Degrader fusion constructs

Abstract

The present application relates to: a degradant, a composition and a chimeric molecule comprising said degradant, in particular a fusion protein of a degradant and a binding moiety; and methods of using such degraders and chimeric molecules, in particular for the treatment of diseases caused by protein accumulation and / or aggregation, in particular neurodegenerative diseases or neuromuscular diseases such as ALS or Huntington's disease. The binding moieties are preferably antibodies, in particular scFv fragments that are specific for different targets. The degraders and chimeric molecules provided herein are effective to target proteins and / or aggregates, such as TDP-43 or Huntingtin, for degradation. In the present application, a specific degrader is fused to an scFv that targets human TDP-43 and human Huntingtin (HTT).

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 366,665, filed on June 20, 2022, the contents of which are incorporated herein by reference in their entirety.

[0003] Sequence Listing

[0004] The contents of the electronically submitted Sequence Listing XML (name: 200720_SL.xml; size: 448,112 bytes; created on June 17, 2023) are incorporated herein by reference in their entirety. Background Art

[0005] The feature of nervous system disease (such as ALS, frontotemporal dementia, Huntington's disease) is the misfolding and aggregation of endogenous proteins. These misfolded and aggregated proteins can not be effectively degraded by the protein degradation system of cells, causing them to accumulate and cause toxic function acquisition and / or physiological function loss. Promoting the degradation of pathogenic proteins and aggregates by targeting for degraded proteins is a kind of attractive therapeutic strategy for these protein diseases. Traditional small molecule inhibitors face major challenges, such as poor drug selectivity, treatment resistance and most proteins are still not druggable. Therefore, there is a lack of therapy for the protein degradation of directly controlling pathogenic proteins and / or aggregates.

[0006] RNA interference has become a common approach for reducing gene expression of these proteins, which can result in reduced protein expression and prevent aggregate formation. These therapies are not always effective for diseases accompanied by accumulation of protein aggregates, as RNA and protein levels are not necessarily directly correlated. In addition, it remains challenging to effectively target abnormal GC-rich repetitive sequences, which are common in many neurodegenerative disorders. Therefore, patients with diseases associated with accumulated pathogenic proteins may benefit from treatments that directly reduce protein and / or aggregate levels.

[0007] Therefore, there is a need in the art for treatments that promote the clearance of pathogenic proteins by targeting protein degradation. Summary of the invention

[0008] Degradons, compositions and chimeric molecules comprising the degradons, and methods of using the same are provided herein. In one aspect, the chimeric molecules provided comprise degradons and binding moieties. Degradons and chimeric molecules provided herein effectively target proteins and / or aggregates (e.g., TDP-43, huntingtin) for degradation. Degradons and chimeric molecules provided herein overcome deficiencies in the field of treating diseases (e.g., ALS, Huntington's disease) caused by protein accumulation and / or aggregation.

[0009] In one aspect, provided herein is a chimeric molecule comprising a degron and a binding moiety, wherein the degron comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21. In embodiments, the amino acid sequence of the degron consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21. In embodiments, the degron consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21.

[0010] In an embodiment, the length of the degradon does not exceed 215 amino acids. In an embodiment, the length of the degradon does not exceed 50 amino acids.

[0011] In embodiments, the binding moiety is a small molecule, a nucleic acid, a lipid or a polypeptide. In embodiments, the binding moiety is a polypeptide.

[0012] In an embodiment, the polypeptide is at least 20 amino acids in length. In an embodiment, the polypeptide is at least 50 amino acids in length.

[0013] In embodiments, the chimeric molecule comprises more than one degron.

[0014] In an embodiment, the binding moiety is an antibody, a binding entity, a scaffold protein, or an antibody mimetic. In an embodiment, the binding moiety is an antibody. In an embodiment, the antibody is a scFv, a heavy chain antibody only, a variable domain of a novel antigen receptor (VNAR), an antibody fragment, an antigen binding (Fab) fragment, a monoclonal antibody, a DARPin, a VHH antibody, or a nanobody.

[0015] In an embodiment, the degradon is connected to the N-terminus and the C-terminus of the polypeptide. In an embodiment, the degradon is connected to the N-terminus of the polypeptide. In an embodiment, the degradon is connected to the C-terminus of the polypeptide.

[0016] In an embodiment, the binding moiety is connected to the degradon via a linker. In an embodiment, the degradon is connected to the variable heavy chain region (VH) and / or the variable light chain region (VL) of the antibody. In an embodiment, the degradon is connected to the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 or CDRL3 of the antibody. In an embodiment, the linker is a peptide or chemical linker. In an embodiment, the linker is a peptide linker.

[0017] In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron; a peptide linker; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker; and a degron. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 8; a peptide linker; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker; and a degron comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 8.

[0018] In an embodiment, the length of the peptide linker is 1 to 25 amino acids. In an embodiment, the peptide linker comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33. In an embodiment, the peptide linker comprises the amino acid sequence of SEQ ID NO: 22. In an embodiment, the peptide linker comprises the amino acid sequence of SEQ ID NO: 23.

[0019] In an embodiment, the antibody is a scFv that specifically binds to human TDP-43. In an embodiment, the scFv specifically binds to human TDP-43 at an epitope comprising the following amino acids of SEQ ID NO: 290: amino acids 65-71, 104-176, 115-118, 247, 201-211, 121-127, 213-223, 381-391, 133-139, 9-15, 409-410, 317-343, 215-222, 140-200, 181-195, 199-213, 307-321, 352-366, 389-411, or 397-411. In an embodiment, the degradon comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1 to 19. In an embodiment, the scFv comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain and the light chain variable domain respectively comprise the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.In an embodiment, the heavy chain variable domain and the light chain variable domain respectively comprise the amino acid sequence of: SEQ ID NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0020] In an embodiment, the polypeptide is a scFv or nanobody that specifically binds to human huntingtin protein. In an embodiment, the scFv or nanobody specifically binds to human huntingtin protein at an epitope comprising the following amino acids of SEQ ID NO: 291: amino acids 1-17, 18-38, 39-49, 50-64, 62-65, 67-76, 73-87, 80-89, 575-584, 585-516. In an embodiment, the scFv comprises a heavy chain variable domain and a light chain variable domain, and the heavy chain variable domain and the light chain variable domain comprise the following CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences: SEQ ID NO: NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336 ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387. In an embodiment, the heavy chain variable domain and the light chain variable domain comprise the amino acid sequence of SEQ ID NO: 388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415. In an embodiment, the Nanobody comprises a heavy chain variable domain comprising the CDRH1, CDRH2 and CDRH3 amino acid sequences of SEQ ID NO: 337, 338 and 339; or 340, 341 and 342; or a light chain variable domain comprising the CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 298, 299 and 300; or 349, 350 and 351. In an embodiment, the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:395 or 396; or the light chain variable domain comprises the amino acid sequence of SEQ ID NO:405 or 413.In an embodiment, the degradon comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 17 and 20.

[0021] In an embodiment, the polypeptide is a scFv that specifically binds to human polyglutamine (polyQ) protein. In an embodiment, the polypeptide is a scFv that specifically binds to human α-synuclein. In an embodiment, the polypeptide is a scFv that specifically binds to human tau protein. In an embodiment, the polypeptide is a scFv that specifically binds to human beta amyloid protein. In an embodiment, the polypeptide is a scFv that specifically binds to human lamin (e.g., lamin A / C). In an embodiment, the polypeptide is a scFv that specifically binds to human phospholamban (PLN) protein.

[0022] In one aspect, provided herein is a pharmaceutical composition comprising: a chimeric molecule disclosed herein; and a pharmaceutically acceptable carrier.

[0023] In one aspect, a polynucleotide is provided herein that encodes a chimeric molecule disclosed herein. In embodiments, the polynucleotide is an mRNA. In embodiments, the polynucleotide is a viral genome. In embodiments, the polynucleotide is an AAV genome.

[0024] In one aspect, an expression vector is provided herein, comprising a polynucleotide disclosed herein. In one aspect, a host cell is provided herein, comprising a polynucleotide disclosed herein.

[0025] In one aspect, provided herein is a method for producing a chimeric molecule, the method comprising culturing a host cell disclosed herein under conditions such that the polynucleotide is expressed and the chimeric molecule is produced.

[0026] In one aspect, provided herein is a recombinant adeno-associated virus (rAAV) comprising a capsid and a viral genome, wherein the viral genome comprises at least one inverted terminal repeat (ITR) region and a polynucleotide encoding a chimeric molecule disclosed herein.

[0027] In an embodiment, the capsid comprises a clade A, clade B, clade C, clade D, clade E, clade F, clade G, clade H, clade I, AAVgo.1, AAV3, AAV4, AAV10, AAV11, AAV12, rh.32, rh32.33, rh.33, rh.34, BAAV, AAV5.2 or AAV5 capsid protein, or an engineered variant thereof.

[0028] In an embodiment, the capsid protein comprises the amino acid sequence of any one of SEQ ID NOs: 258 to 289.

[0029] In one aspect, provided herein is a pharmaceutical composition comprising: the rAAV disclosed herein; and a pharmaceutically acceptable carrier.

[0030] In one aspect, provided herein is a method for reducing the level of human TDP-43 or human huntingtin protein in a cell, the method comprising introducing a chimeric molecule disclosed herein, a pharmaceutical composition disclosed herein, a polynucleotide disclosed herein, an expression vector disclosed herein, or a rAAV disclosed herein into the cell.

[0031] In one aspect, provided herein is a method for reducing the level of protein aggregates in a cell, the method comprising introducing a chimeric molecule disclosed herein, a pharmaceutical composition disclosed herein, a polynucleotide disclosed herein, an expression vector disclosed herein, or a rAAV disclosed herein into the cell. In an embodiment, the protein is intracellular. In an embodiment, the protein is extracellular.

[0032] In one aspect, provided herein is a method for reducing the level of human TDP-43 or human huntingtin protein in a cell, the method comprising expressing a chimeric molecule disclosed herein, a polynucleotide disclosed herein, an expression vector disclosed herein, or a rAAV disclosed herein in the cell.

[0033] In one aspect, provided herein is a method for reducing the level of protein aggregates in a cell, the method comprising expressing a chimeric molecule disclosed herein, a polynucleotide disclosed herein, an expression vector disclosed herein, or a rAAV disclosed herein in the cell.

[0034] In embodiments, the cell is a myocyte, a microglia, an astrocyte, a neuron, or a cardiomyocyte.

[0035] In an embodiment, the protein is human TDP-43, human huntingtin polyglutamine (PolyQ) protein, α-synuclein, tau protein, β-amyloid protein, lamin, phospholamban (PLN) protein.

[0036] In one aspect, provided herein is a method of treating a neurodegenerative or neuromuscular disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a chimeric molecule disclosed herein, a pharmaceutical composition disclosed herein, a polynucleotide disclosed herein, an expression vector disclosed herein, or an rAAV disclosed herein.

[0037] In one aspect, there is provided herein a method for treating a neurodegenerative or neuromuscular disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a polynucleotide disclosed herein in a delivery vehicle or an expression vector disclosed herein. In an embodiment, the delivery vehicle is a lipid nanoparticle (LNP), a vesicle, an exosome, a liposome or a polymer.

[0038] In an embodiment, the neurodegenerative disease or disorder is selected from the group consisting of motor neuron disease (MND), amyotrophic lateral sclerosis (ALS), parkinsonism syndrome, Alzheimer's dementia, progressive supranuclear palsy (PSP), Huntington's disease, multiple system atrophy (MSA), spinocerebellar ataxia (SCAl, 2, 3, 6, 7, 17), spinobulbar muscular atrophy (SBMA), dentatorubral pallidum Lewy body atrophy (DRPLA) and Friedreich's ataxia.

[0039] In an embodiment, the neuromuscular disease or disorder is selected from the group consisting of: myopathy, hereditary cardiomyopathy, metabolic myopathy, distal myopathy, muscular dystrophy, congenital myopathy, spinal muscular atrophy (SMA), motor neuron disease, congenital myopathy, congenital muscular dystrophy, motor neuron disease, Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophy, myotonic dystrophy, myotubular myopathy, centronuclear myopathy, nemaline myopathy, selenoprotein N-related myopathy, Pompe disease, glycogen storage disease type III, spinal muscular atrophy, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, multiple sclerosis, myositis, polymyositis and dermatomyositis.

[0040] In embodiments, the rAAV is administered to the subject intravenously, intraperitoneally, subcutaneously, intramuscularly, intrathecally, intranasally, intracisternal, intracranially, or intradermally.

[0041] In one aspect, provided herein is a degron comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 5.

[0042] In one aspect, provided herein is a chimeric molecule comprising a degron comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 5. In embodiments, the amino acid sequence of the degron consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 5.

[0043] In one aspect, a polynucleotide is provided herein, encoding a degron or chimera disclosed herein. In an embodiment, the polynucleotide is an mRNA. In an embodiment, the polynucleotide is a viral genome. In an embodiment, the polynucleotide is an AAV genome. In one aspect, an expression vector is provided herein, comprising the polynucleotide. In one aspect, a host cell is provided herein, comprising the polynucleotide.

[0044] In one aspect, the present invention provides a method for producing a degron or chimeric molecule, the method comprising culturing the host cell disclosed herein under such conditions that the polynucleotide is expressed and the degron or chimeric molecule is produced.

