Trka RNA interference agents and uses thereof

Abstract

Provided are TrkA RNAi agents for reducing expression of TrkA, which comprise a sense strand and an antisense strand forming a double stranded RNA (dsRNA), compositions comprising these RNAi agents and methods of their use.

Description

TRKA RNA INTERFERENCE AGENTS AND USES THEREOFSEQUENCE LISTING

[0001] The present application is being filed along with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided as a file titled 31072A_US_PRI.xml created October 14, 2025, and is 5,151,350 bytes in size. The Sequence Listing information in the ST.26 XML format is incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0002] The present invention is in the field of medicine and particularly in the treatment of pain.BACKGROUND OF THE INVENTION

[0003] TrkA, also known as tropomyosin receptor kinase A is a high-affinity receptor for nerve growth factor (NGF) that is encoded by the neurotrophic tyrosine kinase receptor 1 (NTRK1) gene. NGF binds to and activates the TrkA protein as part of the pain pathway in the body. This binding potentiates pain signaling through multiple mechanisms. (See WO 2016 / 087677). Accordingly, targeting NGF can potentially be useful in treating pain, and inflammation-related pain can be significantly reduced by neutralizing NGF bioactivity in animal models. (See, for example, WO 2016 / 087677; and U.S. Patent No. 7,449,616). U.S. Patent Application Publication No. 2013 / 0336961, U.S. Patent No. 7,601,818, WO 2000 / 73344 and WO 2016 / 087677 recite various antibodies that are designed to bind to TrkA. The protein sequence for human TrkA is provided in U.S. Patent Application Publication No. 2013 / 0336961.

[0004] Persistent and / or chronic pain represents a major health problem and causes significant losses in quality of life. Persistent and / or chronic pain may present with different levels of severity, and is associated with a variety of pathologies, such as back injury or degenerative disk disease, migraine headaches, arthritis, diabetic neuropathy, cancer, and other diseases. Mild pain is presently treated with acetaminophen, aspirin, and other medications. Moderate pain may be controlled using corticosteroidal drugs such as cortisol and prednisone. Problems with the effectiveness and / or tolerability of existing treatments are well known, and corticosteroids for example display remarkable adverse effects including weight gain, insomnia, and immune system weakening. Moderate or severe pain may be treated with opioids such asmorphine and fentanyl, but long-term use of opiates is limited by several serious drawbacks, including development of addiction, tolerance and physical dependence. Potential overuse of opioids has been characterized as an “opioid epidemic” in view of the growing number of people that use and may be addicted to opioids.

[0005] RNA interference (RNAi) is a highly conserved regulatory mechanism in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA molecules (dsRNA) (Fire et al., Nature 391:806-811, 1998).

[0006] As current pain therapies are often poorly effective and / or have serious undesirable side effects, an urgent need exists to develop drugs which are directed to new molecular targets and may provide a combination of improved pharmacological properties, including safety, potency, efficacy, and tolerability, in particular for the treatment of chronic pain. To date, no agents targeting TrkA signaling have been approved for the treatment of pain, e.g., by utilizing RNAi. Thus, there remains a need for agents that can inhibit TrkA signaling, such as siRNA targeting TrkA transcript for degradation. There is also a need for such an agent that provides a therapeutic benefit.SUMMARY OF THE INVENTION

[0007] In certain aspects, the present invention provides an RNAi agent for reducing tropomysin receptor kinase A (TrkA / NTRKl) mRNA and / or protein levels, the RNAi agent comprising a sense strand and an antisense strand forming a double stranded RNA (dsRNA), wherein the dsRNA is directed to TrkA (NTRK1) mRNA. In some embodiments, the RNAi agent further comprises a delivery moiety D conjugated to the dsRNA, which delivery moiety D delivers the dsRNA to a DRG neuron. Also provided are compositions comprising such TrkA RNAi agents, and methods of their use for the treatment of a disease or disorder which benefits from reduction of TrkA mRNA or TrkA protein levels. In some embodiments, the disease or disorder is pain, which may be acute or chronic pain of nociceptive, inflammatory, neuropathic, nociplastic, or mixed etiologies.

[0008] In some embodiments, the compositions comprising TrkA RNAi agents and methods using these compositions are used to treat pain. In some embodiments, pain is acute or chronic pain that is musculoskeletal or neuropathic in origin. Specific, non-limiting examples of pain include, for example, post-surgical pain, rheumatoid arthritis pain, osteoarthritis pain, neuropathic pain, diabetic neuropathic pain (DNP), and chronic lower back pain (CLBP), including non-radicular (non-neuropathic) and radicular lower back pain (which are sometimesreferred to as lumbosacral radiculopathy (LSR) or sciatica) as well as visceral pain (such as, for example, chronic prostatitis, interstitial cystiris (bladder pain) or chronic pelvic pain).

