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Building IP: BMY Patent Application re "ANTIBODIES TO ALPHA-SYNUCLEIN AND USES THEREOF"
ANTIBODIES TO ALPHA-SYNUCLEIN AND USES THEREOF Disclosed herein are anti-.alpha.-synuclein antibodies which preferentially bind to oligomeric .alpha.-synuclein over monomeric .alpha.-synuclein, therapeutic compositions comprising the antibodies, and methods of using the antibodies to treat synucleinopathies.
1-20. (canceled) 21. A method of treating a disease or lessening the severity of a disease characterized by the presence of Lewy bodies or pathological aggregates of .alpha.-synuclein in neurons and/or glia comprising administering to a human subject with the disease an effective amount of an isolated antibody comprising: a heavy chain variable region comprising the following CDRs: i. CDR1 having the amino acid sequence of SEQ ID NO:12; ii. CDR2 having the amino acid sequence of SEQ ID NO:13; and iii. CDR3 having the amino acid sequence of SEQ ID NO:14; and a light chain variable region comprising the following CDRs: i. CDR1 having the amino acid sequence of SEQ ID NO:15; ii. CDR2 having the amino acid sequence of SEQ ID NO:16; and iii. CDR3 having the amino acid sequence of SEQ ID NO:17; wherein the antibody binds to human .alpha.-synuclein (SEQ ID NO:1). 22. A method of treating a disease or lessening the severity of a disease characterized by the presence of Lewy bodies or pathological aggregates of .alpha.-synuclein in neurons and/or glia comprising administering to a human subject with the disease an effective amount of an isolated antibody comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:18 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:19, wherein the antibody binds to human .alpha.-synuclein (SEQ ID NO:1). 23. A method of treating a disease or lessening the severity of a disease characterized by the presence of Lewy bodies or pathological aggregates of .alpha.-synuclein in neurons and/or glia comprising administering to a human subject with the disease an effective amount of an isolated antibody comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:20 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:21, wherein the antibody binds to human .alpha.-synuclein (SEQ ID NO:1). 24. A method of treating a disease or lessening the severity of a disease characterized by the presence of Lewy bodies or pathological aggregates of .alpha.-synuclein in neurons and/or glia comprising administering to a human subject with the disease an effective amount of an isolated antibody comprising two heavy chains and two light chains, wherein each of the heavy chains comprises the amino acid sequence set forth in SEQ ID NO:20 and each of the light chains comprises the amino acid sequence set forth in SEQ ID NO:21, wherein the antibody binds to human .alpha.-synuclein (SEQ ID NO:1). 25. The method of claim 21, wherein the disease is Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, Lewy body disease, multiple system atrophy, or pure autonomic failure. 26. The method of claim 22, wherein the disease is Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, Lewy body disease, multiple system atrophy, or pure autonomic failure. 27. The method of claim 23, wherein the disease is Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, Lewy body disease, multiple system atrophy, or pure autonomic failure. 28. The method of claim 24, wherein the disease is Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, Lewy body disease, multiple system atrophy, or pure autonomic failure. 29. The method of claim 21, comprising administering one or more additional therapeutic agents. 30. The method of claim 22, comprising administering one or more additional therapeutic agents. 31. The method of claim 23, comprising administering one or more additional therapeutic agents. 32. The method of claim 24, comprising administering one or more additional therapeutic agents. 33. The method of claim 21, wherein the isolated antibody binds to at least one or more of amino acid residues 123-128 of SEQ ID NO: 1. 34. The method of claim 22, wherein the isolated antibody binds to at least one or more of amino acid residues 123-128 of SEQ ID NO: 1. 35. The method of claim 23, wherein the isolated antibody binds to at least one or more of amino acid residues 123-128 of SEQ ID NO: 1. 36. The method of claim 24, wherein the isolated antibody binds to at least one or more of amino acid residues 123-128 of SEQ ID NO: 1. RELATED APPLICATION INFORMATION [0001] This application is a continuation of U.S. patent application Ser. No. 16/486,238, filed Aug. 15, 2019, which is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2018/000032, filed on Feb. 16, 2018, which claims the benefit of U.S. Provisional Patent Application No. 62/460,416, filed Feb. 17, 2017, each of which are incorporated herein by reference in their entirety. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jan. 11, 2021, is named MXI-554USCN_Sequence_Listing.txt and is 139,758 bytes in size. BACKGROUND [0003] .alpha.-synuclein (aSyn) is a 140 amino acid protein preferentially expressed in neurons at pre-synaptic terminals where it is thought to play a role in regulating synaptic transmission (Bendor et al., Neuron 2013; 79:1044-66). It has been proposed to exist natively as both an unfolded monomer (Fauvet et al., JBC 2012; 287:15345-64) and a stable tetramer of .alpha.-helices (Bartels et al., Nature 2011; 477:107-10; Wang et al., PNAS 2011; 108:17797-802) and has been shown to undergo several posttranslational modifications (Beyer and Ariza, Mol Neurobiol 2013; 47:509-24). One modification that has been extensively studied is phosphorylation of .alpha.Syn at amino acid residue serine 129 (S129). Normally, only a small percentage of .alpha.Syn is constitutively phosphorylated at S129 (pS129), whereas the vast majority of .alpha.Syn found in pathological intracellular inclusions is pS129 .alpha.Syn (Oueslati, J Parkinsons Dis 2016; 6:39-51). These pathological inclusions consist of aggregated, insoluble accumulations of misfolded .alpha.Syn proteins and are a characteristic feature of a group of neurodegenerative diseases collectively known as synucleinopathies (Galvin et al., Arch Neurol 2001; 58:186-90). [0004] In synucleinopathies, .alpha.Syn can form pathological aggregates in neurons know as Lewy bodies, which are characteristic of both Parkinson's Disease (PD) and dementia with Lewy bodies (DLB). Additionally, abnormal .alpha.Syn-rich lesions called glial cytoplasmic inclusions (GCIs) are found in oligodendrocytes, and represent the pathologic hallmark of a rapidly progressing, fatal synucleinopathy known as multiple systems atrophy (MSA). The initial evidence for the propagation of pathologic .alpha.Syn throughout the brain comes from the stereotypical progression of brain pathology described in PD (Braak et al., 2003) and from evidence of host-to-graft spreading of .alpha.Syn aggregates in PD patients (Kordower et al., 2008). Intriguingly, reports of either undetectable (Ozawa et al., Acta Neuropathologica 2001; 102:188-190; Miller et al., J Neural Transm (Vienna) 2005; 112:1613-24; Jin et al., Journal of Medical and Dental Sciences 2008; 555:145-53) or low levels (Asi et al., Glia 2014; 62:964-70) of .alpha.Syn mRNA expression in oligodendrocytes suggests that some pathological form of .alpha.Syn is propagated from neurons, where it is highly expressed, to oligodendrocytes. Recent work supports this idea of .alpha.Syn propagation, demonstrating that .alpha.Syn is taken up by oligodendrocytes (Reyes et al., Glia 2014; 62:387-98) and by neurons (Volpicelli-Daley et al., Neuron 2011; 72:57-71; Luk et al., Science 2012; 338: 949-953). Moreover, inoculation of human brain homogenates from MSA patients into .alpha.Syn transgenic mice or purified LB extracts from PD brains into mice and nonhuman primates results in neurological dysfunction and extensive pS129 neuronal deposits (Watts et al., PNAS 2013; 110:19555-60; Prusiner et al., PNAS 2015; 112:E5308-17; Recasens et al., Annals Neurology 2014; 75:351-62). [0005] There is currently a lack of therapeutics that target synucleinopathies from the perspective of .alpha.Syn propagation. Accordingly, therapeutic agents that preferentially target the pathological form of .alpha.Syn would be desirable in the treatment of patients with synucleinopathies such as PD, DLB, and MSA. SUMMARY [0006] Provided herein are isolated antibodies, such as monoclonal antibodies, that specifically bind to .alpha.-synuclein and have desirable functional properties. These properties include binding preferentially to oligomeric .alpha.-synuclein compared to monomeric .alpha.-synuclein, and the ability to inhibit the generation of soluble or insoluble .alpha.-synuclein aggregates (e.g., serine-129 phosphorylated .alpha.-synuclein aggregates) in vitro and in vivo. The anti-.alpha.-synuclein antibodies described herein can be used to treat, lessen the severity of, delay the progression of, reducing the risk of developing, delaying the onset of, and diagnosing synucleinopathies, a family of diseases characterized by the presence of Lewy bodies or pathological aggregates of .alpha.-synuclein in the brain. [0007] In one aspect, provided herein are antibodies, or antigen-binding portions thereof, which bind to .alpha.-synuclein and exhibit one or more of the following properties: [0008] (a) binds to mouse and rat .alpha.-synuclein; [0009] (b) binds to human .beta.