[0045] On the one hand, a recombinant adeno-associated virus (rAAV) is provided herein, comprising a capsid and a viral genome, wherein the viral genome comprises at least one inverted terminal repeat (ITR) region and a degradon or chimeric polynucleotide encoding disclosed herein. In an embodiment, the capsid comprises clade A, clade B, clade C, clade D, clade E, clade F, clade G, clade H, clade I, AAVgo.1, AAV3, AAV4, AAV10, AAV11, AAV12, rh.32, rh32.33, rh.33, rh.34, BAAV, AAV5.2 or AAV5 capsid protein, or an engineered variant thereof. In an embodiment, the capsid protein comprises SEQ ID NO:258 to 289 amino acid sequences.

[0046] In one aspect, provided herein is a pharmaceutical composition comprising: a degron, chimeric molecule or rAAV disclosed herein; and a pharmaceutically acceptable carrier. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 is a graph showing the average level of TDP-43 aggregates in the cytoplasm of U2OS cells after transfection with TDP43-ΔNLS2KQ-GFP and TDP-43scFv or non-TDP-43scFv control. The graph shows the results of three independent experiments. Statistical evaluation was calculated by Student's t-test.

[0048] Figure 2A and Figure 2B Figure 2 shows the level of TDP-43 aggregates quantified by cell imaging in the cytoplasm of U2OS cells after transfection with a panel of degrader-TDP-43 scFv constructs (#104 to 124) compared to a scFv construct without a degrader (#51). Figure 2A ) or the levels of phosphorylated TDP-43 aggregates analyzed by densitometry analysis of Western blots ( Figure 2B). The figure shows the results of three independent experiments. Statistical evaluation was calculated by Student's t-test.

[0049] Figure 3A is a Western blot showing the levels of chimeric degron-TDP-43 scFv construct #104 compared to scFv construct #51 without degron in U2OS cells with or without MG132 treatment. Figure 3B It shows Figure 3A Figure 4. Densitometry analysis of western blots.

[0050] Figure 4A is a graph showing the percentage of cells showing expression of TDP-43 scFv after transfection with degron-scFv constructs #104 or 122 and scFv construct #51 (without degron) in U2OS cells treated with a proteasome inhibitor (MG132) or an autophagy inhibitor (CQ). Figure 4B is a graph showing ubiquitin levels after transfection with degron-scFv constructs #104 or #122 and scFv construct #51 (without degron) in U2OS cells treated with a proteasome inhibitor (MG132).

[0051] Figure 5A and Figure 5B Figure 2 shows the expression of degrader-scFv construct #121 ( Figure 5A ) or #122( Figure 5B ) after transfection, quantitative imaging ( Figure 5A ) and densitometry analysis of Western blots ( Figure 5B ) Graph showing determination of the level of TDP-43scFv in the cytoplasm of U2OS cells.

[0052] Fig. 6A is a graph showing the levels of Q97 HTT aggregates quantified by cell imaging in cells treated with HTT scFv + degrader constructs (#346 to 366) compared to HTT scFv backbone constructs without degrader (#252). Figure 6B is a graph showing quantification of soluble HTT exon 1 Q97 protein obtained by densitometry analysis of Western blots. The membrane contains lysates from cells treated with HTT scFv + degron constructs (#346 to 366) and compared to the HTT scFv backbone construct without degron (#252).

[0053] Fig. 7Ais a graph showing the levels of Q97 HTT aggregates quantified by cell imaging in cells treated with HTT scFv + degron constructs (#391 to 528) compared to HTT scFv backbone constructs without degron (#240). Figure 7B is a graph showing quantification of soluble HTT exon 1 Q97 protein obtained by densitometry analysis of Western blots. The membrane contains lysates from cells treated with HTT scFv + degron constructs (#391 to 528) and compared to the HTT scFv backbone construct without degron (#240). DETAILED DESCRIPTION

[0054] Degradons, compositions and chimeric molecules comprising the degradons, and methods of using the same are provided herein. In one aspect, the chimeric molecules provided comprise degradons and binding moieties. Degradons and chimeric molecules provided herein effectively promote the degradation of proteins (e.g., TDP-43, Huntington protein). Degradons and chimeric molecules provided herein overcome deficiencies in the field of treating diseases (e.g., ALS, Huntington's disease) caused by protein accumulation and / or aggregation.

[0055] definition

[0056] As used herein, the term "degradon" refers to an amino acid sequence that can cause intracellular degradation of the molecule to which it is attached (e.g., by the ubiquitin-proteasome system (UPS) or by autophagy (e.g., by chaperone-mediated autophagy (CMA))). The term "degradon" does not encompass full-length, naturally occurring polypeptides. In an embodiment, the length of a degradon does not exceed 215 amino acids. In an embodiment, the length of a degradon does not exceed 50 amino acids.

[0057] As used herein, the term "chimeric molecule" refers to any molecule comprising a degron and a second molecular entity that are not essentially linked. In certain embodiments, the second molecular entity is a small molecule, a nucleic acid, a carbohydrate, a lipid or a polypeptide.

[0058] As used herein, the term "antibody" or "antibodies" includes full-length antibodies, antigen-binding fragments of full-length antibodies, and molecules comprising antibody CDRs, VH regions, and / or VL regions. Examples of antibodies include, but are not limited to, monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intrabodies, heteroconjugate antibodies, antibody-drug conjugates, single domain antibodies, monovalent antibodies, single chain antibodies or single chain Fv (scFv), camelized antibodies, affibodies, F(ab')2 fragments, disulfide-linked Fv (sdFv), anti-idiotypic (anti-Id) antibodies (including, e.g., anti-anti-Id antibodies), neoantigen receptor variable domains (VNARs), antigen binding (Fab) fragments, monomers, DARPins, VHH antibodies, and antigen binding fragments of any of the above. The antibody can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2), or any subclass (e.g., IgG2a or IgG2b) of immunoglobulin molecule.

[0059] As used herein, the term "CDR" or "complementarity determining region" means the non-contiguous antigen binding sites found within the variable regions of the heavy and light chain polypeptides. For example, Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991), Chothia et al., J. Mol. Biol. 196: 901-917 (1987) and MacCallum et al., J. Mol. Biol. 262: 732-745 (1996) have described these specific regions, all of which are incorporated herein by reference in their entirety, wherein the definitions include overlapping or subsets of amino acid residues when compared to each other. In an embodiment, the term "CDR" is a CDR as defined by MacCallum et al., J. Mol. Biol. 262: 732-745 (1996) and Martin A. "Protein Sequence and Structure Analysis of Antibody Variable Domains," in Antibody Engineering, Kontermann and Dübel, eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001). In an embodiment, the term "CDR" is a CDR as defined by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991). In an embodiment, different conventions are used to define the heavy chain CDR and light chain CDR of an antibody. In an embodiment, the heavy chain CDR and / or light chain CDR are defined by performing a structural analysis of the antibody and identifying residues in the variable region that are predicted to contact the epitope region of the target molecule. CDRH1, CDRH2 and CDRH3 represent heavy chain CDRs, and CDRL1, CDRL2 and CDRL3 represent light chain CDRs.

[0060] As used herein, the terms "variable region" and "variable domain" are used interchangeably and are common in the art. A variable region generally refers to a part of an antibody, generally a part of a light chain or a heavy chain, typically about 110 to 120 amino acids or 110 to 125 amino acids at the amino terminal in a mature heavy chain, and about 90 to 115 amino acids in a mature light chain, which are very different in sequence between antibodies and are used for the binding and specificity of a particular antibody to its specific antigen. The variability of the sequence is concentrated in those regions known as complementary determining regions (CDRs), while the more highly conserved regions in the variable region are known as framework regions (FRs). It is not desirable to be bound by any particular mechanism or theory, and it is believed that the CDRs of light and heavy chains are primarily responsible for the interaction and specificity of antibodies to antigens. In certain embodiments, the variable region is a human variable region. In certain embodiments, the variable region comprises rodent or mouse CDRs and human framework regions (FRs). In an embodiment, the variable region is a primate (e.g., non-human primate) variable region. In embodiments, the variable regions comprise rodent or murine CDRs and primate (eg, non-human primate) framework regions (FRs).

[0061] As used herein, the terms "VH" and "VL" refer to the antibody heavy chain variable region and light chain variable region, respectively, as described in Kabat et al., (1991) Sequences of proteins of immunological interest (NIH Publication No. 91-3242, Bethesda), which is incorporated herein by reference in its entirety.

[0062] As used herein, the term "constant region" is common in the art. The constant region is an antibody portion, e.g., the carboxyl terminal portion of a light chain and / or a heavy chain, which is not directly involved in binding of the antibody to an antigen, but which may exhibit various effector functions, such as interaction with an Fc receptor (e.g., an Fcγ receptor).

[0063] As used herein, the term "heavy chain" when used in reference to an antibody can refer to any of the different types based on the amino acid sequence of the constant region, e.g., alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), which give rise to the IgA, IgD, IgE, IgG, and IgM classes of antibodies, respectively, including the subclasses of IgG, e.g., IgG1, IgG2, IgG3, and IgG4.

[0064] As used herein, the term "light chain" when used to refer to an antibody can refer to any of the different types based on the amino acid sequence of the constant region, for example, kappa (κ) or lambda (λ). Light chain amino acid sequences are well known in the art. In an embodiment, the light chain is a human light chain.

[0065] As used herein, the term "AAV" is the standard abbreviation for adeno-associated virus.

[0066] As used herein, the term "recombinant adeno-associated virus" or "rAAV" refers to an AAV comprising a genome lacking functional rep and cap genes.

[0067] As used herein, the term "cap gene" refers to a nucleic acid sequence encoding a capsid protein. For AAV, the capsid protein may be VP1, VP2 or VP3. VP1, VP2 and / or VP3 capsid proteins are assembled into a capsid surrounding the rAAV genome.

[0068] As used herein, the term "rep gene" refers to a nucleic acid sequence encoding non-structural proteins required for AAV replication and production (eg, rep78, rep68, rep52, and rep40).

[0069] As used herein, the term "rAAV genome" refers to a nucleic acid molecule (e.g., DNA and / or RNA) comprising the genomic sequence of rAAV. The skilled artisan will appreciate that when the rAAV genome comprises a transgene (e.g., an antibody), the rAAV genome may be in a sense or antisense orientation relative to the transcription direction of the transgene.

[0070] As used herein, an "isolated polynucleotide" refers to a polynucleotide that has been separated from one or more nucleic acid molecules present in the natural source of the polynucleotide.

[0071] As used herein, "vector" refers to a nucleic acid molecule that serves as a vehicle for introducing a nucleic acid molecule (eg, a polynucleotide disclosed herein) into a cell.

[0072] As used herein, "expression vector" refers to a vector comprising transcriptional regulatory elements operably linked to a gene of interest (eg, a polynucleotide disclosed herein), which promotes expression of the gene of interest in cells and / or in a cell-free expression system.

[0073] As used herein, the term "transgene" refers to a non-AAV nucleic acid sequence encoding a polypeptide (e.g., an antibody or scFv) or a non-coding RNA (e.g., miRNA, shRNA, siRNA, antisense RNA, gRNA, antagomir, miRNA sponge, RNA aptamer, RNA ribozyme, or RNA aptamer).

[0074] As used herein, the term "transcriptional regulatory element" or "TRE" refers to a cis-acting nucleotide sequence, such as a DNA sequence, which regulates (e.g., controls, increases or decreases) the transcription of an operably linked nucleotide sequence by RNA polymerase to form an RNA molecule. The TRE may comprise one or more promoter elements and / or enhancer elements. It will be appreciated by the skilled artisan that promoter and enhancer elements in a gene may be close in position, and the term "promoter" may refer to a sequence comprising a promoter element and an enhancer element. Therefore, the term "promoter" does not exclude an enhancer element in a sequence. Promoter and enhancer elements do not need to be derived from the same gene or species, and the sequence of each promoter or enhancer element may be identical or substantially identical to the corresponding endogenous sequence in the genome.

[0075] As used herein, the term "operably linked" is used to describe the connection between a TRE and a polynucleotide sequence to be transcribed (e.g., a transgene disclosed herein). Typically, gene expression is placed under the control of a TRE comprising one or more promoter and / or enhancer elements. A transgene is "operably linked" to a TRE if transcription of the transgene is controlled or influenced by the TRE. The promoter and enhancer elements of the TRE may be in any orientation and / or distance relative to the transgene as long as the desired transcriptional activity is obtained. In an embodiment, the TRE is located upstream of the transgene.

[0076] As used herein, the "percent identity" between two nucleotide sequences or between two amino acid sequences is calculated by multiplying the number of matches between the aligned sequence pairs by 100 and dividing by the length of the aligned region (including internal gaps). The identity score only counts perfect matches and does not take into account how similar the amino acids are to each other. When a sequence is described herein as having a certain percentage of identity to a reference sequence, the percent identity to the reference sequence is determined across the full length of the reference sequence.

[0077] As used herein, the term "effective amount" in the context of administering an AAV to a subject refers to the amount of AAV that achieves a desired prophylactic or therapeutic effect.

[0078] Degradon

[0079] In one aspect, provided herein are degrons. The amino acid sequences of exemplary degrons disclosed herein are provided in Table 1 below.

