, gels, beads or fibers (or any solid support comprising bound nucleic acids). See US Patent Nos. 5,770,722, 5,874,219, 5,744,305, 5,677,195 and 5,445,934, which are incorporated herein by reference. The determination of SNCA expression level may also comprise using nucleic acid probes in solution. Page 54 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 In some embodiments, the level of mRNA expression is assessed using branched DNA (bDNA) assays or real time PCR (qPCR). The use of this PCR method is described and exemplified in the Examples presented herein. Such methods can also be used for the detection of SNCA nucleic acids. The level of SNCA protein expression may be determined using any method known in the art for the measurement of protein levels. Such methods include, for example, electrophoresis, capillary electrophoresis, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), hyperdiffusion chromatography, fluid or gel precipitin reactions, absorption spectroscopy, a colorimetric assays, spectrophotometric assays, flow cytometry, immunodiffusion (single or double), immunoelectrophoresis, western blotting, radioimmunoassay (RIA), enzyme-linked immunosorbent assays (ELISAs), immunofluorescent assays, electrochemiluminescence assays, and the like. Such assays can also be used for the detection of proteins indicative of the presence or replication of SNCA proteins. In some embodiments, the efficacy of the methods of the disclosure in the treatment of a SNCA-related disease is assessed by a decrease in SNCA mRNA level (e.g, by assessment of a CSF sample for SNCA level, by brain biopsy, or otherwise). In some embodiments, the efficacy of the methods of the disclosure in the treatment of a SNCA-related disease is assessed by a decrease in SNCA mRNA level (e.g, by assessment of a liver sample for SNCA level, by biopsy, or otherwise). In some embodiments of the methods of the disclosure, the RNAi agent is administered to a subject such that the RNAi agent is delivered to a specific site within the subject. The inhibition of expression of SNCA may be assessed using measurements of the level or change in the level of SNCA mRNA or SNCA protein in a sample derived from a specific site within the subject, e.g., CNS cells. In certain embodiments, the methods include a clinically relevant inhibition of expression of SNCA, e.g. as demonstrated by a clinically relevant outcome after treatment of a subject with an agent to reduce the expression of SNCA. As used herein, the terms detecting or determining a level of an analyte are understood to mean performing the steps to determine if a material, e.g., protein, RNA, is present. As used herein, methods of detecting or determining include detection or determination of an analyte level that is below the level of detection for the method used. Page 55 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 VIII. Methods of Treating or Preventing SNCA-Associated Neurodegenerative Diseases The present disclosure also provides methods of using an RNAi agent of the disclosure or a formulation containing an RNAi agent of the disclosure to reduce or inhibit SNCA expression in a cell. The methods include contacting the cell with a dsRNA of the disclosure and maintaining the cell for a time sufficient to obtain degradation of the mRNA transcript of a SNCA gene, thereby inhibiting expression of the SNCA gene in the cell. Reduction in gene expression can be assessed by any methods known in the art. For example, a reduction in the expression of SNCA may be determined by determining the mRNA expression level of SNCA using methods routine to one of ordinary skill in the art, e.g., northern blotting, qRT-PCR; by determining the protein level of SNCA using methods routine to one of ordinary skill in the art, such as western blotting, immunological techniques, and mass-spectrometry. In the methods of the disclosure the cell may be contacted in vitro or in vivo, i.e., the cell may be within a subject. A cell suitable for treatment using the methods of the disclosure may be any cell that expresses a SNCA gene. A cell suitable for use in the methods of the disclosure may be a mammalian cell, e.g., a primate cell (such as a human cell or a non-human primate cell, e.g., a monkey cell or a chimpanzee cell), a non-primate cell (such as a a rat cell, or a mouse cell. In one embodiment, the cell is a human cell, e.g., a human CNS cell. In one embodiment, the cell is a human cell, e.g., a human liver cell. In one embodiment, the cell is a human cell, e.g., a human CNS cell and a human liver cell. SNCA expression is inhibited in the cell by at least about 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, or about 100%, i.e., to below the level of detection. In preferred embodiments, SNCA expression is inhibited by at least 50 %. The in vivo methods of the disclosure may include administering to a subject a composition containing an RNAi agent, where the RNAi agent includes a nucleotide sequence that is complementary to at least a part of an RNA transcript of the SNCA gene of the mammal to be treated. When the organism to be treated is a mammal such as a human, the composition can be administered by any means known in the art including, but not limited to oral, intraperitoneal, or parenteral routes, including intracranial (e.g., intraventricular, intraparenchymal, and intrathecal), intravenous, intramuscular, intravitreal, subcutaneous, transdermal, airway (aerosol), nasal, rectal, and topical (including buccal and