-synuclein and human .gamma.-synuclein; [0010] (c) has a greater affinity for .alpha.-synuclein oligomers over .alpha.-synuclein monomers; [0011] (d) inhibits the generation of .alpha.-synuclein oligomer-induced insoluble .alpha.-synuclein aggregates (e.g., serine-129 phosphorylated .alpha.-synuclein aggregates); [0012] (e) depletes the molecular species that produces soluble or insoluble .alpha.-synuclein aggregates (e.g., serine-129 phosphorylated .alpha.-synuclein aggregates) from PFF and/or brain lysate prepared from patients with pathological aggregates of .alpha.-synuclein in the brain; [0013] (f) binds to all or a portion of amino acid positions 123-128 of human .alpha.-synuclein (SEQ ID NO: 1); [0014] (g) binds to all or a portion of amino acid positions 125-128 of human .alpha.-synuclein (SEQ ID NO: 1); [0015] (h) binds to all or a portion of amino acid positions 130-139 of human .alpha.-synuclein (SEQ ID NO: 1); [0016] (i) binds to all or a portion of amino acid positions 119-126 of human .alpha.-synuclein (SEQ ID NO: 1); and [0017] (j) binds to all or a portion of amino acid positions 130-138 of human .alpha.-synuclein (SEQ ID NO: 1). [0018] In certain embodiments, the .alpha.-synuclein oligomer is PFF, for example, prepared as described in Example 3. In some embodiments, the .alpha.-synuclein oligomers are soluble .alpha.-synuclein oligomers. In other embodiments, the .alpha.-synuclein oligomers are insoluble .alpha.-synuclein oligomers. [0019] In some embodiments, the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, have a greater affinity for .alpha.-synuclein PFF, soluble aggregates (oligomers) or insoluble aggregates over .alpha.-synuclein monomers, as assessed by, e.g., an .alpha.-synuclein monomer/.alpha.-synuclein PFF binding ratio, for example, as described in Example 3. In some embodiments, the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, have an .alpha.-synuclein monomer/.alpha.-synuclein PFF binding ratio of 100 or greater, for example, 500 or greater, 700 or greater, 1500 or greater 3000 or greater, or 5000 or greater. [0020] In some embodiments, the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, bind to monomeric .alpha.-synuclein with an EC50 of 500 nM or greater, and binds to PFF with an EC.sub.50 of 0.5 nM or less. In some embodiments, the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, inhibit PFF-induced .alpha.-synuclein serine-129 phosphorylation with an IC.sub.50 of 0.1 nM or less, as assessed, e.g., using the assay described in Example 10. [0021] In another aspect, provided herein are isolated monoclonal antibodies, or antigen-binding portions thereof, which specifically bind to .alpha.-synuclein and comprise the three variable heavy chain CDRs and the three variable light chain CDRs that are in the variable heavy chain and variable light chain pairs selected from the group consisting of SEQ ID NOs: 8 and 9, 18 and 19, 28 and 29, 38 and 39, 48 and 49, 58 and 59, 68 and 69, 78 and 79, 94 and 95, 94 and 96, 94 and 97, and 106 and 107. [0022] In another aspect, provided herein are isolated monoclonal antibodies, or antigen-binding portions thereof, which bind to .alpha.-synuclein, comprising: [0023] (a) heavy chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 2-4, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 5-7, respectively; [0024] (b) heavy chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 22-24, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 25-27, respectively; [0025] (c) heavy chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 22-24, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 28-30, respectively; [0026] (d) heavy chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 37-39, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 40-42, respectively; [0027] (e) heavy chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 47-49, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 50-52, respectively; [0028] (f) heavy chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 57-59, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 60-62, respectively; [0029] (g) heavy chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 67-69, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 70-72, respectively; [0030] (h) heavy chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 77-79, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 80-82, respectively; [0031] (i) heavy chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 87-89, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 90-92, respectively; [0032] (j) heavy chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 87-89, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 93-95, respectively; [0033] (k) heavy chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 87-89, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 96-98, respectively; or [0034] (l) heavy chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 107-109, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 110-112, respectively. [0035] In another aspect, provided herein are isolated monoclonal antibodies, or antigen-binding portions thereof, which bind to .alpha.