[0080] Table 1. Amino acid sequences of exemplary degraders

[0081]

[0082]

[0083] In embodiments, the degradon comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21. In embodiments, the amino acid sequence of the degradon consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21. In embodiments, the degradon comprises the amino acid sequence of SEQ ID NO: 1. In embodiments, the amino acid sequence of the degradon consists of the amino acid sequence of SEQ ID NO: 1. In embodiments, the degradon comprises the amino acid sequence of SEQ ID NO: 2. In embodiments, the amino acid sequence of the degradon consists of the amino acid sequence of SEQ ID NO: 2. In embodiments, the degradon comprises the amino acid sequence of SEQ ID NO: 3. In embodiments, the amino acid sequence of the degradon consists of the amino acid sequence of SEQ ID NO: 3. In embodiments, the degradon comprises the amino acid sequence of SEQ ID NO: 4. In embodiments, the amino acid sequence of the degradon consists of the amino acid sequence of SEQ ID NO: 4. In embodiments, the degradon comprises the amino acid sequence of SEQ ID NO: 5. In embodiments, the amino acid sequence of the degradon consists of the amino acid sequence of SEQ ID NO: 5.

[0084] In one aspect, provided herein is a composition comprising a degradon, the degradon comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21. In an embodiment, the amino acid sequence of the degradon consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21.

[0085] In one aspect, provided herein is a composition comprising a degradon, the degradon comprising the amino acid sequence of SEQ ID NO: 1. In an embodiment, the amino acid sequence of the degradon consists of the amino acid sequence of SEQ ID NO: 1.

[0086] In one aspect, provided herein is a composition comprising a degradon, the degradon comprising the amino acid sequence of SEQ ID NO: 2. In an embodiment, the amino acid sequence of the degradon consists of the amino acid sequence of SEQ ID NO: 2.

[0087] In one aspect, provided herein is a composition comprising a degradon, the degradon comprising the amino acid sequence of SEQ ID NO: 3. In an embodiment, the amino acid sequence of the degradon consists of the amino acid sequence of SEQ ID NO: 3.

[0088] In one aspect, provided herein is a composition comprising a degradon, the degradon comprising the amino acid sequence of SEQ ID NO: 4. In an embodiment, the amino acid sequence of the degradon consists of the amino acid sequence of SEQ ID NO: 4.

[0089] In one aspect, provided herein is a composition comprising a degradon, the degradon comprising the amino acid sequence of SEQ ID NO: 5. In an embodiment, the amino acid sequence of the degradon consists of the amino acid sequence of SEQ ID NO: 5.

[0090] In an embodiment, a degron causes protein degradation of intracellular protein via the ubiquitin-proteasome system (UPS). In an embodiment, a degron causes protein degradation of intracellular protein via autophagy (e.g., by chaperone-mediated autophagy (CMA)). In an embodiment, a degron causes protein degradation of extracellular protein via the ubiquitin-proteasome system (UPS). In an embodiment, a degron causes protein degradation of extracellular protein via autophagy (e.g., by chaperone-mediated autophagy (CMA)).

[0091] chimeric molecules

[0092] In one aspect, provided herein is a chimeric molecule comprising a degron and a binding moiety, wherein the degron comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21. In embodiments, the amino acid sequence of the degron consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21. In embodiments, the degron consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21.

[0093] In an embodiment, the length of the degron is no more than 215 amino acids, for example, a length of 214, 213, 212, 211, 210, 209, 208, 207, 206, 205, 204, 203, 202, 201, 200, 199, 198, 197, 196, 195, 194, 193, 192, 191, 190, 189, 188, 187, 186, 185, 184, 183, 182 , 181, 180, 179, 178, 177, 176, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 164, 163, 162, 161, 160, 159, 158, 157, 156, 155, 154, 153, 152, 151, 150, 149, 148, 147, 146, 145, 144, 143, 142 , 141, 140, 139, 138, 137, 136, 135, 134, 133, 132, 131, 130, 129, 128, 127, 126, 125, 124, 123, 122, 121, 120, 119, 118, 117, 116, 115, 114, 113, 112, 111, 110, 109, 108, 107, 106, 105, 104, 103, 102 , 101, 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52 or 51 amino acids.

[0094] In an embodiment, the degron is no more than 50 amino acids in length, for example, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 amino acids in length.

[0095] In an embodiment, the binding moiety is a small molecule, a nucleic acid, a lipid or a polypeptide. In an embodiment, the binding moiety is a non-coding RNA (e.g., miRNA, shRNA, siRNA, antisense RNA, gRNA, antagene, miRNA sponge, RNA aptamer, RNA ribozyme or RNA aptamer). In an embodiment, the binding moiety is an oligonucleotide.

[0096] In an embodiment, the chimeric molecule comprises: a degron containing the amino acid sequence of SEQ ID NO:1; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, the chimeric molecule comprises: a degron containing the amino acid sequence of SEQ ID NO:2; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, the chimeric molecule comprises: a degron containing the amino acid sequence of SEQ ID NO:3; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, the chimeric molecule comprises: a degron containing the amino acid sequence of SEQ ID NO:4; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, the chimeric molecule comprises: a degron containing the amino acid sequence of SEQ ID NO:5; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, the chimeric molecule comprises: a degron containing the amino acid sequence of SEQ ID NO:6; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, the chimeric molecule comprises: a degron containing the amino acid sequence of SEQ ID NO:7; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, a chimeric molecule comprises: a degron containing an amino acid sequence of SEQ ID NO: 8; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, a chimeric molecule comprises: a degron containing an amino acid sequence of SEQ ID NO: 9; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, a chimeric molecule comprises: a degron containing an amino acid sequence of SEQ ID NO: 10; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, a chimeric molecule comprises: a degron containing an amino acid sequence of SEQ ID NO: 11; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, a chimeric molecule comprises: a degron containing an amino acid sequence of SEQ ID NO: 12; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, a chimeric molecule comprises: a degron containing an amino acid sequence of SEQ ID NO: 13; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, a chimeric molecule comprises: a degron containing an amino acid sequence of SEQ ID NO: 14; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, the chimeric molecule comprises: a degron comprising an amino acid sequence of SEQ ID NO: 15; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, the chimeric molecule comprises: a degron comprising an amino acid sequence of SEQ ID NO: 16; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, the chimeric molecule comprises: a degron comprising an amino acid sequence of SEQ ID NO: 17; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, the chimeric molecule comprises: a degron comprising an amino acid sequence of SEQ ID NO: 18; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, the chimeric molecule comprises: a degron comprising an amino acid sequence of SEQ ID NO: 19; and a small molecule, a nucleic acid, a lipid, or a polypeptide.In an embodiment, the chimeric molecule comprises: a degron comprising the amino acid sequence of SEQ ID NO: 20; and a small molecule, a nucleic acid, a lipid, or a polypeptide. In an embodiment, the chimeric molecule comprises: a degron comprising the amino acid sequence of SEQ ID NO: 21; and a small molecule, a nucleic acid, a lipid, or a polypeptide.

[0097] In an embodiment, the binding moiety is a polypeptide. In an embodiment, the polypeptide has a length of at least 20 amino acids. In an embodiment, the polypeptide has a length of at least 50 amino acids, for example, a length of at least 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 amino acids.

[0098] In embodiments, the polypeptide is between 20-100, 20-200, 20-300, 20-400, 20-500, 20-600, 20-700, 20-800, 20-900, 20-1000, 20-1100, 20-1200, 20-1300, 20-1400, 20-1500, 20-1600, 20-1700, 20-1800, 20-1900, or 20-2000 amino acids in length. In embodiments, the polypeptide is between 50-100, 50-200, 50-300, 50-400, 50-500, 50-600, 50-700, 50-800, 50-900, 50-1000, 50-1100, 50-1200, 50-1300, 50-1400, 50-1500, 50-1600, 50-1700, 50-1800, 50-1900, or 50-2000 amino acids in length. In embodiments, the polypeptide is between 75-100, 75-200, 75-300, 75-400, 75-500, 75-600, 75-700, 75-800, 75-900, 75-1000, 75-1100, 75-1200, 75-1300, 75-1400, 75-1500, 75-1600, 75-1700, 75-1800, 75-1900, or 75-2000 amino acids in length. In embodiments, the polypeptide is between 100-200, 100-300, 100-400, 100-500, 100-600, 100-700, 100-800, 100-900, 100-1000, 100-1100, 100-1200, 100-1300, 100-1400, 100-1500, 100-1600, 100-1700, 100-1800, 100-1900, or 100-2000 amino acids in length.

[0099] In embodiments, the chimeric molecule comprises more than one degradon. In embodiments, the chimeric molecule comprises 2, 3, 4 or 5 degradons. In embodiments, each of the degradons comprises the same amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21. In embodiments, each of the degradons comprises a different amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21.

[0100] In an embodiment, the chimeric molecule comprises a first degradon and a second degradon. In an embodiment, the first degradon and the second degradon comprise the same amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21. In an embodiment, the first degradon and the second degradon comprise the same amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21. In an embodiment, the first degradon and the second degradon comprise different amino acid sequences selected from the group consisting of SEQ ID NOs: 1 to 21. In an embodiment, the first degradon and the second degradon are both connected to the N-terminus of the polypeptide. In an embodiment, the first degradon and the second degradon are both connected to the C-terminus of the polypeptide. In an embodiment, the first degradon is connected to the N-terminus of the polypeptide and the second degradon is connected to the C-terminus of the polypeptide.

[0101] In embodiments, the binding moiety is an antibody, a binding entity, a scaffold protein, or an antibody mimetic. In embodiments, the binding moiety is an antibody. In embodiments, the antibody is a scFv, a heavy chain antibody only, a variable domain of a novel antigen receptor (VNAR), an antibody fragment, an antigen binding (Fab) fragment, a monoclonal antibody, a DARPin, a VHH antibody, or a nanobody. In embodiments, the antibody mimetic is an affibody, an adectin, an aptamer, an affimer, an affitin, anticalin, an avimer, a fynomer, an armadillo repeat protein, or a knottin.

[0102] In an embodiment, the degradon is connected to the N-terminus and the C-terminus of the polypeptide. In an embodiment, the degradon is connected to the N-terminus of the polypeptide. In an embodiment, the degradon is connected to the C-terminus of the polypeptide.

[0103] In an embodiment, the degron is connected to the variable heavy chain region (VH) and / or the variable light chain region (VL) of the antibody. In an embodiment, the degron is connected to the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 or LCDR3 of the antibody.

[0104] In an embodiment, the binding moiety is connected to the degradon by a joint. In an embodiment, the joint is a peptide disulfide or a chemical joint. In an embodiment, the chemical joint is an imine, an oxime, a hydrazone, a phosphoramide, an acetal group, N-ethoxybenzylimidazole (NEBI) or a maleic acid derived joint. In an embodiment, the joint is a peptide joint. The amino acid sequence of an exemplary peptide joint is listed in the following table 2.

[0105] Table 2. Amino acid sequences of exemplary peptide linkers

[0106] SEQ ID NO: Amino acid sequence 22 GSGSGSS 23 GSGSS 24 NS 25 AAAYPYDVPDYA 26 GSGSG 27 GSGSGGSGSG 28 GSGSGGSGGSGSGGSGGSGSG 29 LEGGGGSAAA 30 SGS 31 GGSGS 32 GGGGS 33 EQKLISEEDLS

[0107] In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron; a peptide linker; and an antibody.

[0108] In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 1; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyglutamine (polyQ) protein, α-synuclein, tau, beta amyloid, lamin, or phospholamban (PLN) protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 2; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, beta amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 3; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, beta amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 4; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 5; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 6; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 7; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 8; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein.In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 9; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 10; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 11; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 12; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 13; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 14; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 15; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 16; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein.In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 17; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 18; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 19; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 20; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 21; a peptide linker; and an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein.

[0109] In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 1; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 2; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 3; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 4; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 5; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 6; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 7; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 8; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 9; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 10; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 11; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody.In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 12; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 13; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 14; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 15; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 16; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 17; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 18; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 19; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 20; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 22 to 33; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 21; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 22 to 33; and an antibody.

[0110] In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 1; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 2; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 3; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 4; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 5; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 6; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 7; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 8; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 9; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 10; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43.In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 11; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 12; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 13; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 14; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 15; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 16; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 17; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 18; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 19; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to TDP-43.In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 20; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 22 to 33; and an antibody that specifically binds to TDP-43. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 21; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 22 to 33; and an antibody that specifically binds to TDP-43.

[0111] In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 1; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 2; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 3; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 4; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 5; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 6; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 7; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 8; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 9; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 10; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to huntingtin protein.In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 11; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 12; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 13; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 14; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 15; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 16; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 17; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising an amino acid sequence of SEQ ID NO: 18; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to Huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 19; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to huntingtin protein. In an embodiment, the chimeric molecule comprises, from the N-terminus to the C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 20; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and an antibody that specifically binds to huntingtin protein.In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising the amino acid sequence of SEQ ID NO: 21; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 22 to 33; and an antibody that specifically binds to huntingtin protein.