sublingual) administration. In certain embodiments, the compositions are administered by intravenous infusion or injection. In certain embodiments, the compositions are administered by Page 56 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 subcutaneous injection. In certain embodiments, the compositions are administered by intrathecal injection. In some embodiments, the administration is via a depot injection. A depot injection may release the RNAi agent in a consistent way over a prolonged time period. Thus, a depot injection may reduce the frequency of dosing needed to obtain a desired effect, e.g., a desired inhibition of SNCA, or a therapeutic or prophylactic effect. A depot injection may also provide more consistent serum concentrations. Depot injections may include subcutaneous injections or intramuscular injections. In preferred embodiments, the depot injection is a subcutaneous injection. In some embodiments, the administration is via a pump. The pump may be an external pump or a surgically implanted pump. In certain embodiments, the pump is a subcutaneously implanted osmotic pump. In other embodiments, the pump is an infusion pump. An infusion pump may be used for intracranial, intravenous, subcutaneous, arterial, or epidural infusions. In preferred embodiments, the infusion pump is a subcutaneous infusion pump. In other embodiments, the pump is a surgically implanted pump that delivers the RNAi agent to the CNS. The mode of administration may be chosen based upon whether local or systemic treatment is desired and based upon the area to be treated. The route and site of administration may be chosen to enhance targeting. In one aspect, the present disclosure also provides methods for inhibiting the expression of a SNCA gene in a mammal. The methods include administering to the mammal a composition comprising a dsRNA that targets a SNCA gene in a cell of the mammal and maintaining the mammal for a time sufficient to obtain degradation of the mRNA transcript of the SNCA gene, thereby inhibiting expression of the SNCA gene in the cell. Reduction in gene expression can be assessed by any methods known it the art and by methods, e.g. qRT-PCR, described herein. Reduction in protein production can be assessed by any methods known it the art and by methods, e.g. ELISA, described herein. In one embodiment, a CNS biopsy sample or a cerebrospinal fluid (CSF) sample serves as the tissue material for monitoring the reduction in SNCA gene or protein expression (or of a proxy therefore). The present disclosure further provides methods of treatment of a subject in need thereof. The treatment methods of the disclosure include administering an RNAi agent of the disclosure to a subject, e.g., a subject that would benefit from inhibition of SNCA expression, in a therapeutically effective amount of an RNAi agent targeting a SNCA gene or a pharmaceutical composition comprising an RNAi agent targeting a SNCA gene. Page 57 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 In addition, the present disclosure provides methods of preventing, treating or inhibiting the progression of a SNCA-associated neurodegenerative disease or disorder, such as a synucleinopathy, such as PD, multiple system atrophy, Lewy body dementia (LBD), pure autonomic failure (PAF), Pick's disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic grain disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer's disease, Huntington's disease, Down’s syndrome, psychosis, schizophrenia and Creutzfeldt-Jakob disease. The methods include administering to the subject a therapeutically effective amount of any of the RNAi agent, e.g., dsRNA agents, or the pharmaceutical composition provided herein, thereby preventing, treating or inhibiting the progression of the SNCA-associated neurodegenerative disease or disorder in the subject. An RNAi agent of the disclosure may be administered as a “free RNAi agent.” A free RNAi agent is administered in the absence of a pharmaceutical composition. The naked RNAi agent may be in a suitable buffer solution. The buffer solution may comprise acetate, citrate, prolamine, carbonate, or phosphate, or any combination thereof. In one embodiment, the buffer solution is phosphate buffered saline (PBS). The pH and osmolarity of the buffer solution containing the RNAi agent can be adjusted such that it is suitable for administering to a subject. Alternatively, an RNAi agent of the disclosure may be administered as a pharmaceutical composition, such as a dsRNA liposomal formulation. Subjects that would benefit from a reduction or inhibition of SNCA gene expression are those having a SNCA-associated neurodegenerative disease. The disclosure further provides methods for the use of an RNAi agent or a pharmaceutical composition thereof, e.g., for treating a subject that would benefit from reduction or inhibition of SNCA expression, e.g., a subject having a SNCA-associated neurodegenerative disorder, in combination with other pharmaceuticals or other therapeutic methods, e.g., with known pharmaceuticals or known therapeutic methods, such as, for example, those which are currently employed for treating these disorders. For example, in certain embodiments, an RNAi agent targeting SNCA is administered in combination with, e.g., an agent useful in treating a SNCA-associated neurodegenerative disorder as described elsewhere herein or as otherwise known in the art. For example, additional agents and treatments suitable for treating a subject that would