[0009] In some embodiments of the TrkA RNAi agent, one or more nucleotides of the sense strand and one or more nucleotides of the antisense strand are independently modified nucleotides, and wherein optionally one or more intemucleotide linkages of the sense strand and one or more internucleotide linkages of the antisense strand are modified internucleotide linkages. In some embodiments of the TrkA RNAi agent, the antisense strand further comprises a U nucleotide at its 5’ end. In some embodiments of the TrkA RNAi agent, the antisense strand further comprises one, two, three or four additional nucleotides at its 3’ end. In some embodiments of the TrkA RNAi agent, the antisense strand further comprises one, two, three or four additional nucleotides at its 3’ end, wherein the one, two, three and / or four additional nucleotides are complementary to the target mRNA sequence. In some embodiments of the TrkA RNAi agent, each sense strand is 14, 15, 16, 17, 18, 19, 20 or 21 nucleotides long and each antisense strand is 18, 19, 20, 21, 22, or 23 nucleotides long.

[0010] In one aspect, the invention provides a TrkA RNAi agent comprising a sense strand and an antisense strand forming a double stranded RNA (dsRNA), wherein:(a) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 2, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 15,(b) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 3, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 16,(c) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 17,(d) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 5, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 18,(e) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 6, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 19,(f) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 7, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 20,(g) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(h) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 22,(i) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 10, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 23,(j) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 11, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 24,(k) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 12, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 25,(l) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 13, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 26,(m) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 14, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 27,(n) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 109,(o) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 105, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(p) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 105, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 109,(q) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 105, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 110,(r) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(s) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 109,(t) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 110,(u) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(v) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 109,(w) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 110,(x) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 111,(y) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(z) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 110,(aa) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 111,(bb) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 126, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 184,(cc) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 127, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 185,(dd) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 128, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 186,(ee) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 129, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 187,(ff) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 130, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 188,(gg) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 131, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 189,(hh) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 132, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 190,(ii) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 133, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 191,(jj) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 134, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 192,(kk) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 135, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 193,(11) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 136, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 194,(mm) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 137, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 195,(nn) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 138, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 196,(oo) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 139, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 197,(pp) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 140, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 198,(qq) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 141, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 199,(rr) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 142, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 200,(ss) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 143, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 201,(tt) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 144, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 202,(uu) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 145, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 203,(vv) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 146, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 204,(ww) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 147, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 205,(xx) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 148, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 206,(yy) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 149, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 207,(zz) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 150, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 208,(aaa) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 151, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 209,(bbb) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 152, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 210,(ccc) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 153, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 211,(ddd) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 154, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 212,(eee) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 155, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 213,(fff) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 156, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 214,(ggg) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 157, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 215,(hhh) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 158, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 216,(iii) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 159, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 217,(jjj) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 160, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 218,(kkk) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 161, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 219,(111) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 162, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 220,(mmm) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 163, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 221,(nnn) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 164, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 222,(ooo) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 165, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 223,(ppp) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 166, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 224,(qqq) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 167, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 225,(rrr) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 168, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 226,(sss) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 169, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 227,(ttt) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 170, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 228,(uuu) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 171, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 229,(vvv) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 172, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 230,(www) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 173, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 231,(xxx) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 174, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 232,(yyy) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 175, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 233,(zzz) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 176, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 234,(aaaa) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 177, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 235,(bbbb) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 236,(cccc) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 237,(dddd) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 238,(eeee) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 239,(ffff) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 178, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 22,(gggg) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 179, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 22,(hhhh) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 180, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 22,(iiii) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 181, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 22,(jjjj) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 240,(kkkk) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 241,(1111) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 242,(mmmm) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 243,(nnnn) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 244,(oooo) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 245,(PPPP) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 246,(qqqq) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 247,(rrrr) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 182, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(ssss) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 248,(tttt) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 183, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 17,(uuuu) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 7, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 249,(vvvv) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 250, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 260,(wwww) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 260,(xxxx) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 261,(yyyy) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 251, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 261,(zzzz) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 7, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 249,(aaaaa)the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 111,(bbbbb) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 109,(ccccc) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 263,(ddddd) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 252, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 263,(eeeee)the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 252, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(fffff) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 264,(ggggg) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 265,(hhhhh) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 253, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 265,(iiiii) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 254, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 264,(jjjjj) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 255, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 266,(kkkkk) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 256, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 266,(11111) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 256, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 267,(mmmmm) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 257, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 267,(nnnnn) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 257, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 268,(ooooo) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 258, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 20,(ppppp) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 258, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 268,(qqqqq) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 258, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 269,(rrrrr) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 259, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 267,(sssss) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 259, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 268,(ttttt) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 259, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 269,(uuuuu) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 262,(vvvvv) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 597, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 610,(wwwww) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 598, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 611,(xxxxx) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 599, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 612,(yyyyy) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 600, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 613,(zzzzz)the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 601, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 614,(aaaaaa) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 602, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 615,(bbbbbb) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 603, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 616,(cccccc) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 604, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 617,(dddddd) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 605, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 618,(eeeeee) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 606, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 619,(ffffff) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 607, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 620,(gggggg) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 608, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 621, or(hhhhhh) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 609, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 622.