[0112] In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: an antibody; a peptide linker; and a degradon. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, beta amyloid, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 1. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, beta amyloid, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 2. In an embodiment, the chimeric molecule comprises from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 3. In an embodiment, the chimeric molecule comprises from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 4. In an embodiment, the chimeric molecule comprises from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 5. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, amyloid beta, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 6. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, amyloid beta, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 7. In an embodiment, the chimeric molecule comprises from the N-terminus to the C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, amyloid beta, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 8.In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, amyloid beta, lamin, or PLN protein; a peptide linker; and a degradon, comprising the amino acid sequence of SEQ ID NO: 9. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, amyloid beta, lamin, or PLN protein; a peptide linker; and a degradon, comprising the amino acid sequence of SEQ ID NO: 10. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, amyloid beta, lamin, or PLN protein; a peptide linker; and a degradon, comprising the amino acid sequence of SEQ ID NO: 11. In an embodiment, the chimeric molecule comprises from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, amyloid beta, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 12. In an embodiment, the chimeric molecule comprises from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, amyloid beta, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 13. In an embodiment, the chimeric molecule comprises from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, amyloid beta, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 14. In an embodiment, the chimeric molecule comprises from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, amyloid beta, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 15. In an embodiment, the chimeric molecule comprises from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, amyloid beta, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 16.In an embodiment, the chimeric molecule comprises from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 17. In an embodiment, the chimeric molecule comprises from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 18. In an embodiment, the chimeric molecule comprises from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, β-amyloid, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 19. In an embodiment, the chimeric molecule comprises from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, amyloid beta, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 20. In an embodiment, the chimeric molecule comprises from N-terminus to C-terminus: an antibody that specifically binds to TDP-43, huntingtin, polyQ protein, α-synuclein, tau, amyloid beta, lamin, or PLN protein; a peptide linker; and a degradon, which comprises the amino acid sequence of SEQ ID NO: 21.

[0113] In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising the amino acid sequence of SEQ ID NO: 1. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising the amino acid sequence of SEQ ID NO: 2. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising the amino acid sequence of SEQ ID NO: 3. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising the amino acid sequence of SEQ ID NO: 4. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising an amino acid sequence of SEQ ID NO: 5. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising an amino acid sequence of SEQ ID NO: 6. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising an amino acid sequence of SEQ ID NO: 7. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising an amino acid sequence of SEQ ID NO: 8. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising an amino acid sequence of SEQ ID NO: 9. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising an amino acid sequence of SEQ ID NO: 10. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising an amino acid sequence of SEQ ID NO: 11.In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising the amino acid sequence of SEQ ID NO: 12. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising the amino acid sequence of SEQ ID NO: 13. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising the amino acid sequence of SEQ ID NO: 14. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising the amino acid sequence of SEQ ID NO: 15. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising an amino acid sequence of SEQ ID NO: 16. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising an amino acid sequence of SEQ ID NO: 17. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising an amino acid sequence of SEQ ID NO: 18. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising an amino acid sequence of SEQ ID NO: 19. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising an amino acid sequence of SEQ ID NO: 20. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33; and a degron comprising an amino acid sequence of SEQ ID NO: 21.

[0114] In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 1. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 2. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 3. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 4. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 5. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 6. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 7. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 8. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 9. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 10.In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 11. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 12. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 13. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 14. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 15. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 16. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 17. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 18. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 19.In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising the amino acid sequence of SEQ ID NO: 20. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to TDP-43; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising the amino acid sequence of SEQ ID NO: 21.

[0115] In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising the amino acid sequence of SEQ ID NO: 1. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising the amino acid sequence of SEQ ID NO: 2. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising the amino acid sequence of SEQ ID NO: 3. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising the amino acid sequence of SEQ ID NO: 4. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 5. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 6. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 7. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 8. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin protein; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 9. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin protein; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 10.In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 11. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 12. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 13. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 14. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 15. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 16. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 17. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 18. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin protein; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 19. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin protein; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising an amino acid sequence of SEQ ID NO: 20.In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody that specifically binds to huntingtin protein; a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33, and a degron comprising the amino acid sequence of SEQ ID NO: 21.

[0116] In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: a degron comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 8; a peptide linker; and an antibody. In an embodiment, the chimeric molecule comprises, from N-terminus to C-terminus: an antibody; a peptide linker; and a degron comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 8.

[0117] In an embodiment, the length of the peptide linker is 1 to 25 amino acids. In an embodiment, the peptide linker comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 22 to 32. In an embodiment, the peptide linker comprises the amino acid sequence of SEQ ID NO: 22. In an embodiment, the peptide linker comprises the amino acid sequence of SEQ ID NO: 23.

[0118] In embodiments, the antibody is a scFv that specifically binds to human TDP-43. In embodiments, the scFv specifically binds to phosphorylated human TDP-43. In embodiments, the scFv specifically binds to human TDP-43 at an epitope comprising the following amino acids of SEQ ID NO: 290: amino acids 65-71, 104-176, 115-118, 247, 201-211, 121-127, 213-223, 381-391, 133-139, 9-15, 409-410, 317-343, 215-222, 140-200, 181-195, 199-213, 307-321, 352-366, 389-411, or 397-411.

[0119] Amino acid sequence of TDP-43 (SEQ ID NO: 290)

[0120] MSEYIRVTEDENDEPIEIPSEDDGTVLLSTVTAQFPGACGLRYRNPVSQCMRGVRLVEGILHAPDAGWGNLVYVVNYPKDNKRKMDETDASSAVKVKRAVQKT SDLIVLGLPWKTTEQDLKEYFSTFGEVLMVQVKKDLKTGHSKGFGFVRFTEYETQVKVMSQRHMIDGRWCDCKLPNSKQSQDEPLRSRKVFVGRCTEDMTEDEL REFFSQYGDVMDVFIPKPFRAFAFVTFADDQIAQSLCGEDLIIKGISVHISNAEPKHNSNRQLERSGRFGGNPGGFGNQGGFGNSRGGGAGLGNNQGSNMGGGMNFGAFSINPAMMAAAQAALQSSWGMMGMLASQQNQSGPSGNNQNQGNMQREPNQAFGSGNNSYSGSNSGAAIGWGSASNAGSGSGFNGGFGSSMDSKSSGWGM

[0121] The amino acid sequences of exemplary TDP-43 scFvs are listed in Tables 3 to 5 below.

[0122] Table 3. Amino acid sequences of CDRs of exemplary TDP-43 scFv

[0123]

[0124]

[0125]

[0126]

[0127] Table 4. Amino acid sequences of VH of exemplary TDP-43 scFv

[0128]

[0129]

[0130]

[0131] Table 5. Amino acid sequences of VL of exemplary TDP-43 scFv

[0132]

[0133]

[0134] In an embodiment, a scFv that specifically binds to TDP-43 comprises a heavy chain variable domain comprising the CDRH1, CDRH2, CDRH3 amino acid sequences of SEQ ID NO: 34, 35 and 36; 40, 41 and 42; 46, 47 and 48; 52, 53 and 54; 58, 59 and 60; 64, 65 and 66; 70, 71 and 72; 76, 77 and 78; 82, 83 and 84; 88, 89 and 90; 94, 95 and 96; 100, 101 and 102; 106, 107 and 108; 112, 113 and 114; 118, 119 and 120; 124 , 125 and 126; 130, 131, 132; 136, 137 and 138; 142, 143 and 144; 148, 149 and 150; 154, 155 and 156; 160, 161 and 162; 166, 167 and 168; 172, 173 and 174; 178, 179 and 180; 184, 185 and 186; 190, 191 and 192; or 196, 197 and 198.

[0135] In an embodiment, a scFv that specifically binds to TDP-43 comprises a light chain variable domain comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs: 37, 38, and 39; 43, 44, and 45; 49, 50, and 51; 55, 56, and 57; 61, 62, and 63; 67, 68, and 69; 73, 74, and 75; 79, 80, and 81; 85, 86, and 87; 91, 92, and 93; 97, 98, and 99; 103, 104, and 105; 109, 110, and 111; 115, 116, and 117; 121, 122, and 123; 127 , 128 and 129; 133, 134 and 135; 139, 140 and 141; 145, 146 and 147; 151, 152 and 153; 157, 158 and 159; 163, 164 and 165; 169, 170 and 171; 175, 176 and 177; 181, 182 and 183; 187, 188 and 189; 193, 194 and 195; or 199, 200 and 201.

[0136] In an embodiment, a scFv that specifically binds to TDP-43 comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain and the light chain variable domain respectively comprise the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0137] In an embodiment, the heavy chain variable domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 202 to 229; and the light chain variable domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 230 to 257.

[0138] In an embodiment, the heavy chain variable domain and the light chain variable domain respectively comprise the amino acid sequence of: SEQ ID NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0139] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-19.

[0140] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 1, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0141] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 2, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0142] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO:3, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO:34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0143] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO:4, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO:34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0144] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO:5, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO:34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0145] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO:6, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO:34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0146] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO:7, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO:34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0147] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 8, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0148] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 9, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0149] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 10, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0150] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 11, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0151] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 12, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0152] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 13, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0153] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 14, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0154] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 15, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0155] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 16, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0156] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 17, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0157] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 18, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0158] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 19, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

[0159] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 1, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0160] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 2, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0161] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 3, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0162] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 4, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0163] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 5, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0164] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 6, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0165] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 7, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0166] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 8, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0167] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 9, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0168] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 10, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0169] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 11, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0170] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 12, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0171] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 13, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0172] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 14, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0173] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 15, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0174] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 16, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0175] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 17, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0176] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 18, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of: SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0177] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human TDP-43 and a degron comprising the amino acid sequence of SEQ ID NO: 19, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

[0178] In an embodiment, the polypeptide is a scFv or nanobody that specifically binds to human huntingtin protein. In an embodiment, the scFv or nanobody specifically binds to human huntingtin protein at an epitope comprising the following amino acids of SEQ ID NO: 291: amino acids 1-17, 18-38, 39-49, 50-64, 62-65, 67-76, 73-87, 80-89, 575-584 or 585-516.

[0179] Amino acid sequence of huntingtin protein (SEQ ID NO: 291)

[0180]

[0181] The amino acid sequences of exemplary huntingtin scFvs and Nanobodies are listed in Tables 6 to 8 below.

[0182] Table 6. Amino acid sequences of CDRs of exemplary huntingtin scFv and nanobodies

[0183]

[0184]

[0185]

[0186] Table 7. Amino acid sequences of exemplary huntingtin scFv and VH of nanobodies

[0187]

[0188]

[0189] Table 8. Amino acid sequences of exemplary huntingtin scFv and VL of nanobodies

[0190]

[0191]

[0192] In an embodiment, the scFv comprises a heavy chain variable domain comprising the CDRH1, CDRH2 and CDRH3 amino acid sequences of SEQ ID NO: 292, 293 and 294; 301, 302 and 303; 307, 308 and 309; 313, 314 and 315; 319, 320 and 321; 325, 326 and 327; 331, 332 and 333; 343, 344 and 345; 352, 353 and 354; 358, 359 and 360; 364, 365 and 366; 370, 371 and 372; 376, 377 and 378; or 382, ​​383 and 384, respectively.

[0193] In an embodiment, the scFv comprises a light chain variable domain comprising the CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 295, 296 and 297; 304, 305 and 306; 310, 311 and 312; 316, 317 and 318; 322, 323 and 324; 328, 329 and 330; 334, 335 and 336; 346, 347 and 348; 355, 356 and 357; 361, 362 and 363; 367, 368 and 369; 373, 374 and 375; 379, 380 and 381; or 385, 386 and 387, respectively.

[0194] In an embodiment, the scFv comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain and the light chain variable domain respectively comprise the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336 ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0195] In an embodiment, the scFv comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 388 to 394 or 397 to 399; or a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 404, 406 to 412, 414 or 415.

[0196] In an embodiment, the heavy chain variable domain and the light chain variable domain comprise the amino acid sequences of SEQ ID NO: 388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415, respectively.

[0197] In an embodiment, the Nanobody comprises a heavy chain variable domain comprising the CDRH1, CDRH2 and CDRH3 amino acid sequences of SEQ ID NOs: 337, 338 and 339; or 340, 341 and 342, respectively; or a light chain variable domain comprising the CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NOs: 298, 299 and 300; or 349, 350 and 351, respectively.

[0198] In an embodiment, the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:395 or 396; or the light chain variable domain comprises the amino acid sequence of SEQ ID NO:405 or 413.

[0199] In an embodiment, the chimeric molecule comprises a scFv or nanobody that specifically binds to human huntingtin protein and a degron comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 17 and 20.

[0200] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 1, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0201] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 2, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0202] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 3, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0203] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:4, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO:292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0204] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:5, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0205] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:6, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0206] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:7, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO:292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0207] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:8, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0208] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:9, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO:292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0209] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 10, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0210] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 11, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0211] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 12, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0212] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 13, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0213] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 14, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0214] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 15, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0215] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 16, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0216] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 17, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0217] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 20, wherein the scFv comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336, respectively. ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

[0218] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 1, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO: 388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0219] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:2, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO:388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0220] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:3, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO:388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0221] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:4, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO:388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0222] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:5, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO: 388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0223] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:6, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO:388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0224] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:7, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO:388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0225] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:8, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO:388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0226] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:9, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO:388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0227] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 10, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: 388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0228] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:11, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO:388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0229] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 12, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO: 388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0230] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 13, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO: 388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0231] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 14, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO: 388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0232] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 15, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO: 388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0233] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 16, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: 388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0234] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO: 17, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of SEQ ID NO: 388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0235] In an embodiment, the chimeric molecule comprises a scFv that specifically binds to human huntingtin protein and a degron comprising the amino acid sequence of SEQ ID NO:20, wherein the heavy chain variable domain and the light chain variable domain of the scFv respectively comprise the amino acid sequences of the following items: SEQ ID NO:388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

[0236] In an embodiment, the polypeptide is a scFv that specifically binds to human polyglutamine (polyQ) protein. In an embodiment, the polypeptide is a scFv that specifically binds to human α-synuclein. In an embodiment, the polypeptide is a scFv that specifically binds to human tau protein. In an embodiment, the polypeptide is a scFv that specifically binds to human beta amyloid protein. In an embodiment, the polypeptide is a scFv that specifically binds to human lamin. In an embodiment, the polypeptide is a scFv that specifically binds to human phospholamban (PLN) protein.