-synuclein and comprises heavy and light chain variable regions, wherein the heavy chain variable region comprises an amino acid sequence which is at least 90% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 18, 31, 43, 53, 63, 73, 83, 99, and 113. [0036] In another aspect, provided herein are isolated monoclonal antibodies, or antigen-binding portions thereof, which bind to to .alpha.-synuclein and comprises heavy and light chain variable regions, wherein the light chain variable region comprises an amino acid sequence which is at least 90% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 19, 32, 33, 44, 54, 64, 74, 84, 100, 101, 102, and 114. [0037] In another aspect, provided herein are isolated monoclonal antibodies, or antigen-binding portions thereof, which bind to .alpha.-synuclein and comprise heavy and light chain variable region sequences at least 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequences selected from the group consisting of: (a) SEQ ID NOs: 8 and 9, 18 and 19, 31 and 32, 31 and 33, 43 and 44, 53 and 54, 63 and 64, 73 and 74, 83 and 84, 99 and 100, 99 and 101, 99 and 102; and SEQ ID NOs: 113 and 114. [0038] In another aspect, provided herein are isolated monoclonal antibodies, or antigen-binding portions thereof, which bind to .alpha.-synuclein and comprises heavy chain and light chain sequences at least 80%, 85%, 90%, 95%, 96%, 97%, 98% 99%, or 100% identical to the amino acid sequences selected from the group consisting of SEQ ID NOs: 10 and 11, 20 and 21, 34 and 35, 34 and 36, 45 and 46, 55 and 56, 65 and 66, 75 and 76, 85 and 86, 103 and 104, 103 and 105, 103 and 106, and 115 and 116. In some embodiments, the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, bind to all or a portion of amino acid positions 123-128 of human .alpha.-synuclein (SEQ ID NO: 1). In some embodiments, the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, bind to all or a portion of amino acid positions 125-128 of human .alpha.-synuclein (SEQ ID NO: 1). the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, bind to all or a portion of amino acid positions 130-139 of human .alpha.-synuclein (SEQ ID NO: 1). the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, bind to all or a portion of amino acid positions 119-126 of human .alpha.-synuclein (SEQ ID NO: 1). the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, bind to all or a portion of amino acid positions 130-138 of human .alpha.-synuclein (SEQ ID NO: 1). [0039] In some embodiments, the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, bind to rat and mouse .alpha.-synuclein. In some embodiments, the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, bind to human .beta.-synuclein and human .gamma.-synuclein. In some embodiments, the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, have greater affinity for .alpha.-synuclein PFF, soluble aggregates (oligomers) or insoluble aggregates than .alpha.-synuclein monomers, as assessed by an .alpha.-synuclein monomer/.alpha.-synuclein PFF binding ratio (monomer:PFF binding ratio), as described, e.g., in Example 3. In some embodiments, the monomer:PFF binding ratio is 100 or greater, 500 or greater, 700 or greater, 1500 or greater, 3000 or greater, or 5000 or greater. [0040] In some embodiments, the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, bind to the same epitope as the anti-.alpha.-synuclein antibodies described herein (e.g., antibodies 7A10, 7A10-T93A, 11H11-1, 11H11-2, 15A5, 21A3, 36A3, 44B11, 2E2, 23H8-1, 23H8-2, 23H8-3, and 1E8). In some embodiments, the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, compete for binding to to human .alpha.-synuclein with the anti-.alpha.-synuclein antibodies described herein (e.g., antibodies 7A10, 7A10-T93A, 11H11-1, 11H11-2, 15A5, 21A3, 36A3, 44B11, 2E2, 23H8-1, 23H8-2, 23H8-3, and 1E8). [0041] In some embodiments, the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, are igG1, IgG2, IgG3, or IgG4 antibodies, or variants thereof. In some embodiments, the anti-.alpha.-synuclein antibodies comprise an Fc region with reduced or no effector function, for example, an effectorless IgG1 Fc with the following mutations: L234A, L235E, and G257A. [0042] In some embodiments, the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, are chimeric, humanized, or human antibodies. In some embodiments, the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, are modified to reduce immunogenicity in humans. In one embodiment, the anti-.alpha.