[0011] In some embodiments, provided herein are TrkA RNAi agents having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand and the antisense strand comprise a pair of nucleic acid sequences selected from:(a) the sense strand comprises SEQ ID NO: 2, and the antisense strand comprises SEQ ID NO: 15,(b) the sense strand comprises SEQ ID NO: 3, and the antisense strand comprises SEQ ID NO: 16,(c) the sense strand comprises SEQ ID NO: 4, and the antisense strand comprises SEQ ID NO: 17,(d) the sense strand comprises SEQ ID NO: 5, and the antisense strand comprises SEQ ID NO: 18,(e) the sense strand comprises SEQ ID NO: 6, and the antisense strand comprises SEQ ID NO: 19,(f) the sense strand comprises SEQ ID NO: 7, and the antisense strand comprises SEQ ID NO: 20,(g) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 21,(h) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 22,(i) the sense strand comprises SEQ ID NO: 10, and the antisense strand comprises SEQ ID NO: 23,(j) the sense strand comprises SEQ ID NO: 11, and the antisense strand comprises SEQ ID NO: 24,(k) the sense strand comprises SEQ ID NO: 12, and the antisense strand comprises SEQ ID NO: 25,(l) the sense strand comprises SEQ ID NO: 13, and the antisense strand comprises SEQ ID NO: 26,(m)the sense strand comprises SEQ ID NO: 14, and the antisense strand comprises SEQID NO: 27,(n) the sense strand comprises SEQ ID NO: 8 and the antisense strand comprises SEQ ID NO: 109;(o) the sense strand comprises SEQ ID NO: 105 and the antisense strand comprises SEQ ID NO: 21;(p) the sense strand comprises SEQ ID NO: 105 and the antisense strand comprises SEQ ID NO: 109;(q) the sense strand comprises SEQ ID NO: 105 and the antisense strand comprises SEQ ID NO: 110;(r) the sense strand comprises SEQ ID NO: 106 and the antisense strand comprises SEQ ID NO: 21;(s) the sense strand comprises SEQ ID NO: 106 and the antisense strand comprises SEQ ID NO: 109;(t) the sense strand comprises SEQ ID NO: 106 and the antisense strand comprises SEQ ID NO: 110;(u) the sense strand comprises SEQ ID NO: 107 and the antisense strand comprises SEQ ID NO: 21;(v) the sense strand comprises SEQ ID NO: 107 and the antisense strand comprises SEQ ID NO: 109;(w)the sense strand comprises SEQ ID NO: 107 and the antisense strand comprises SEQ ID NO: 110;(x) the sense strand comprises SEQ ID NO: 107 and the antisense strand comprises SEQ ID NO: 111 ;(y) the sense strand comprises SEQ ID NO: 108 and the antisense strand comprises SEQ ID NO: 21;(z) the sense strand comprises SEQ ID NO: 108 and the antisense strand comprises SEQ ID NO: 110; or(aa) the sense strand comprises SEQ ID NO: 108 and the antisense strand comprises SEQ ID NO: 111(bb) the sense strand comprises SEQ ID NO: 126, and the antisense strand comprises SEQ ID NO: 184,(cc) the sense strand comprises SEQ ID NO: 127, and the antisense strand comprises SEQ ID NO: 185,(dd) the sense strand comprises SEQ ID NO: 128, and the antisense strand comprises SEQ ID NO: 186,(ee) the sense strand comprises SEQ ID NO: 129, and the antisense strand comprises SEQ ID NO: 187,(ff) the sense strand comprises SEQ ID NO: 130, and the antisense strand comprises SEQ ID NO: 188,(gg) the sense strand comprises SEQ ID NO: 131, and the antisense strand comprises SEQ ID NO: 189,(hh) the sense strand comprises SEQ ID NO: 132, and the antisense strand comprises SEQ ID NO: 190,(ii) the sense strand comprises SEQ ID NO: 133, and the antisense strand comprises SEQ ID NO: 191,(jj) the sense strand comprises SEQ ID NO: 134, and the antisense strand comprises SEQ ID NO: 192,(kk) the sense strand comprises SEQ ID NO: 135, and the antisense strand comprises SEQ ID NO: 193,(11) the sense strand comprises SEQ ID NO: 136, and the antisense strand comprises SEQ ID NO: 194,(mm) the sense strand comprises SEQ ID NO: 137, and the antisense strand comprises SEQ ID NO: 195,(nn) the sense strand comprises SEQ ID NO: 138, and the antisense