[0237] Polynucleotides, vectors and methods for producing chimeric molecules

[0238] In one aspect, provided herein are isolated polynucleotides encoding the chimeric molecule proteins disclosed herein.

[0239] In an embodiment, polynucleotides are optimized, for example, by codon / RNA optimization, replacement with heterologous signal sequences and / or elimination of mRNA unstable elements. The method for producing optimized polynucleotides for recombinant expression by introducing codon changes and / or eliminating inhibitory regions in mRNA can be performed by adopting, for example, U.S. Patent Nos. 5,965,726; 6,174,666; 6,291,664; 6,414,132; and the optimization method described in 6,794,498, therefore, all of these U.S. Patents are incorporated herein by reference in their entirety. For example, potential splicing sites and unstable elements (e.g., elements rich in A / T or A / U) in RNA can be mutated without changing the amino acid encoded by the nucleic acid sequence to increase the stability of the RNA for recombinant expression. These changes utilize the degeneracy of the genetic code, for example, using alternative codons of the same amino acid. In an embodiment, one or more codons may need to be changed to encode conservative mutations, for example, similar amino acids with chemical structures and properties and / or functions similar to the original amino acids. Such methods can increase expression of the encoded chimeric molecule relative to expression of the chimeric molecule encoded by the non-optimized polynucleotide.

[0240] In one aspect, a vector is provided herein, comprising a polynucleotide disclosed herein. Suitable vectors include, but are not limited to, plasmids, viruses, cosmids, artificial chromosomes, linear DNA, and mRNA. In an embodiment, the vector is a plasmid or a viral vector. In an embodiment, the vector is a retroviral vector, a herpes virus vector, a baculovirus vector, or an adenovirus vector. In an embodiment, the vector is an expression vector.

[0241] The vector (e.g., expression vector) can be introduced into a cell (using any technique known in the art) to propagate the vector and / or express a chimeric molecule encoded by the vector. Therefore, in another aspect, the present disclosure provides a recombinant cell comprising a polynucleotide or vector (e.g., expression vector) disclosed herein. In another aspect, the present disclosure provides a method of producing a chimeric molecule, the method comprising culturing a recombinant cell under conditions of expressing a polynucleotide, and producing a chimeric molecule.

[0242] A variety of host cells and expression vector systems can be used to express the chimeric molecules described herein. In these expression systems, the coding sequence of interest can be produced and subsequently purified. These expression systems also represent cells that can in situ express the chimeric molecules described herein when transformed or transfected with the appropriate nucleotide coding sequences. These include, but are not limited to, microorganisms such as bacteria (e.g., E. coli and Bacillus subtilis) transformed with, for example, a recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vector containing a chimeric molecule coding sequence; yeast (e.g., Pichia pastoris) transformed with, for example, a recombinant yeast expression vector containing a chimeric molecule coding sequence; insect cell systems infected with, for example, a recombinant virus expression vector (e.g., baculovirus) containing a chimeric molecule coding sequence; plant cell systems (e.g., green algae, such as Chlamydomonas reinhardtii) infected with, for example, a recombinant virus expression vector (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with, for example, a recombinant plasmid expression vector (e.g., Ti plasmid) containing a chimeric molecule coding sequence; or mammalian cell systems (e.g., COS (e.g., COS1 or COS), CHO, BHK, MDCK, HEK 293, NS0, PER.C6, VERO, CRL7030, HsS78Bst, HeLa, and NIH 3T3, HEK-293T, HepG2, SP210, R1.1, BW, LM, BSC1, BSC40, YB / 20 and BMT10 cells). In embodiments, the cells used to express the chimeric molecules described herein are human cells, such as human cell lines. In embodiments, the mammalian expression vector is pOptiVEC TM Or pcDNA3.3. In an embodiment, bacterial cells (such as E. coli) or eukaryotic cells (e.g., mammalian cells) are used for expression of chimeric molecules. For example, mammalian cells (such as CHO or HEK293 cells) combined with vectors (such as major intermediate early gene promoter elements from human cytomegalovirus) are effective expression systems for chimeric molecules disclosed herein. In an embodiment, insect cells (e.g., Sf9 cells) are used for expression of chimeric molecules.

[0243] For example, in insect systems, Autographa californica nuclear polyhedrosis virus (AcNPV) can be used as a vector for expressing foreign genes. The virus grows in Spodoptera frugiperda cells. The capsid protein coding sequence can be cloned separately into a non-essential region of the virus (e.g., a polyhedrin gene) and placed under the control of an AcNPV promoter (e.g., a polyhedrin promoter).

[0244] For long-term, high-yield production of recombinant proteins, stable expressing cells can be generated. For example, cell lines that stably express the capsid proteins described herein can be engineered.

[0245] In an embodiment, instead of using an expression vector containing a viral origin of replication, a polynucleotide (e.g., DNA or RNA) and a selectable marker can be used to transform a host cell that is controlled by an appropriate transcriptional regulatory element (e.g., promoter, enhancer, sequence, transcription terminator, polyadenylation site, etc.). After introducing the polynucleotide, the engineered cell can be grown in an enriched medium for 1 to 2 days, and then converted to a selective medium. The selectable marker in the recombinant plasmid confers resistance to selection, and allows cells to stably integrate the plasmid into their chromosome and grow to form a focus, which can then be cloned and amplified into a cell line. The method can be advantageously used for engineered cell lines expressing chimeric molecules described herein or fragments thereof.

[0246] A number of selection systems can be used, including but not limited to the herpes simplex virus thymidine kinase (Wigler M et al., (1977) Cell 11(1):223-32), hypoxanthine guanine phosphoribosyltransferase (Szybalska EH and Szybalski W (1962) PNAS 48(12):2026-2034), and adenine phosphoribosyltransferase (Lowy I et al., (1980) Cell 22(3):817-23) genes in tk cells, hgprt cells, or aprt cells, respectively, all of which are incorporated herein by reference in their entirety. In addition, antimetabolite resistance can be used as the basis for selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler M et al., (1980) PNAS 77(6):3567-70; O'Hare K et al., (1981) PNAS 78:1527-31); gpt, which confers resistance to mycophenolic acid (Mulligan RC and P (1981) PNAS 78(4):2072-6); neo, which confers resistance to the aminoglycoside G-418 (Wu GY and Wu CH (1991) Biotherapy 3:87-95; Tolstoshev P (1993) Ann Rev Pharmacol Toxicol 32:573-596; Mulligan RC (1993) Science 260:926-932; Morgan RA and Anderson WF (1993) Ann Rev Biochem 62: 191-217; and Nabel GJ and Felgner PL (1993) Trends Biotechnol 11(5):211-5); and hygro, which confers resistance to hygromycin (Santerre RF et al., (1984) Gene 30(1-3): 147-56), all of which are incorporated herein by reference in their entirety.Methods generally known in the field of recombinant DNA technology can be routinely applied to select the desired recombinant clones, and such methods are described, for example, in Ausubel FM et al., (eds.), Current Protocols in Molecular Biology, John Wiley and Sons, NY (1993); Kriegler M, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990); and in Chapters 12 and 13, Dracopoli NC et al., (eds.), Current Protocols in Human Genetics, John Wiley and Sons, NY (1994); Colbère-Garapin F et al., (1981) J Mol Biol 150: 1-14, all of which are incorporated herein by reference in their entirety.

[0247] AAV composition

[0248] In one aspect, provided herein is a recombinant adeno-associated virus (rAAV) comprising a capsid and a viral genome, wherein the viral genome comprises at least one inverted terminal repeat (ITR) region and a polynucleotide encoding a chimeric molecule disclosed herein.

[0249] In an embodiment, the capsid comprises a clade A, clade B, clade C, clade D, clade E, clade F, clade G, clade H, clade I, AAVgo.1, AAV3, AAV4, AAV10, AAV11, AAV12, rh.32, rh32.33, rh.33, rh.34, BAAV, AAV5.2 or AAV5 capsid protein, or an engineered variant thereof.

[0250] In an embodiment, the capsid protein comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 258-289.

[0251] Table 9. Amino acid sequences of AAV capsid proteins

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262] Additional examples of recombinant AAV capsid proteins disclosed herein are listed in Table S1 below.

[0263] Table S1. Amino acid sequences of additional recombinant AAV capsid proteins

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274] In embodiments, the capsid protein comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 420-450.

[0275] In embodiments, the recombinant AAV capsid protein comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 258 to 289 and 420 to 450. In embodiments, the amino acid sequence of the recombinant AAV capsid protein consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 258 to 289 and 420 to 450.

[0276] In one aspect, provided herein is a pharmaceutical composition comprising: the rAAV disclosed herein; and a pharmaceutically acceptable carrier.

[0277] The rAAV disclosed herein generally comprises a recombinant genome (e.g., a rAAV genome) packaged in a capsid. The rAAV genome can be any type that can be packaged in an AAV capsid disclosed herein. For example, in an embodiment, the rAAV genome is a single-stranded DNA genome. In an embodiment, the rAAV genome is a self-complementary genome, for example, as described in US7790154, which is incorporated herein by reference in its entirety.

[0278] In embodiments, the rAAV genome comprises a transgene. In embodiments, the transgene encodes a therapeutic protein. In embodiments, the transgene encodes an antibody or fragment thereof (e.g., Fab, scFv, or full-length antibody). In embodiments, the transgene encodes a scFv, a nanobody, or a VHH. In embodiments, the transgene encodes a non-coding RNA.

[0279] In an embodiment, the transgene encodes a reporter sequence that generates a detectable signal when expressed. Such reporter sequences include, but are not limited to, DNA sequences encoding: β-lactamase; β-galactosidase (LacZ); alkaline phosphatase; thymidine kinase; green fluorescent protein (GFP); red fluorescent protein (RFP); chloramphenicol acetyltransferase (CAT); luciferase; membrane-bound proteins, including, for example, CD2, CD4, CD8; influenza hemagglutinin protein and other proteins well known in the art, for which high-affinity antibodies are present or can be produced by conventional means; and fusion proteins comprising membrane-bound proteins, which are appropriately fused to antigen tag domains from hemagglutinin or Myc, etc.

[0280] In an embodiment, the rAAV genome comprises a TRE operably connected to a transgenic to control the expression of RNA or polypeptides encoded by the transgenic. In an embodiment, TRE comprises a constitutive promoter. In an embodiment, TRE is active in any mammalian cell (e.g., any human cell). In an embodiment, TRE is active in a wide range of human cells. Such TRE may comprise a constitutive promoter and / or enhancer element, including any of those elements described herein and any of those elements known to those skilled in the art. In an embodiment, TRE comprises an inducible promoter. In an embodiment, TRE is a tissue-specific TRE, that is, it is active in a specific tissue and / or organ. Tissue-specific TRE comprises one or more tissue-specific promoters and / or enhancer elements, and optionally one or more constitutive promoters and / or enhancer elements. Tissue-specific promoters and / or enhancer elements can be separated from genes specifically expressed in tissues by methods well known in the art.

[0281] Suitable promoters include, for example, the cytomegalovirus promoter (CMV) (Stinski et al., (1985) Journal of Virology 55(2):431-441), CMV early enhancer / chicken β-actin (CBA) promoter / rabbit β-globin intron (CAG) (Miyazaki et al., (1989) Gene 79(2):269-277), a hybrid form of the CBA promoter (CBh) (Gray et al., (2011) Hum Gene Ther. 22(9):1143-53), CB SB (Jacobson et al., (2006) Molecular Therapy 13(6):1074-1084), human elongation factor 1α promoter (EF1α) (Kim et al., (1990) Gene 91(2):217-223), human phosphoglycerate kinase promoter (PGK) (Singer-Sam et al., (1984) Gene 32(3):409-417), mitochondrial heavy chain promoter (Lodeiro et al., (2012) PNAS 109(17):6513-6518), ubiquitin promoter (Wulff et al., (1990) FEBS Letters 261:101-105).

[0282] In one aspect, provided herein is a pharmaceutical composition comprising a rAAV disclosed herein and a pharmaceutically acceptable excipient, adjuvant, diluent, vehicle or carrier or a combination thereof. A "pharmaceutically acceptable carrier" includes any material that, when combined with the active ingredient of the composition, allows the ingredient to maintain biological activity and does not cause a disruptive physiological response (such as an unexpected immune response). Pharmaceutically acceptable carriers include water, phosphate-buffered saline, emulsions (such as oil / water emulsions), and wetting agents. Compositions containing such carriers are formulated by well-known conventional methods, such as those listed in the following references: Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton Pa. 18042, USA; A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy", 20th edition, Lippincott, Williams and Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) HC Ansel et al., 7th edition, Lippincott, Williams and Wilkins; and Handbook of Pharmaceutical Excipients (2000) AK Kibbe et al., 3rd edition, Amer. Pharmaceutical Assoc.