benefit from reducton in SNCA expression, Page 58 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 e.g., a subject having a SNCA-associated neurodegenerative disorder, may include agents currently used to treat symptoms of SNCA. The RNAi agent and additional therapeutic agents may be administered at the same time or in the same combination, e.g., intrathecally, or the additional therapeutic agent can be administered as part of a separate composition or at separate times or by another method known in the art or described herein. Exemplary additional therapeutics and treatments include dopamine-modulating agents, among others, for example, carbidopa-levodopa, levodopa, entacopone, tolcapone, opicapone, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, rivastigmine, donepezil, galantamine and memantine, as well as physical, occupational and speech therapy, an exercise program including cardiorespiratory, resistance, flexibility, and gait and balance exercises, and deep brain stimulation (DBS) involving the implantation of an electrode into a targeted area of the brain. In one embodiment, the method includes administering a composition featured herein such that expression of the target SNCA gene is decreased, for at least one month. In certain embodiments, expression is decreased for at least 2 months, 3 months, or 6 months. Optionally, the RNAi agents useful for the methods and compositions featured herein specifically target RNAs (primary or processed) of the target SNCA gene. Compositions and methods for inhibiting the expression of these genes using RNAi agents can be prepared and performed as described herein. Administration of the dsRNA according to the methods of the disclosure may result in a reduction of the severity, signs, symptoms, or markers of such diseases or disorders in a patient with a SNCA-associated neurodegenerative disorder. By “reduction” in this context is meant a statistically significant or clinically significant decrease in such level. The reduction can be, for example, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 100%. Efficacy of treatment or prevention of disease can be assessed, for example by measuring disease progression, disease remission, symptom severity, reduction in pain, quality of life, dose of a medication required to sustain a treatment effect, level of a disease marker or any other measurable parameter appropriate for a given disease being treated or targeted for prevention. It is well within the ability of one skilled in the art to monitor efficacy of treatment or prevention by measuring any one of such parameters, or any combination of parameters. For example, efficacy of treatment of a SNCA-associated neurodegenerative disorder may be assessed, for example, by periodic monitoring of a subject’s cognition, learning, or memory. Page 59 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 Comparisons of the later readings with the initial readings provide a physician an indication of whether the treatment is effective. It is well within the ability of one skilled in the art to monitor efficacy of treatment or prevention by measuring any one of such parameters, or any combination of parameters. In connection with the administration of an RNAi agent targeting SNCA or pharmaceutical composition thereof, "effective against" a SNCA-associated neurodegenerative disorder indicates that administration in a clinically appropriate manner results in a beneficial effect for at least a statistically significant fraction of patients, such as an improvement of symptoms, a cure, a reduction in disease, extension of life, improvement in quality of life, or other effect generally recognized as positive by medical doctors familiar with treating SNCA-associated neurodegenerative disorders and the related causes. A treatment or preventive effect is evident when there is a statistically significant improvement in one or more parameters of disease status, or by a failure to worsen or to develop symptoms where they would otherwise be anticipated. As an example, a favorable change of at least 10% in a measurable parameter of disease, and optionally at least 20%, 30%, 40%, 50% or more can be indicative of effective treatment. Efficacy for a given RNAi agent drug or formulation of that drug can also be judged using an experimental animal model for the given disease as known in the art. When using an experimental animal model, efficacy of treatment is evidenced when a statistically significant reduction in a marker or symptom is observed. Alternatively, the efficacy can be measured by a reduction in the severity of disease as determined by one skilled in the art of diagnosis based on a clinically accepted disease severity grading scale. Any positive change resulting in e.g., lessening of severity of disease measured using the appropriate scale, represents adequate treatment using an RNAi agent or RNAi agent formulation as described herein. Subjects can be administered a therapeutic amount of dsRNA, such as about 0.01 mg / kg to about 200 mg / kg. The RNAi agent can be administered intrathecally, via intravitreal injection, or by intravenous infusion over a period of time, on a regular basis. In certain embodiments, after an initial treatment regimen, the treatments can be administered on a less frequent basis. Administration of the RNAi agent can reduce SNCA levels, e.g., in a cell, tissue, blood, CSF sample or other compartment of the patient by at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70,% 