-synuclein antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions set forth in SEQ ID NOs: 18 and 19, respectively. [0043] In another aspect, provided herein are bispecific molecules comprising an anti-.alpha.-synuclein antibody linked to a molecule having a second binding specificity. [0044] In another aspect, provided herein are nucleic acids encoding the CDRs, or the heavy and/or light chain variable regions, or the heavy and/or light chains of the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, described herein, expression vectors comprising the nucleic acid molecules, and cells transformed with the expression vectors. [0045] In another aspect, provided herein are immunoconjugates comprising anti-.alpha.-synuclein antibodies linked to a moiety, such as a binding moiety, a labeling moiety, a biologically active moiety, or a therapeutic agent. [0046] In another aspect, provided herein are compositions comprising anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, and a carrier. Also provided herein are kits comprising the anti-.alpha.-synuclein antibodies, or antigen-binding portions thereof, and instructions for use. [0047] In another aspect, provided herein is a method of preparing an anti-.alpha.-synuclein antibody, or antigen-binding portion thereof, comprising expressing the antibody, or antigen binding portion thereof, in a cell and isolating the antibody, or antigen binding portion thereof, from the cell. [0048] In another aspect, provided herein is a method of detecting .alpha.-synuclein in a sample comprising contacting the sample with a anti-.alpha.-synuclein antibody, or antigen-binding portion thereof, bispecific antibody, or immunoconjugate described herein under conditions that allow for formation of a complex between the antibody, or antigen-binding portion thereof, and .alpha.-synuclein, and detecting the formation of the complex. [0049] In another aspect, provided herein is a method of inhibiting the generation of insoluble or soluble .alpha.-synuclein aggregates (e.g., serine-129 phosphorylated .alpha.-synuclein aggregates) in a cell comprising contacting the cell with an effective amount of the anti-.alpha.-synuclein antibody, or antigen-binding portion thereof, bispecific antibody, or immunoconjugate described herein. In some embodiments, the antibodies inhibit the generation of insoluble or soluble .alpha.-synuclein aggregates that do not contain serine-129 phosphorylated .alpha.-synuclein. In some embodiments, phosphorylation of serine-129 is induced by .alpha.-synuclein oligomers. In some embodiments, .alpha.-synuclein oligomers are pre-formed .alpha.-synuclein fibrils. In other embodiments, the .alpha.-synuclein oligomers are derived from brain samples from patients with synucleinopathies. [0050] In another aspect, provided herein is a method of treating, lessening the severity of, delaying the progression of, reducing the risk of developing, and/or delaying the onset of, a disease characterized by the presence of Lewy bodies or pathological aggregates of .alpha.-synuclein in the brain comprising administering to a subject with the disease an effective amount of the anti-.alpha.-synuclein antibody, or antigen-binding portion thereof, bispecific antibody, or immunoconjugate described herein. [0051] In another aspect, provided herein is a method of diagnosing a disease characterized by the presence of Lewy bodies or pathological aggregates of .alpha.-synuclein in a subject comprising: [0052] (a) contacting a sample from the subject with the anti-.alpha.-synuclein antibody, or antigen-binding portion thereof, bispecific antibody, or immunoconjugate described herein such that an antibody-antigen complex is formed; [0053] (b) measuring the amount of the complex formed; and [0054] (c) comparing the amount of the complex in the sample with the amount in a control wherein an elevated level of the complex in the sample relative to the control indicates the subject has a disease characterized by the presence of Lewy bodies or pathological aggregates of .alpha.-synuclein. In some embodiments, the sample is cerebrospinal fluid, brain tissue extract, urine, or blood. [0055] In some embodiments, the disease in the methods described above is Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, Lewy body disease, multiple system atrophy, or pure autonomic failure. In some embodiments, the methods described above further comprise administering one or more additional therapeutic agents. |
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