strand comprises SEQ ID NO: 196,(oo) the sense strand comprises SEQ ID NO: 139, and the antisense strand comprises SEQ ID NO: 197,(pp) the sense strand comprises SEQ ID NO: 140, and the antisense strand comprises SEQ ID NO: 198,(qq) the sense strand comprises SEQ ID NO: 141, and the antisense strand comprises SEQ ID NO: 199,(rr) the sense strand comprises SEQ ID NO: 142, and the antisense strand comprises SEQ ID NO: 200,(ss)the sense strand comprises SEQ ID NO: 143, and the antisense strand comprises SEQ ID NO: 201,(tt) the sense strand comprises SEQ ID NO: 144, and the antisense strand comprisesSEQ ID NO: 202,(uu) the sense strand comprises SEQ ID NO: 145, and the antisense strand comprises SEQ ID NO: 203,(vv) the sense strand comprises SEQ ID NO: 146, and the antisense strand comprises SEQ ID NO: 204,(ww) the sense strand comprises SEQ ID NO: 147, and the antisense strand comprises SEQ ID NO: 205,(xx) the sense strand comprises SEQ ID NO: 148, and the antisense strand comprises SEQ ID NO: 206,(yy) the sense strand comprises SEQ ID NO: 149, and the antisense strand comprises SEQ ID NO: 207,(zz) the sense strand comprises SEQ ID NO: 150, and the antisense strand comprises SEQ ID NO: 208,(aaa) the sense strand comprises SEQ ID NO: 151, and the antisense strand comprises SEQ ID NO: 209,(bbb) the sense strand comprises SEQ ID NO: 152, and the antisense strand comprises SEQ ID NO: 210,(ccc) the sense strand comprises SEQ ID NO: 153, and the antisense strand comprises SEQ ID NO: 211,(ddd) the sense strand comprises SEQ ID NO: 154, and the antisense strand comprises SEQ ID NO: 212,(eee) the sense strand comprises SEQ ID NO: 155, and the antisense strand comprises SEQ ID NO: 213,(fff) the sense strand comprises SEQ ID NO: 156, and the antisense strand comprises SEQ ID NO: 214,(ggg) the sense strand comprises SEQ ID NO: 157, and the antisense strand comprises SEQ ID NO: 215,(hhh) the sense strand comprises SEQ ID NO: 158, and the antisense strand comprises SEQ ID NO: 216,(iii)the sense strand comprises SEQ ID NO: 159, and the antisense strand comprises SEQ ID NO: 217,(jjj)the sense strand comprises SEQ ID NO: 160, and the antisense strand comprisesSEQ ID NO: 218,(kkk) the sense strand comprises SEQ ID NO: 161, and the antisense strand comprises SEQ ID NO: 219,(lll)the sense strand comprises SEQ ID NO: 162, and the antisense strand comprisesSEQ ID NO: 220,(mmm)the sense strand comprises SEQ ID NO: 163, and the antisense strand comprisesSEQ ID NO: 221,(nnn) the sense strand comprises SEQ ID NO: 164, and the antisense strand comprises SEQ ID NO: 222,(ooo) the sense strand comprises SEQ ID NO: 165, and the antisense strand comprises SEQ ID NO: 223,(ppp) the sense strand comprises SEQ ID NO: 166, and the antisense strand comprises SEQ ID NO: 224,(qqq) the sense strand comprises SEQ ID NO: 167, and the antisense strand comprises SEQ ID NO: 225,(rrr) the sense strand comprises SEQ ID NO: 168, and the antisense strand comprises SEQ ID NO: 226,(sss) the sense strand comprises SEQ ID NO: 169, and the antisense strand comprises SEQ ID NO: 227,(ttt)the sense strand comprises SEQ ID NO: 170, and the antisense strand comprisesSEQ ID NO: 228,(nun) the sense strand comprises SEQ ID NO: 171, and the antisense strand comprises SEQ ID NO: 229,(vvv) the sense strand comprises SEQ ID NO: 172, and the antisense strand comprises SEQ ID NO: 230,(www) the sense strand comprises SEQ ID NO: 173, and the antisense strand comprises SEQ ID NO: 231,(xxx) the sense strand comprises SEQ ID NO: 174, and the antisense strand comprises SEQ ID NO: 232,(yyy) the sense strand comprises SEQ ID NO: 175, and the antisense strand comprises SEQ ID NO: 233,(zzz) the sense strand comprises SEQ ID NO: 176, and the antisense strand comprises SEQ ID NO: 234,(aaaa) the sense strand comprises SEQ ID NO: 177, and the antisense strand comprises SEQ ID NO: 235,(bbbb) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 