[0283] How to use

[0284] In one aspect, provided herein is a method for reducing the level of human TDP-43 in a cell, the method comprising introducing a chimeric molecule disclosed herein, a pharmaceutical composition disclosed herein, a polynucleotide disclosed herein, an expression vector disclosed herein, or a rAAV disclosed herein into the cell.

[0285] In one aspect, provided herein is a method for reducing the level of human huntingtin protein in a cell, the method comprising introducing the chimeric molecule disclosed herein, the pharmaceutical composition disclosed herein, the polynucleotide disclosed herein, the expression vector disclosed herein, or the rAAV disclosed herein into the cell.

[0286] In one aspect, provided herein is a method for reducing the level of polyglutamine (PolyQ) protein, α-synuclein, tau protein, β-amyloid protein, lamin or phospholamban (PLN) protein in a cell, the method comprising introducing a chimeric molecule disclosed herein, a pharmaceutical composition disclosed herein, a polynucleotide disclosed herein, an expression vector disclosed herein or an rAAV disclosed herein into the cell.

[0287] In one aspect, provided herein is a method for reducing the level of protein aggregates in a cell, the method comprising introducing a chimeric molecule disclosed herein, a pharmaceutical composition disclosed herein, a polynucleotide disclosed herein, an expression vector disclosed herein, or a rAAV disclosed herein into the cell. In an embodiment, the protein is intracellular. In an embodiment, the protein is extracellular.

[0288] In one aspect, provided herein is a method for reducing the level of human TDP-43 in a cell, the method comprising expressing a chimeric molecule disclosed herein, a polynucleotide disclosed herein, an expression vector disclosed herein, or a rAAV disclosed herein in the cell.

[0289] In one aspect, provided herein is a method for reducing the level of human huntingtin protein in a cell, the method comprising expressing a chimeric molecule disclosed herein, a polynucleotide disclosed herein, an expression vector disclosed herein, or a rAAV disclosed herein in the cell.

[0290] In one aspect, provided herein is a method for reducing the level of human phosphorylated TDP-43 in a cell, the method comprising expressing a chimeric molecule disclosed herein, a polynucleotide disclosed herein, an expression vector disclosed herein, or a rAAV disclosed herein in the cell.

[0291] In one aspect, provided herein is a method for reducing the level of exon 1 of human huntingtin protein in a cell, the method comprising expressing a chimeric molecule disclosed herein, a polynucleotide disclosed herein, an expression vector disclosed herein, or a rAAV disclosed herein in the cell.

[0292] In one aspect, provided herein is a method for reducing the level of polyglutamine (PolyQ) protein, α-synuclein, tau protein, β-amyloid protein, lamin or phospholamban (PLN) protein in a cell, the method comprising expressing a chimeric molecule disclosed herein, a polynucleotide disclosed herein, an expression vector disclosed herein or an rAAV disclosed herein in the cell.

[0293] In one aspect, provided herein is a method for reducing the level of protein aggregates in a cell, the method comprising expressing a chimeric molecule disclosed herein, a polynucleotide disclosed herein, an expression vector disclosed herein, or an rAAV disclosed herein in the cell. In embodiments, the protein is intracellular. In embodiments, the protein is extracellular.

[0294] In embodiments, the cell is a myocyte, a microglia, an astrocyte, a neuron, or a cardiomyocyte.

[0295] In an embodiment, the protein is human TDP-43, human huntingtin polyglutamine (PolyQ) protein, α-synuclein, tau protein, β-amyloid protein, lamin, phospholamban (PLN) protein. In an embodiment, the protein is phosphorylated TDP-43.

[0296] In one aspect, provided herein is a method of treating a neurodegenerative or neuromuscular disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a chimeric molecule disclosed herein, a pharmaceutical composition disclosed herein, a polynucleotide disclosed herein, an expression vector disclosed herein, or an rAAV disclosed herein.

[0297] In one aspect, there is provided herein a method for treating a neurodegenerative or neuromuscular disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a polynucleotide disclosed herein in a delivery vehicle or an expression vector disclosed herein. In an embodiment, the delivery vehicle is a lipid nanoparticle (LNP), a vesicle, an exosome, a liposome or a polymer.

[0298] In an embodiment, the neurodegenerative disease or disorder is selected from the group consisting of: motor neuron disease (MND), amyotrophic lateral sclerosis (ALS), Parkinson's syndrome, Alzheimer's dementia, progressive supranuclear palsy (PSP), Huntington's disease, multiple system atrophy (MSA), spinocerebellar ataxia (SCAl, 2, 3, 6, 7, 17), spinal bulbar muscular atrophy (SBMA), dentatorubral pallidum Lewy body atrophy (DRPLA) and Friedreich's ataxia.

[0299] In an embodiment, the neuromuscular disease or disorder is selected from the group consisting of: myopathy, hereditary cardiomyopathy, metabolic myopathy, distal myopathy, muscular dystrophy, congenital myopathy, spinal muscular atrophy (SMA), motor neuron disease, congenital myopathy, congenital muscular dystrophy, motor neuron disease, Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophy, myotonic dystrophy, myotubular myopathy, centronuclear myopathy, nemaline myopathy, selenoprotein N-related myopathy, Pompe disease, glycogen storage disease type III, spinal muscular atrophy, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, multiple sclerosis, myositis, polymyositis and dermatomyositis.

[0300] In embodiments, the rAAV is administered to the subject intravenously, intraperitoneally, subcutaneously, intramuscularly, intrathecally, intranasally, intracisternal, intracranially, or intradermally.

[0301] A degradon comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 5.

[0302] In one aspect, provided herein is a chimeric molecule comprising a degron comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 5. In embodiments, the amino acid sequence of the degron consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 5.

[0303] Adeno-associated virus packaging system

[0304] In one aspect, the present invention provides a packaging system for the recombinant preparation of a recombinant adeno-associated virus (rAAV) disclosed herein. Such a packaging system generally comprises: a first nucleotide sequence encoding one or more AAV Rep proteins; a second nucleotide sequence encoding an AAV capsid protein; and a third nucleotide sequence containing any one of the AAV genome sequences disclosed herein, wherein the packaging system is effective in a cell for encapsulating the AAV genome in a capsid to form rAAV.

[0305] In an embodiment, the packaging system comprises a first vector (comprising a first nucleotide sequence encoding one or more AAV Rep proteins and a second nucleotide sequence encoding an AAV capsid protein) and a second vector (comprising a third nucleotide sequence containing an rAAV genome). As used in the context of the packaging system described herein, "vector" refers to a nucleic acid molecule (e.g., a plasmid, a virus, a cosmid, an artificial chromosome, etc.) that is used as a vehicle for introducing nucleic acid into a cell.

[0306] Any AAV Rep protein can be used in the packaging system disclosed herein. In one embodiment of the packaging system, the Rep nucleotide sequence encodes an AAV2 Rep protein. Suitable AAV2 Rep proteins may include, but are not limited to, Rep 78 / 68 or Rep68 / 52.

[0307] In an embodiment, the packaging system further comprises a fourth nucleotide sequence comprising one or more helper virus genes. In an embodiment, the fourth nucleotide sequence comprises adenovirus E2, E4 and VA genes. In an embodiment, the packaging system further comprises a third vector (e.g., a helper virus vector) comprising the fourth nucleotide sequence. The third vector can be an independent third vector, integrated with the first vector, or integrated with the second vector.

[0308] In one embodiment of the packaging system, the helper virus is selected from the group consisting of adenovirus, herpes virus (including herpes simplex virus (HSV)), poxvirus (such as vaccinia virus), cytomegalovirus (CMV) and baculovirus. In one embodiment where the helper virus is an adenovirus, the adenovirus genome comprises one or more adenovirus RNA genes selected from the group consisting of E1, E2, E4 and VA. In an embodiment, the adenovirus genome comprises one or more adenovirus RNA genes selected from the group consisting of E2, E4 and VA. In one embodiment where the helper virus is HSV, the HSV genome comprises one or more HSV genes selected from the group consisting of UL5 / 8 / 52, ICPO, ICP4, ICP22 and UL30 / UL42.

[0309] In one embodiment of the packaging system, the first vector, the second vector and / or the third vector are contained within one or more plasmids. In an embodiment, the first vector and the third vector are contained within a first plasmid. In an embodiment, the second vector and the third vector are contained within a second plasmid.

[0310] In one embodiment of the packaging system, the first vector, the second vector and / or the third vector are contained in one or more recombinant helper viruses. In an embodiment, the first vector and the third vector are contained in a recombinant helper virus. In an embodiment, the second vector and the third vector are contained in a recombinant helper virus.

[0311] In one aspect, the present invention provides a method for the recombinant preparation of rAAV as described herein, wherein the method comprises transfecting or transducing cells with a packaging system as described herein under effective conditions to encapsulate the rAAV genome in a capsid to form an rAAV as described herein. Exemplary methods for the recombinant preparation of rAAV include transient transfection (e.g., with one or more transfection plasmids containing a first vector, a second vector, and an optional third vector as described herein), viral infection (e.g., with one or more recombinant helper viruses containing a first vector and a second vector as described herein and an optional third vector, such as adenovirus, poxvirus (such as vaccinia virus), herpes virus (including HSV, cytomegalovirus or baculovirus)), and stable production cell line transfection or infection (e.g., having a stable production cell containing a Rep nucleotide sequence encoding one or more AAVRep proteins and / or a Cap nucleotide sequence encoding one or more AAV capsid proteins, such as a mammalian cell or an insect cell, and having a transfer genome as described herein delivered in the form of a plasmid or a recombinant helper virus).

[0312] Therefore, the present disclosure provides a packaging system for preparing rAAV, wherein the packaging system comprises: a first nucleotide sequence encoding one or more AAV Rep proteins; a second nucleotide sequence encoding the AAV capsid protein disclosed herein; a third nucleotide sequence containing the rAAV genome sequence described herein; and optionally a fourth nucleotide sequence containing one or more helper virus genes (e.g., adenovirus E2, E4 and VA genes).

[0313] Examples

[0314] Example 1: Analysis of TDP-43 scFv

[0315] Mutant forms of TDP-43 lead to cytoplasmic aggregates that act as inclusion bodies in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Targeting mutant forms of TDP-43 can restore the balance between the ratio of wild-type TDP-43 and pathologically aggregated TDP-43.

[0316] A panel of TDP-43 scFvs were analyzed for their ability to reduce TDP-43 aggregate levels in U2OS cells. The TDP-43 scFvs used in this example are listed in Table 10 below.

[0317] Table 10. Epitope specificity of TDP-43 scFv

[0318]

[0319] In a 24-well plate, U2OS cells were transfected with TDP-43-ΔNLS2KQ-GFP and anti-TDP-43 scFv (clones #50 to 64 and 93 to 103, sequences see Tables 3 to 5) or non-TDP43 scFv (clones #65 to 66) for 48 hours. The cells were then fixed with 4% formaldehyde solution and stained with DAPI and mouse-α-FLAG, followed by goat-α-mouse 568. The samples were then imaged using the ImageXpress PICO system.

[0320] TDP-43 aggregates were quantified using the spot scoring module present in the Cell Reporter Expression software. The level of TDP-43 aggregates per cell was normalized to control cells (transfected with clone #65). Figure 1 The results shown in show that several anti-TDP-43 scFvs resulted in a reduction in the level of TDP-43 aggregates per cell compared to cells transfected with non-TDP-43 scFvs. Clone 51 did not show a reduction in TDP-43 aggregates and, therefore, was chosen for the design of scFv-degraders to determine the effect of each degrader on TDP-43 aggregates.

[0321] Example 2: Design of chimeric degron-scFv molecules

[0322] Chimeric degrader-scFv construct is developed with degrader, and described degrader guides protein degradation by ubiquitin proteasome system (UPA), chaperone-mediated autophagy (CMA) or macroautophagy connected to anti-TDP-43scFv.Specifically, degrader disclosed in Table 1 is connected to the N-terminal or C-terminal of anti-TDP-43scFv (clone #51).The details of each degrader-scFv construct are described in Table 11 below.Joint sequence GSGSGSS (SEQ ID NO:22) and GSGSS (SEQ ID NO:23) are used to connect degrader to scFv.Construct also includes FLAG tag for experimental analysis.

[0323] Table 11. Degradon-TDP-43 scFv constructs

[0324] Constructs# Degradon Location of degraders Protein degradation pathway 104 1 (SEQ ID NO: 19) C-terminus ups 105 2 (SEQ ID NO:9) C-terminus ups 106 3 (SEQ ID NO: 20) C-terminus ups 107 4 (SEQ ID NO: 10) C-terminus ups 108 5 (SEQ ID NO: 11) N-terminus ups 109 6 (SEQ ID NO: 12) C-terminus ups 110 7 (SEQ ID NO: 13) C-terminus ups 111 8 (SEQ ID NO: 14) C-terminus ups 112 9 (SEQ ID NO:6) C-terminus ups 113 10 (SEQ ID NO:7) C-terminus ups 114 11 (SEQ ID NO: 18) N-terminus ups 115 12 (SEQ ID NO: 15) C-terminus ups 116 13 (SEQ ID NO: 16) N-terminus ups 117 14 (SEQ ID NO: 21) C-terminus CMA 118 15 (SEQ ID NO: 8) C-terminus CMA 119 16 (SEQ ID NO: 17) C-terminus CMA 120 17 (SEQ ID NO: 1) C-terminus CMA 121 18 (SEQ ID NO: 2) N-terminus Macroautophagy 122 19 (SEQ ID NO: 3) C-terminus Macroautophagy 123 20 (SEQ ID NO: 4) N-terminus Macroautophagy 124 21 (SEQ ID NO: 5) C-terminus Macroautophagy

[0325] Example 3: Analysis of Aggregation Reduction by Chimeric Degron-scFv Constructs

[0326] A panel of chimeric degrader-TDP-43-scFv molecules was analyzed for their ability to reduce TDP-43 aggregates in U2OS cells.