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or at least about 99% or more. In a preferred embodiment, administration of the RNAi agent can reduce SNCA levels, e.g., in a cell, tissue, blood, CSF sample or other compartment of the patient by at least 50%. Page 60 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 Alternatively, the RNAi agent can be administered subcutaneously, i.e., by subcutaneous injection. One or more injections may be used to deliver the desired, e.g., monthly dose of RNAi agent to a subject. The injections may be repeated over a period of time. The administration may be repeated on a regular basis. IX. Kits In certain aspects, the instant disclosure provides kits that include a suitable container containing a pharmaceutical formulation of a nucleic acid agent (e.g., a siRNA compound, e.g., a double-stranded siRNA compound, or a precursor to a siRNA compound (e.g., a precursor, e.g., a larger siRNA compound which can be processed into a siRNA compound, or a DNA which encodes an siRNA compound, e.g., a double-stranded siRNA compound, or siRNA compound, or precursor thereof)), and instructions for its use. In certain embodiments the individual components of the pharmaceutical formulation may be provided in one container. Alternatively, it may be desirable to provide the components of the pharmaceutical formulation separately in two or more containers, e.g., one container for a nucleic acid agent (e.g., a siRNA compound) preparation, and at least another for a carrier compound. The kit may be packaged in a number of different configurations such as one or more containers in a single box. The different components can be combined, e.g., according to instructions provided with the kit. The components can be combined according to a method described herein, e.g., to prepare and administer a pharmaceutical composition. The kit can also include a delivery device. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the RNAi agents and methods featured in the disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Page 61 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 EXAMPLES Example 1: Manufacture of ALN-1747580 siRNA agents targeting the human alpha-synuclein gene (SNCA), are described in International Publication No. WO2022 / 072447 (International application no. PCT / US2021 / 052580),and International Publication No. WO2023 / 192977 (International application no. PCT / US2023 / 065196); each of which are hereby incorporated by reference in their entireties. Such oligonucleotides can be prepared with suitable and protected phosphoramidites on an automatic solid phase synthesizer using universal or custom supports, such as controlled pore glass (CPG) (see, e.g., F. Eckstein (ed.), Oligonucleotides and Analogues, a Practical Approach (Oxford University Press, New York 1991)); see also, themethods disclosed in WO2019 / 217459 and WO 2020 / 132227, each of which is herebyincorporated by reference in its entirety. 3’-RNA containing agents can be prepared according to the process disclosed in International Publication no. WO 2021 / 108291, which is hereby incorporated by reference in its entirety. Where the source of a reagent is not specifically given herein, such reagent can be obtained from any supplier of reagents for molecular biology at a quality / purity standard for application in molecular biology. Table 3. List of Abbreviations and Acronyms Duplex Formation To ensure the equimolar ratio between the two single strands, the solution of one strand was titrated with the other strand. The titration process was monitored through non-denaturing ion-paring reverse phase (IPRP) HPLC. Antisense strand excess should be in the range of 1 – 2 % to minimize solubility risk in drug product formulation. Finally, the duplex solution was Page 62 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920RUX`Q^QP MSMUZ `T^[aST M )'+ pY RUX`Q^ UZ`[ M <8D9 _`Q^UXQ O[Z`MUZQ^ [R M\\^[\^UM`Q b[XaYQ' HTQsolution may be lyophilized for storage and compounding. A typical chromatogram from the duplex annealing method is presented in FIG.3.Example 2. Preparation of ALN-1747580 Drug Product (DP)The formulation details are as follows and are provided in Table 5. An excipient solution was prepared by adding sodium chloride, potassium chloride, magnesium chloride hexahydrate, and calcium chloride dihydrate to a compounding container followed by addition of water for injection (WFI) with stirring. The excipient solution was filtered through a 0.2- micron filter and stored at 2 – 8 °C until day of compounding. Lyophilized Drug Substance (DS), above, equilibrated at room temperature (15 – 25 ºC) for 2 - 24 h and compounded using the excipient solution. The pH was measured and, if necessary, adjusted with NaOH (0.25 N) or HCl (0.1N) to meet the acceptable range (6.6 – 7.0, for target 6.8). The excipient solution was used to dissolve the DS, and used to arrive at final concentration of 60 mg / mL (free acid basis). The solution was filtered through a 0.2-micron filter and stored at 2 – 8 °C until day of fill. Release osmolality of the formulations was 210-390 mOsm / kg, and the release particulate was >=10 um, NMT 6000 per container; >=25 um, NMT 600 per container where “container” is 5 mL in a 10R vial. The chemical properties of the ALN-1747580 are presented in Table 4. The sodium salt molecular weight is the powdered form of the drug substance. The free acid molecular weight is related to the weight of the active duplex in solution. The