[0327] To analyze the effect of degrader constructs on TDP-43 aggregation, TDP43-ΔNLS2KQ-GFP constructs were co-expressed with TDP-43scFv+degrader constructs (#104 to 124) or scFv backbone constructs without degraders (#51) in U2OS cells in 24-well plates for 48 hours. Samples were then imaged using the ImageXpress PICO system. Figure 2A The results in show that degron-TDP-43 scFv constructs #104, 105, 110, 113 to 115, 118, and 122 to 124 significantly reduced the level of TDP-43 aggregates compared to the control construct.

[0328] The effect of the degrader-scFv construct on the level of phosphorylated TDP-43 was evaluated by Western blot and densitometry analysis. U2OS cells stably expressing TDP-43 under the IPTG promoter were transfected with degrader-scFv constructs (#104 to 124) or empty scFv backbone (clone #51) in 24-well plates. After treatment with 250 μM NaAsO2 for 2 hours, the samples were lysed for 24 hours and subjected to Western blot analysis. The Western blot was stained with rat-α-pTDP-43 and then detected with goat-α-rat-800. For loading controls, the blot was stained with rabbit-α-TUBB3 and then detected with goat-α-rabbit 680. Figure 2B The results in show that degron-TDP-43 scFv constructs #108 and 112 to 114 significantly reduced the level of phosphorylated TDP-43 aggregates compared to the control construct.

[0329] Example 4: Analysis of specific protein degradation pathways

[0330] Cells were treated with proteasome and autophagy inhibitors to analyze the specific protein degradation effect of the degradation sub-scFv construct. Specifically, in a 24-well plate, U2OS cells were transfected with 25, 50 or 100ng of degradation sub-scFv construct #104 or scFv construct #51 without degradation sub for 24 hours. After transfection, cells were treated with 10 μM proteasome inhibitor MG132 for 8 hours or not, and then lysed. Western blots were stained with mouse-α-FLAG, then detected with goat-α-mouse-800 (TDP-43scFv+degrader) and rabbit-α-TUBB3, and then detected with goat-α-rabbit 680 (loading control). Figure 3A and Figure 3B The results in show that the degrader TDP-43scFv construct #104 accumulated when cells were treated with MG132, indicating that construct #104 was degraded via the ubiquitin proteasome system.

[0331] In a 24-well plate, U2OS cells were transfected with 25, 50 or 100ng of degrader-TDP-43scFv constructs (#104 or 122) and empty scFv backbones without degraders (#51) for 24 hours. Untransfected cells were used as controls. Cells were then treated with 10μM proteasome inhibitor MG132 for 8 hours, or 10μM autophagy inhibitor chloroquine (CQ) for 8 hours. Untreated cells were used as controls. The samples were then fixed and stained with DAPI and mouse-α-FLAG, followed by goat-α-mouse 568. The samples were also fixed and stained with DAPI and rabbit-α-ubiquitin, followed by goat-α-rabbit 647 to analyze ubiquitin levels. The samples were then imaged using the ImageXpress PICO system. Images were quantified using the cell scoring module present in the cell reporter expression software of Molecular Devices. Figure 4A The results in show that degrader-scFv construct #104 accumulated after treatment with MG132, and degrader-scFv construct #122 accumulated after treatment with CQ, indicating that these degrader constructs induce degradation via the ubiquitin proteasome system and autophagy, respectively. Figure 4B The results in show that ubiquitin levels are increased after treatment with MG132.

[0332] In order to further analyze the degradation of degradation by macroautophagy, U2OS cells were transfected with 50ng of degradation-TDP-43-scFv construct #121 or 122 in 24-well plates for 24 hours. Cells were then treated with 0.1, 1 or 10 μM of autophagy inhibitor chloroquine (CQ), PI3K inhibitor LY294002, wortmannin or DMSO for 8 hours. Untreated samples were used as controls. The samples were then fixed and stained with DAPI and mouse-α-FLAG, and then stained with goat-α-mouse 568. The samples were then imaged using the ImageXpress PICO system. Images were quantified using the cell scoring module present in the cell reporter expression software of Molecular Devices. Western blots were stained with mouse-α-FLAG, then detected with goat-α-mouse-800 (TDP-43scFv+degradation) and rabbit-α-TUBB3, and then detected with goat-α-rabbit 680 (loading control). Figure 5A and Figure 5B The results in show that upon treatment with CQ, degron-TDP-43-scFv constructs #121 and 122 accumulated, suggesting that these degron constructs induce degradative autophagy.

[0333] Example 5: Analysis of Huntingtin (HTT) aggregates or soluble HTT protein by chimeric degron-scFv constructs White reduction

[0334] Chimeric degradon-scFv construct is developed with degradon, and the degradon guides protein degradation by ubiquitin proteasome system (UPS), chaperone-mediated autophagy (CMA) or macroautophagy connected to anti-HTT scFv. Specifically, the degradon disclosed in Table 1 is connected to the N-terminal or C-terminal of anti-HTT scFv (clone #252 or #240). The details of each degradon-scFv construct are described in Tables 12 to 13 below. Joint sequence GSGSGSS (SEQ ID NO:22) and GSGSS (SEQID NO:23) are used to connect the degradon to scFv. Construct also includes the FLAG tag for experimental analysis.

[0335] Table 12. Degradon-HTT INT41 scFv constructs

[0336] Constructs# Degradon Location of degraders Protein degradation pathway 252(INT41) not applicable not applicable not applicable 354 9 (SEQ ID NO:6) C-terminus ups 346 1 (SEQ ID NO: 19) C-terminus ups 347 2 (SEQ ID NO:9) C-terminus ups 348 3 (SEQ ID NO: 20) C-terminus ups 349 4 (SEQ ID NO: 10) C-terminus ups 350 5 (SEQ ID NO: 11) N-terminus ups 352 7 (SEQ ID NO: 13) C-terminus ups 353 8 (SEQ ID NO: 14) C-terminus ups 355 10 (SEQ ID NO:7) C-terminus ups 356 11 (SEQ ID NO: 18) N-terminus ups 357 12 (SEQ ID NO: 15) C-terminus ups 358 13 (SEQ ID NO: 16) N-terminus ups 359 14 (SEQ ID NO: 21) C-terminus CMA 360 15 (SEQ ID NO: 8) C-terminus CMA 361 16 (SEQ ID NO: 17) C-terminus CMA 362 17 (SEQ ID NO: 1) C-terminus CMA 363 18 (SEQ ID NO: 2) N-terminus Macroautophagy 364 19 (SEQ ID NO: 3) C-terminus Macroautophagy 365 20 (SEQ ID NO: 4) N-terminus Macroautophagy 366 21 (SEQ ID NO: 5) C-terminus Macroautophagy 351 6 (SEQ ID NO: 12) C-terminus ups Comparison not applicable not applicable not applicable

[0337] Table 13. Degradon-HTT C4 scFv constructs

[0338]

[0339]

[0340] A panel of chimeric degrader-HTT scFv molecules were analyzed for their ability to reduce HTT aggregates or soluble HTT in U2OS cells. To analyze the effect of the degrader constructs on HTT aggregates, the HTTexon1-Q97-IRES-GFP-Q16 construct was co-expressed with either HTT scFv + degrader constructs or scFv backbone constructs without degraders in U2OS cells for 48 hours in 24-well plates. The samples were then imaged using the ImageXpress Micro-confocal system. Fig. 6A The results in show that several degron-HTT scFv constructs # increased the reduction of Q97 HTT aggregates compared to control constructs using either an HTT scFv backbone construct without a degron (clone #252) or a non-HTT binding anti-cocaine control scFv (control). Fig. 7A Several degron-HTT scFv constructs # showed improved reduction of Q97 HTT aggregates compared to control constructs using either an HTT scFv backbone construct without a degron (clone #240) or a non-HTT binding anti-cocaine control scFv (control).

[0341] A panel of chimeric degrader-HTT scFv molecules were further analyzed for their ability to reduce soluble exon 1 HTT protein in U2OS cells. To analyze the effect of the degrader constructs on HTT aggregates, the HTTexon1-Q97-IRES-GFP-Q16 construct was co-expressed with either HTT scFv + degrader constructs or scFv backbone constructs without degraders in U2OS cells for 48 hours in 24-well plates. Samples were then lysed and analyzed by western blot and imaged using the ChemiDoc system. Figure 6B It was demonstrated that several degron-HTT scFv constructs # enhanced the reduction of soluble HTT exon 1 Q97 protein compared to control constructs using either an HTT scFv backbone construct without a degron (clone #252) or a non-HTT binding anti-cocaine control scFv (control). Figure 7B It was demonstrated that several degron-HTT scFv constructs # enhanced the reduction of soluble HTT exon 1 Q97 protein compared to control constructs using either an HTT scFv backbone construct without a degron (clone #240) or a non-HTT binding anti-cocaine control scFv (control).

[0342] ***

[0343] The scope of the present invention is not limited by the specific embodiments described herein. In fact, various modifications of the present invention, in addition to the modifications described, will become apparent to those skilled in the art from the foregoing description and the accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

[0344] All references (e.g., publications or patents or patent applications) cited herein are incorporated by reference in their entirety and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

Claims

1. A chimeric molecule comprising a degron and a binding portion, wherein the degron comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21.

2. The chimeric molecule of claim 1, wherein the amino acid sequence of the degradon consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21.

3. The chimeric molecule of claim 1, wherein the length of the degron does not exceed 215 amino acids.

4. The chimeric molecule of claim 1, wherein the degron is no longer than 50 amino acids.

5. The chimeric molecule of any one of claims 1 to 4, wherein the binding moiety is a small molecule, a nucleic acid, a lipid or a polypeptide.

6. The chimeric molecule of any one of claims 1 to 5, wherein the binding moiety is a polypeptide.

7. The chimeric molecule of claim 6, wherein the polypeptide is at least 20 amino acids in length.

8. The chimeric molecule of claim 6, wherein the polypeptide is at least 50 amino acids in length.

9. The chimeric molecule of any one of the preceding claims, wherein the chimeric molecule comprises more than one degron.

10. The chimeric molecule of any preceding claim, wherein the binding moiety is an antibody, a binding entity, a scaffold protein or an antibody mimetic.

11. The chimeric molecule of any one of the preceding claims, wherein the binding moiety is an antibody.

12. The chimeric molecule of claim 11, wherein the antibody is a scFv, a heavy chain only antibody, a variable domain of a novel antigen receptor (VNAR), an antibody fragment, an antigen binding (Fab) fragment, a monoclonal antibody, a DARPin, a VHH antibody, or a nanobody.

13. The chimeric molecule of any one of claims 6 to 12, wherein the degron is linked to the N-terminus and the C-terminus of the polypeptide.

14. The chimeric molecule of any one of claims 6 to 12, wherein the degron is linked to the N-terminus of the polypeptide.

15. The chimeric molecule of any one of claims 6 to 12, wherein the degron is linked to the C-terminus of the polypeptide.

16. The chimeric molecule of any one of the preceding claims, wherein the binding moiety is linked to the degradon via a linker.

17. The chimeric molecule of any of the preceding claims, wherein the degron is linked to the variable heavy chain region (VH) and / or the variable light chain region (VL) of the antibody.

18. The chimeric molecule of any of the preceding claims, wherein the degron is linked to CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 or CDRL3 of the antibody.

19. The chimeric molecule of any one of claims 16 to 18, wherein the linker is a peptide linker, a disulfide linker or a chemical linker.

20. The chimeric molecule of claim 19, wherein the linker is a peptide linker.

21. The chimeric molecule of claim 1, wherein the chimeric molecule comprises, from N-terminus to C-terminus: a) Degradants; b) a peptide linker; and c) Antibodies.

22. The chimeric molecule of claim 1, wherein the chimeric molecule comprises, from N-terminus to C-terminus: a) Antibodies; b) a peptide linker; and c) Degraders.

23. The chimeric molecule of claim 1, wherein the chimeric molecule comprises, from N-terminus to C-terminus: a) a degron comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 8; b) a peptide linker; and c) Antibodies.

24. The chimeric molecule of claim 1, wherein the chimeric molecule comprises, from N-terminus to C-terminus: a) Antibodies; b) a peptide linker; and c) a degron comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 8.

25. The chimeric molecule of any one of claims 20 to 24, wherein the peptide linker is 1 to 25 amino acids in length.

26. The chimeric molecule of any one of claims 20 to 25, wherein the peptide linker comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 33.

27. The chimeric molecule of any one of claims 20 to 26, wherein the peptide linker comprises the amino acid sequence of SEQ ID NO:

22.