ratio of the two is the molecular weight of the free acid divided by the molecular weight of the sodium salt and is used forconversion between the two forms. Drug product composition is presented in Table 5. Therewas no significant change in purity between the DS and DP and the current DP compounding process is compatible with SNCA DS. Table 4. Duplex Properties Page 63 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 Table 5. Drug Product Composition Page 64 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 Conclusions DP has the following attributes: • pH: 6.8 • Concentration: 60 mg / mL • Solubility: NLT 78 mg / mL • Density: 1.0299 mg / mL @ 20 °C • Osmolality: 301 mOsm / kg • Viscosity: 1.621 cP @ 20 °C • Appearance: clear, colorless to yellow solution free of foreign particles. Example 3. Comparative Stability of ALN-1747580 (Drug Product) DP Formulation Stability testing of the ALN-1747580 DP without phosphate buffer was conducted out to the 9-month time point under the following conditions: (i) 2-8 °C;(ii) (ii) 25 °C ± 2 °C at 60 % ± 5 % relative humidity (RH); and(iii) (iii) 30 °C ± 2 °C at 75 % ± 5 % RH, and until the 6-month time point underthe following condition: 40 °C ± 2 °C at 75 % ± 5% RH. Details of the DP formulation are provided in Table 5. The abbreviations used in the stability data tables are defined in Table 6. The DP was prepared with double strand (DS) annealed with a 1-2% antisense strand excess. The results of the stability testing studies for a representative lot are shown in Tables 7-10. Table 6. Abbreviations Used in Stability Data Page 65 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 Page 66 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 02942-103121:.o Ntekco D yttA ern.oto 3 C 9 1 6 2.6 6 0 7 m 6 S(r e t e o g LikermS P / ni egea ni aa P T CF % Fae% L ema ms tntC / on Oovitg E ara e8.rag mcrcat rmernotS 0 791.0 79 2 6 2.8pep es6 1 0 e n r o T pireettoaM the N g Rirstncate % :sek / srna m reP Celro eitif er itirLsDcnolulniatfoap Oreu %m / 0 m 0 p 0p g0.r ro a 0s ,0e e0o:ns0estac0t em + +m6 6x8i9r n noni i95,.lac0 0wcp5el 6luer 3T T-a at ta7iotT - $ '7lo pa 6t0. -yc0 n nac% &e l rlu L M M4 o0e a .0 4 1m o o7a c cA C y m p D N T 1 5 2 6 / N / N1- n )o ; ;gNit5 ; 9nirLc.3.3.1eVu > > >2 2 9. . .AypUtrs a5 1 82 2 2tre8 9 8-nCnI. . .de r r r7 7 7oofLo mlu u u< < <rdta -hotP E E EucnaP P Ptt e. . .eoRsoiS S SVp h h ha hPn(M V U S p P U P U P UID"y !tri())rl ee ti- di(t1hbatcyt .va$oamt6ir'lee 9cSl yut$ e# t5as erenetiPl9: $aflfiat (6ur++7 / axlo 4irub 00ac. o 8ee lyytiueal rim*t5$ '\piprps mturbt(s s%& 1p ua)u H EamSI (A A P D , A O p P / / M T Page 67 of 79ME1\58469596.v1 Atty Docket No.: 121301-24920 02942-103121:.o Ntekco D yttA St e grere omiP %k / neianigaP L T S e CFae% L Fmm / s tnatev g Con iaEraaetrg O mcorcr a ereatot8.S1.m 7 0 7 0 9 2 6 92.8p p n 6 1 0 ese n TroerpireettaMnigairothte NtR scCsae % :k / n e nortni aeseitmsreocL prPeclrituni flfrairmO 0eD 0 nolo ato0.up % / p sag m 0 0,r0e0o:ns0estac0t em + +m6 6x8i9r noni95,.lac0 0wcp5el 6luer 3T T-ata7iotT - $ '7lo pa 6t0. -yc0 nac% &e l rlu L M M4 o0e a .0 4 1m o7a cA C y m p D N T 1 5 2 6 / N / N1- n )o ; ;gNit5 ; 9nirLc.3.3.1eVu > > >2 2 9. . .AypUtrs a5 1 82 2 2tre8 9 8-nCnI. . .de r r r7 7 7oofLo mlu u u< < <rdta -hotP E E EucnaP P Ptt e. . .eoRsoiS S SVp h h ha hPn(M V U S p P U P U P UID"y !tri())rl ee ti- di(t1hbatcyt .va$oamt6ir'lee 9cSl yut$ e# t5as erenetiPl9: $aflfiat (6ur++8 / axlo 4irub 00ac. o 8ee lyytiueal rim*t5$ '\piprps mturbt(s s%& 1p ua)u H EamSI (A A P D , A O p P / / M T Page 68 of 79ME1\58469596.v1 Atty Docket No.: 121301-24920 02942-103121:.o NtePkco D yttA n S 0 9.2 6 2 m.6 1 0 esern Troeirt Mnipeetai ota hte N g c % :kt / n oRrs Psnarte C Deelo ritnifaeseritmsre cirL p colulniOrea foau %m / 0 m 0 p 0 n 8atocos tnsts:0.paeg0,re00 5p, wocnelx 0 cel9milram 095.+06ni+06 6u3erT Ta- tpa7itTo$7-l'aot60. -ycu 0 na%e&cl rL M4lMo0e a .0 4 1omD7c aN T 1 / N A C y m p 5 2 6 / N1- n )o ; ;gNit95 ;nirLc 3 3.1. .eVu >> >92 2.A. .yp tUrs a5 1 822 2tr 8 9 8en-CnI. . .de r r r77 7oofLo m ulu u << <rtda -hoEPtE Eu ncaPP Ptt e.. .eoRsoiSV S S hp h ha hP nI (P U M V U S p P U P UD ytri)rleetidit1habtcyt a .v$oamti6r'leec9l yuSt$#etas5erenetiPl9: $fafliat (r6u ++ / 9 )axloi4ruba00c. oe8e lyyti%uaerlim*t$ '5pip\rpa s mtuert s s(%&b p u 1a)u HrEamSI ( aA A P D , A O p P / / M T 5 Page 69 of 79 ME1\58469596.v1 Atty Docket No.: 121301-24920 02942-103121:.o Ntekco D yttA ito g t C E9.ram 9mas epatnrOeam(1 791t.n n 2 16 92 m.86 12ocp ese 0ocermiT e P % Sae% L g Frerepeg C R F Eraaem / gk / arC 8.ram 7msr niOeao 1ptnr nit ea. ptP D S 0 79 2 06 92 m.86 1on c 0oc0y: 8 ssae % 5em na se%eit aerreprLif eeil t rra7r aea0 pfcc mu / 4ao0loh 0.t0n n p gg7r 0. tr:r,0wes 0e0o s0ka oti c / n x 0t+m +1 m1 6i6-eol9lnn ni i io n 95,.elr0 0p le6lcitumr 3T T Teaa- saNtt tpae 7itT - $t'c iato6-yuu 0ln n n%e rO &LlL M Mc r Moa .04 1oo mDooot s c a c cA C C p N T N 5 2 m 6 / N / NA )r ; ;g 5 ; 9nofir1..3.3Vu >> >2 2.9. .a ytUtra8n 5 1 22 2ta o 8 9 8e-Cn .. .drie r rt77 7oD Lo mlu u u << <rc dta -ehoytEP E Eucn PP Pte.p. .teoi sRsoiS S SV hp h hhlin P nI I (M V U S p P U P U P Ub " 1atyt .v!i6rS l see(c9)l yutk:etas5erene-tiPl(9a0 faefliat (r6u ++1axloip $ 4rruba00coe8'e lyyti)uaerterlimte$ '5pip\$rp#tdsimturt s s a%&b p u 1hatu $ HcEamSI ( aA A P D o / A O p P m / / M T Page 70 of 79ME1\58469596.v1 Atty Docket No.: 121301-24920 EQUIVALENTS Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the following claims. Page 71 of 79 ME1\58469596.v1

Claims

Atty Docket No.: 121301-24920 We claim:

1. A formulation comprising a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of synuclein alpha (SNCA), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand and the antisense strand are selected from the group consisting of the sense strand and the antisense strand sequences listed in Table 1, and wherein the antisense strand is present in the formulation at no less than equimolar amount or at about a 1% to about a 2% excess relative to the sense strand.

2. The formulation of claim 1, wherein the formulation comprises greater than 1 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 5 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 10 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 25 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 50 mg of the dsRNA agent per mL of the formulation, or the formulation comprises greater than 60 mg of the dsRNA agent per mL of the formulation.

3. The formulation of claim 2, wherein the formulation comprises about 50 mg to about 70 mg of the dsRNA agent per mL of the formulation.

4. The formulation of claim 3, wherein the formulation comprises about 60 mg of the dsRNA agent per mL of the formulation.

5. The formulation of any one of claims 1-4, further comprising a sodium source, a potassium source, a magnesium source, and / or a calcium source.

6. The formulation of claim 5, wherein the formulation comprises sodium chloride, magnesium chloride, potassium chloride, and / or calcium chloride.

7. The formulation of claim 6, wherein the formulation comprises sodium chloride at a concentration of about 70 mM to about 100 mM.

8. The formulation of claim 7, wherein the formulation comprises sodium chloride at a concentration of about 87 mM.

9. The formulation of claim 6, wherein the formulation comprises potassium chloride at a concentration of about 1.0 mM to about 2.5 mM. Page 72 of 79 ME1\58469596.v1Atty Docket No.: 121301-24920 10. The formulation of claim 9, wherein the formulation comprises potassium chloride at a concentration of about 1.7 mM 11. The formulation of claim 6, wherein the formulation comprises magnesium chloride at a concentration of about 0.1 mM to about 1.0 mM.

12. The formulation of claim 11, wherein the formulation comprises magnesium chloride at a concentration of about 0.46 mM.

13. The formulation of claim 6, wherein the formulation comprises calcium chloride at a concentration of about 8.0 mM to about 25.0 mM.

14. The formulation of claim 13, wherein the formulation comprises calcium chloride at a concentration of about 16.3 mM.

15. The formulation of any one of claims 1-14, wherein the formulation has a pH between about 6.0 and about 10.

0.

16. The formulation of claim 15, wherein the pH is between about 6.0 and about 8.

0.

17. The formulation of claim 16, wherein the pH is about 6.

8.

18. The formulation of any one of claims 1-17, wherein the formulation has an osmolality between about 200 and 400 mOsm / kg.

19. The formulation of claim 18, wherein the osmolality is about 300 mOsm / kg.

20. The formulation of any one of claims 1-19, wherein the formulation is a pharmaceutical formulation for intrathecal administration of the dsRNA agent to a subject.

21. The formulation of claim 20, wherein the subject is a mammal.

22. The formulation of claim 21, wherein the subject is a human.

23. A formulation for intrathecal administration, comprising (a) a dsRNA agent, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand and the antisense strand are selected from the group consisting of the sense strand and the antisense strand sequences listed in Table 1, and wherein the antisense strand is present in the formulation at Page 73 of 79 ME1\58469596.v1Atty Docket No.: 121301-24920 no less than equimolar amount or at about a 1% to about a 2% excess relative to the sense strand; (b) sodium chloride at a concentration of about 70 mM to about 100 mM; (c) potassium chloride at a concentration of about 1.0 mM to about 2.5 mM; (d) magnesium chloride at a concentration of about 0.1 mM to about 1.0 mM; (e) calcium chloride at a concentration of about 8.0 mM to about 25.0 mM; (f) a pH of about 6.0 to about 8.0; and (g) an osmolality of about 200 to 400 mOsm / kg.