28. The chimeric molecule of any one of claims 20 to 26, wherein the peptide linker comprises the amino acid sequence of SEQ ID NO:

23.

29. The chimeric molecule of any one of claims 10 to 22 or 25 to 28, wherein the antibody is a scFv that specifically binds to human TDP-43.

30. The chimeric molecule of claim 29, wherein the scFv specifically binds to human TDP-43 at an epitope comprising amino acids 65 to 71, 104 to 176, 115 to 118, 247, 201 to 211, 121 to 127, 213 to 223, 381 to 391, 133 to 139, 9 to 15, 409 to 410, 317 to 343, 215 to 222, 140 to 200, 181 to 195, 199 to 213, 307 to 321, 352 to 366, 389 to 411, or 397 to 411 of SEQ ID NO:

290.

31. The chimeric molecule of claim 29 or 30, wherein the degron comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 19.

32. The chimeric molecule of any one of claims 29 to 31, wherein the scFv comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain and the light chain variable domain respectively comprise the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NO: 34, 35, 36, 37, 38 and 39; 40, 41, 42, 43, 44 and 45; 46, 47, 48, 49, 50 and 51; 52, 53, 54, 55, 56 and 57; 58, 59, 60, 61, 62 and 63; 64, 65, 66, 67, 68 and 69; 70, 71, 72, 73, 74 and 75; 76, 77, 78, 79, 80 and 81; 82, 83 , 84, 85, 86 and 87; 88, 89, 90, 91, 92 and 93; 94, 95, 96, 97, 98 and 99; 100, 101, 102, 103, 104 and 105; 106 , 107, 108, 109, 110 and 111; 112, 113, 114, 115, 116 and 117; 118, 119, 120, 121, 122 and 123; 124, 125, 126, 127, 128 and 129; 130, 131, 132, 133, 134 and 135; 136, 137, 138, 139, 140 and 141; 142, 143, 144, 145, 146 and 147; 148, 149, 150, 151, 152 and 153; 154, 155, 156, 157, 158 and 159; 160, 161, 162, 163, 164 and 165; 166, 167, 168, 169, 170 and 171; 172, 173, 174, 175, 176 and 177; 178, 179, 180, 181, 182 and 183; 184, 185, 186, 187, 188 and 189; 190, 191, 192, 193, 194 and 195; or 196, 197, 198, 199, 200 and 201.

33. The chimeric molecule of claim 32, wherein the heavy chain variable domain and the light chain variable domain each comprise the amino acid sequence of: SEQ ID NO:202 and 230; 203 and 231; 204 and 232; 205 and 233; 206 and 234; 207 and 235; 208 and 236; 209 and 237; 210 and 238; 211 and 239; 212 and 240; 213 and 241; 214 and 242; 215 and 243; 216 and 244; 217 and 245; 218 and 246; 219 and 247; 220 and 248; 221 and 249; 222 and 250; 223 and 251; 224 and 252; 225 and 253; 226 and 254; 227 and 255; 228 and 256; or 229 and 257.

34. The chimeric molecule of any one of claims 10 to 22 or 25 to 28, wherein the polypeptide is a scFv or nanobody that specifically binds to human huntingtin protein.

35. The chimeric molecule of claim 34, wherein the scFv or Nanobody specifically binds to human Huntington protein at an epitope comprising the following amino acids of SEQ ID NO: 291: amino acids 1 to 17, 18 to 38, 39 to 49, 50 to 64, 62 to 65, 67 to 76, 73 to 87, 80 to 89, 575 to 584, 585 to 516.

36. The chimeric molecule of claim 34 or 35, wherein the scFv comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain and the light chain variable domain comprise the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NOs: 292, 293, 294, 295, 296 and 297; 301, 302, 303, 304, 305 and 306; 307, 308, 309, 310, 311 and 312; 313, 314, 315, 316, 317 and 318; 319, 320, 321, 322, 323 and 324; 325, 326, 327, 328, 329 and 330; 331, 332, 333, 334, 335 and 336 ; 343, 344, 345, 346, 347 and 348; 352, 353, 354, 355, 356 and 357; 358, 359, 360, 361, 362 and 363; 364, 365, 366, 367, 368 and 369; 370, 371, 372, 373, 374 and 375; 376, 377, 378, 379, 380 and 381; or 382, ​​383, 384, 385, 386 and 387.

37. The chimeric molecule of claim 36, wherein the heavy chain variable domain and the light chain variable domain comprise the amino acid sequence of SEQ ID NO: 388 and 404; 389 and 406; 390 and 407; 391 and 408; 392 and 409; 393 and 410; 394 and 411; 397 and 412; 398 and 414; or 399 and 415.

38. The chimeric molecule of claim 34 or 35, wherein the Nanobody comprises: a) a heavy chain variable domain comprising the CDRH1, CDRH2 and CDRH3 amino acid sequences of SEQ ID NOs: 337, 338 and 339; or 340, 341 and 342; or b) a light chain variable domain comprising the CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NOs: 298, 299 and 300; or 349, 350 and 351.

39. The chimeric molecule of claim 38, wherein: a) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 395 or 396; or b) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 405 or 413.

40. The chimeric molecule of any one of claims 34 to 39, wherein the degron comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 17 and 20.

41. The chimeric molecule of any one of claims 10 to 22 or 25 to 28, wherein the polypeptide is a scFv that specifically binds to human polyglutamine (polyQ) protein.

42. The chimeric molecule of any one of claims 10 to 22 or 25 to 28, wherein the polypeptide is a scFv that specifically binds to human alpha-synuclein.

43. The chimeric molecule of any one of claims 10 to 22 or 25 to 28, wherein the polypeptide is a scFv that specifically binds to human tau protein.

44. The chimeric molecule of any one of claims 10 to 22 or 25 to 28, wherein the polypeptide is a scFv that specifically binds to human amyloid beta.

45. The chimeric molecule of any one of claims 10 to 22 or 25 to 28, wherein the polypeptide is a scFv that specifically binds to human lamin.

46. ​​The chimeric molecule of any one of claims 10 to 22 or 25 to 28, wherein the polypeptide is a scFv that specifically binds to human phospholamban (PLN) protein.

47. A pharmaceutical composition comprising: a chimeric molecule according to any one of the preceding claims; and a pharmaceutically acceptable carrier.

48. A polynucleotide encoding the chimeric molecule according to any one of claims 6 to 46.

49. The polynucleotide of claim 48, wherein the polynucleotide is mRNA.

50. The polynucleotide of claim 48, wherein the polynucleotide is a viral genome.

51. The polynucleotide of claim 48 or 50, wherein the polynucleotide is an AAV genome.

52. An expression vector comprising the polynucleotide according to any one of claims 48 to 51.

53. A host cell comprising a polynucleotide according to any one of claims 48 to 51.

54. A method of producing a chimeric molecule, the method comprising culturing the host cell of claim 53 under conditions such that the polynucleotide is expressed and the chimeric molecule is produced.

55. A recombinant adeno-associated virus (rAAV) comprising a capsid and a viral genome, wherein the viral genome comprises at least one inverted terminal repeat (ITR) region and a polynucleotide encoding a chimeric molecule according to any one of claims 6 to 46.

56. The rAAV of claim 55, wherein the capsid comprises a clade A, clade B, clade C, clade D, clade E, clade F, clade G, clade H, clade I, AAVgo.1, AAV3, AAV4, AAV10, AAV11, AAV12, rh.32, rh32.33, rh.33, rh.34, BAAV, AAV5.2 or AAV5 capsid protein, or an engineered variant thereof.

57. The rAAV of claim 55 or 56, wherein the capsid protein comprises the amino acid sequence of any one of SEQ ID NOs: 258 to 289.

58. A pharmaceutical composition comprising: the rAAV according to any one of claims 55 to 57; and a pharmaceutically acceptable carrier.

59. A method for reducing the level of human TDP-43 or human huntingtin protein in a cell, the method comprising introducing into the cell the chimeric molecule of any one of claims 1 to 46, the pharmaceutical composition of claims 47 or 58, the polynucleotide of any one of claims 48 to 51, the expression vector of claim 52, or the rAAV of any one of claims 55 to 57.

60. A method for reducing the level of aggregates of a protein in a cell, the method comprising introducing into the cell a chimeric molecule according to any one of claims 1 to 46, a pharmaceutical composition according to claim 47 or 58, a polynucleotide according to any one of claims 48 to 51, an expression vector according to claim 52, or an rAAV according to any one of claims 55 to 57.

61. A method for reducing the level of human TDP-43 or human huntingtin protein in a cell, the method comprising expressing in the cell the chimeric molecule of any one of claims 1 to 46, the polynucleotide of any one of claims 48 to 51, the expression vector of claim 52, or the rAAV of any one of claims 55 to 57.

62. A method for reducing the level of aggregates of a protein in a cell, the method comprising expressing in the cell a chimeric molecule of any one of claims 1 to 46, a polynucleotide of any one of claims 48 to 51, an expression vector of claim 52, or an rAAV of any one of claims 55 to 57.

63. The method of any one of claims 59 to 62, wherein the cell is a myocyte, a microglia, an astrocyte, a neuron, or a cardiomyocyte.

64. The method of claim 60 or 62, wherein the protein is human TDP-43, human huntingtin polyglutamine (PolyQ) protein, alpha-synuclein, tau protein, beta amyloid protein, lamin, phospholamban (PLN) protein.

65. A method of treating a neurodegenerative or neuromuscular disease or condition, the method comprising administering to a subject in need thereof an effective amount of a chimeric molecule according to any one of claims 1 to 46, a pharmaceutical composition according to claim 47 or 58, a polynucleotide according to any one of claims 48 to 51, an expression vector according to claim 52, or an rAAV according to any one of claims 55 to 57.

66. A method of treating a neurodegenerative or neuromuscular disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a polynucleotide according to any one of claims 48 to 51 or an expression vector according to claim 52 in a delivery vehicle.

67. The method of claim 66, wherein the delivery vehicle is a lipid nanoparticle (LNP), a vesicle, an exosome, a liposome, or a polymer.

68. The method of any one of claims 65 to 67, wherein the neurodegenerative disease or disorder is selected from the group consisting of motor neuron disease (MND), amyotrophic lateral sclerosis (ALS), Parkinson's syndrome, Alzheimer's dementia, progressive supranuclear palsy (PSP), Huntington's disease, multiple system atrophy (MSA), spinocerebellar ataxia (SCAl, 2, 3, 6, 7, 17), spinal bulbar muscular atrophy (SBMA), dentatorubral pallidum-Lewy body atrophy (DRPLA), and Friedreich's ataxia.

69. The method of any one of claims 65 to 67, wherein the neuromuscular disease or disorder is selected from the group consisting of: myopathy, hereditary cardiomyopathy, metabolic myopathy, distal myopathy, muscular dystrophy, congenital myopathy, spinal muscular atrophy (SMA), motor neuron disease, congenital myopathy, congenital muscular dystrophy, motor neuron disease, Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophy, myotonic dystrophy, myotubular myopathy, centronuclear myopathy, nemaline myopathy, selenoprotein N-related myopathy, Pompe disease, glycogen storage disease type III, spinal muscular atrophy, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, multiple sclerosis, myositis, polymyositis, and dermatomyositis.

70. The method of any one of claims 65 to 69, wherein the rAAV is administered to the subject intravenously, intraperitoneally, subcutaneously, intramuscularly, intrathecally, intranasally, intracisternal, intracranially, or intradermally.

71. A degradon comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 5.

72. A chimeric molecule comprising a degron, wherein the degron comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 5.

73. The chimeric molecule of claim 72, wherein the amino acid sequence of the degradon consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 5.

74. A polynucleotide encoding the degron according to claim 71 or the chimeric molecule according to claim 72 or 73.

75. The polynucleotide of claim 74, wherein the polynucleotide is mRNA.

76. The polynucleotide of claim 74, wherein the polynucleotide is a viral genome.

77. The polynucleotide of claim 74 or 76, wherein the polynucleotide is an AAV genome.

78. An expression vector comprising the polynucleotide according to any one of claims 74 to 77.

79. A host cell comprising a polynucleotide according to any one of claims 74 to 77.

80. A method for producing a degron or chimeric molecule, the method comprising culturing the host cell according to claim 79 under conditions such that the polynucleotide is expressed and the degron or chimeric molecule is produced.

81. A recombinant adeno-associated virus (rAAV) comprising a capsid and a viral genome, wherein the viral genome comprises at least one inverted terminal repeat (ITR) region and a polynucleotide encoding the degradation protein according to claim 71 or the chimeric molecule according to claim 72 or 73.

82. The rAAV of claim 81, wherein the capsid comprises a clade A, clade B, clade C, clade D, clade E, clade F, clade G, clade H, clade I, AAVgo.1, AAV3, AAV4, AAV10, AAV11, AAV12, rh.32, rh32.33, rh.33, rh.34, BAAV, AAV5.2 or AAV5 capsid protein, or an engineered variant thereof.

83. The rAAV of claim 81 or 82, wherein the capsid protein comprises the amino acid sequence of SEQ ID NOs: 258 to 289.

84. A pharmaceutical composition comprising the degradon according to claim 71, the chimeric molecule according to claim 72 or 73, or the rAAV according to any one of claims 81 to 83, and a pharmaceutically acceptable carrier.

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