24. The formulation of any one of claims 1-23, wherein (a) the sense strand comprises the nucleotide sequence.q ;Y&\_&6Y&\_&;Y&7Y&6Y&6TP&;Y&IY&;R&6R&7R&6Y&6Y&6Y&IY&;Y&IY&IY&;Y&\_&;Y&\_&6Y ,q [R G9E =8 BC3 *4 MZP(b) the antisense strand comprises the nucleotide sequence.q JDa&\_&P7&\_&7Y&6Y&P6&7Y&P6&IY&IY&IY&;Y&PH&7Y&6R&7Y&IY&IY&;Y&7Y&IY&7Y&\_&IY&\_&IY ,q [R G9E =8 BC3 +4cTQ^QUZ 6R U_ +q&RXa[^[MPQZ[_UZQ% 7R U_ +q&RXa[^[Oe`UPUZQ% ;R U_ +q&RXa[^[SaMZ[_UZQ%6Y U_ +q&O&YQ`TeXMPQZ[_UZQ% IY U_ +q&O&YQ`TeXa^UPUZQ% 7Y U_ +q&O-methylcytidine, Gm is+q&O&YQ`TeXSaMZ[_UZQ% P6 U_ +q&PQ[deMPQZ[_UZQ% P7 U_ +q&PQ[deOe`UPUZQ% PH U_ +q&PQ[de`TeYUPUZQ% 6TP U_ +q&O&TQdMPQOeXMPQZ[_UZQ% JDa U_ bUZeX\T[_\T[ZM`Q +q&O-YQ`TeXa^UPUZQ% q&q #Te\TQZ$ U_ M ,q&.q \T[_\T[PUQ_`Q^ XUZWMSQ% MZP q&\_&q U_ M ,q&.qphosphorothioate linkage.

25. A formulation for intrathecal administration, comprising about 60 g / L of a free acid of a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of synuclein alpha (SNCA); about 5.09 g / L of sodium chloride; about 0.128 g / L of potassium chloride; about 0.093 g / L magnesium chloride hexahydrate; about 2.396 g / L calcium chloride dihydrate; Page 74 of 79 ME1\58469596.v1Atty Docket No.: 121301-24920 sterile water for injection; and sufficient quantities of hydrochloric acid and sodium hydroxide such that the pH of the formulation is about 6.6 to about 7.0; wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand consists of the nucleotide sequence.q ;Y&\_&6Y&\_&;Y&7Y&6Y&6TP&;Y&IY&;R&6R&7R&6Y&6Y&6Y&IY&;Y&IY&IY&;Y&\_&;Y&\_&6Y ,q [R G9E =8 BC3 *4 MZP `TQ MZ`U_QZ_Q _`^MZP O[Z_U_`_ [R `TQ ZaOXQ[`UPQsequence.q JDa&\_&P7&\_&7Y&6Y&P6&7Y&P6&IY&IY&IY&;Y&PH&7Y&6R&7Y&IY&IY&;Y&7Y&IY&7Y&\_&IY&\_&IY ,q [R G9E =8 BC3 +4cTQ^QUZ 6R U_ +q&RXa[^[MPQZ[_UZQ% 7R U_ +q&RXa[^[Oe`UPUZQ% ;R U_ +q&RXa[^[SaMZ[_UZQ%6Y U_ +q&O&YQ`TeXMPQZ[_UZQ% IY U_ +q&O&YQ`TeXa^UPUZQ% 7Y U_ +q&O-methylcytidine, Gm is+q&O&YQ`TeXSaMZ[_UZQ% P6 U_ +q&PQ[deMPQZ[_UZQ% P7 U_ +q&PQ[deOe`UPUZQ% PH U_ +q&PQ[de`TeYUPUZQ% 6TP U_ +q&O&TQdMPQOeXMPQZ[_UZQ% JDa U_ bUZeX\T[_\T[ZM`Q +q&O-YQ`TeXa^UPUZQ% q&q #Te\TQZ$ U_ M ,q&.q \T[_\T[PUQ_`Q^ XUZWMSQ% MZP q&\_&q U_ M ,q&.qphosphorothioate linkage.

26. A solid prepared by lyophilization of the formulation of any one of claims 1-25.

27. A kit, comprising (a) the formulation of any one of claims 1-25, and (b) instructions for use, and (c) optionally, a means for administering the formulation to a subject.

28. A method of treating a subject having a disease or disorder that would benefit from a reduction in expression of synuclein alpha (SNCA); or preventing development of a SNCA- associated neurodegenerative disease in a subject; or inhibiting the expression of synuclein alpha (SNCA) in a subject, the method comprising administering to the subject a therapeutically effective amount of a formulation of any one of claims 1-25.

29. The method of claim 28, wherein the subject is a human. Page 75 of 79 ME1\58469596.v1Atty Docket No.: 121301-24920 30. The method of claim 28 or 29, wherein the subject meets at least one diagnostic criterion for a SNCA-associated disease or disorder.

31. The method of any one of claims 28-30, wherein the subject has a SNCA-associated disease.

32. The method of any one of claims 28-30, wherein the subject has been diagnosed with a SNCA-associated disease.

33. The method of any one of claims 30-32, wherein the SNCA-associated disease or disorder is selected from the group consisting of a synucleinopathy, such as PD, multiple system atrophy, Lewy body dementia (LBD), pure autonomic failure (PAF), Pick's disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic grain disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer's disease, Huntington's disease, Down’s syndrome, psychosis, schizophrenia and Creutzfeldt-Jakob disease.

34. The method of any one of claims 28-33, wherein the formulation is administered to the subject intrathecally.

35. The method of any one of claims 28-34, wherein treating comprises amelioration or delay of at least one sign or symptom of the disease or disorder.

36. The method of any one of claims 28-35, where treating comprises prevention or delay of development or progression of the disease or disorder.

37. The method of any one of claims 28-36, wherein the SNCA-associated disease or disorder is characterized by one or more symptoms selected from the group consisting of tremors, slowed movement (bradykinesia), rigid muscles, impaired posture and balance, loss of automatic movements, speech changes, writing changes, visual, auditory, olfactory, or tactile hallucinations, poor regulation of body functions (autonomic nervous systems) such as dizziness, falls and bowel issues, cognitive problems such as confusion, poor attention, visual- spatial problems and memory loss, sleep difficulties such as rapid eye movement (REM) sleep Page 76 of 79 ME1\58469596.v1Atty Docket No.: 121301-24920 behavior disorder (in which dreams are physically acted out while asleep), fluctuating attention including episodes of drowsiness, long periods of staring into space, long naps during the day or disorganized speech, depression, and apathy, orthostatic hypotension (a sudden drop in blood pressure that occurs when a person stands up, causing a person to feel dizzy and lightheaded, and the need to sit, squat, or lie down in order to prevent fainting), clumsiness or incoordination, bladder control problems, contractures (chronic shortening of muscles or tendons around joints, which prevents the joints from moving freely) in the hands or limbs, Pisa syndrome (an abnormal posture in which the body appears to be leaning to one side), antecollis (in which the neck bends forward and the head drops down), and involuntary and uncontrollable sighing or gasping.

38. A method for preparing an SNCA formulation comprising annealing a sense strand and an antisense strand, wherein one of the sense strand and the antisense strand contains a lipophilic modification, to form a duplex solution comprising a SNCA double stranded RNA (dsRNA); lyophilizing the duplex solution to provide a duplex composition; and dissolving the duplex composition in an injection solution, wherein the injection solution comprises a divalent cation and does not comprise a phosphate buffer, wherein the duplex composition comprises about 1-2% molar excess of antisense strand over sense strand, and wherein the sense strand and the antisense strand are selected from the group consisting of the sense strand and the antisense strand sequences listed in Table 1.

39. The method of claim 38, wherein the divalent cation is calcium, magnesium, copper, nickel, zinc, or strontium.

40. The method of claim 38 or 39, wherein (a) the sense strand comprises the nucleotide sequence.q ;Y&\_&6Y&\_&;Y&7Y&6Y&6TP&;Y&IY&;R&6R&7R&6Y&6Y&6Y&IY&;Y&IY&IY&;Y&\_&;Y&\_&6Y ,q [R G9E =8 BC3 *4 MZP(b) the antisense strand comprises the nucleotide sequence.q JDa&\_&P7&\_&7Y&6Y&P6&7Y&P6&IY&IY&IY&;Y&PH&7Y&6R&7Y&IY&IY&;Y&7Y&IY&7Y&\_&IY&\_&IY ,q [R G9E =8 BC3 +4Page 77 of 79 ME1\58469596.v1Atty Docket No.: 121301-24920 cTQ^QUZ 6R U_ +q&RXa[^[MPQZ[_UZQ% 7R U_ +q&RXa[^[Oe`UPUZQ% ;R U_ +q&RXa[^[SaMZ[_UZQ%6Y U_ +q&O&YQ`TeXMPQZ[_UZQ% IY U_ +q&O&YQ`TeXa^UPUZQ% 7Y U_ +q&O-methylcytidine, Gm is+q&O&YQ`TeXSaMZ[_UZQ% P6 U_ +q&PQ[deMPQZ[_UZQ% P7 U_ +q&PQ[deOe`UPUZQ% PH U_ +q&PQ[de`TeYUPUZQ% 6TP U_ +q&O&TQdMPQOeXMPQZ[_UZQ% JDa U_ bUZeX\T[_\T[ZM`Q +q&O-YQ`TeXa^UPUZQ% q&q #Te\TQZ$ U_ M ,q&.q \T[_\T[PUQ_`Q^ XUZWMSQ% MZP q&\_&q U_ M ,q&.qphosphorothioate linkage. Page 78 of 79 ME1\58469596.v1