236,(cccc) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 237,(dddd) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 238,(eeee) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 239,(ffff) the sense strand comprises SEQ ID NO: 178, and the antisense strand comprises SEQ ID NO: 22,(gggg) the sense strand comprises SEQ ID NO: 179, and the antisense strand comprises SEQ ID NO: 22,(hhhh) the sense strand comprises SEQ ID NO: 180, and the antisense strand comprises SEQ ID NO: 22,(iiii) the sense strand comprises SEQ ID NO: 181, and the antisense strand comprises SEQ ID NO: 22,(jjjj) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 240,(kkkk) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 241,(1111) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 242,(mmmm) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 243,(nnnn) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 244,(oooo) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 245,(pppp) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 246,(qqqq) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 247,(rrrr) the sense strand comprises SEQ ID NO: 182, and the antisense strand comprises SEQ ID NO: 21,(ssss) the sense strand comprises SEQ ID NO: 4, and the antisense strand comprises SEQ ID NO: 248.(tttt) the sense strand comprises SEQ ID NO: 183, and the antisense strand comprises SEQ ID NO: 17,(uuuu) the sense strand comprises SEQ ID NO: 7, and the antisense strand comprises SEQ ID NO: 249,(vvvv) the sense strand comprises SEQ ID NO: 250, and the antisense strand comprises SEQ ID NO: 260,(wwww) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 260,(xxxx) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 261,(yyyy) the sense strand comprises SEQ ID NO: 251, and the antisense strand comprises SEQ ID NO: 262,(zzzz) the sense strand comprises SEQ ID NO: 106, and the antisense strand comprises SEQ ID NO: 111,(aaaaa)the sense strand comprises SEQ ID NO: 108, and the antisense strand comprises SEQ ID NO: 109,(bbbbb) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 263,(ccccc)the sense strand comprises SEQ ID NO: 252, and the antisense strand comprises SEQ ID NO: 263,(ddddd) the sense strand comprises SEQ ID NO: 252, and the antisense strand comprises SEQ ID NO: 21,(eeeee)the sense strand comprises SEQ ID NO: 4, and the antisense strand comprises SEQ ID NO: 264,(fffff) the sense strand comprises SEQ ID NO: 4, and the antisense strand comprises SEQ ID NO: 265,(ggggg) the sense strand comprises SEQ ID NO: 253, and the antisense strand comprises SEQ ID NO: 265,(hhhhh) the sense strand comprises SEQ ID NO: 254, and the antisense strand comprises SEQ ID NO: 264,(iiiii) the sense strand comprises SEQ ID NO: 255, and the antisense strand comprises SEQ ID NO: 266,(jjjjj) the sense strand comprises SEQ ID NO: 256, and the antisense strand comprises SEQ ID NO: 266,(kkkkk) the sense strand comprises SEQ ID NO: 256, and the antisense strand comprises SEQ ID NO: 267,(11111) the sense strand comprises SEQ ID NO: 257, and the antisense strand comprises SEQ ID NO: 267,(mmmmm) the sense strand comprises SEQ ID NO: 257, and the antisense strand comprises SEQ ID NO: 268,(nnnnn) the sense strand comprises SEQ ID NO: 258, and the antisense strand comprises SEQ ID NO: 20,(ooooo) the sense strand comprises SEQ ID NO: 258, and the antisense strand comprises SEQ ID NO: 268,(ppppp) the sense strand comprises SEQ ID NO: 258, and the antisense strand comprises SEQ ID NO: 269,(qqqqq) the sense strand comprises SEQ ID NO: 259, and the antisense strand comprises SEQ ID NO: 267,(rrrrr) the sense strand comprises SEQ ID NO: 259, and the antisense strand comprisesSEQ ID NO: 268,(sssss) the sense strand comprises SEQ ID NO: 259, and the antisense strand comprises SEQ ID NO: 269,(ttttt) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 262;(uuuuu) the sense strand comprises SEQ ID NO: 597, and the antisense strand comprises SEQ ID NO: 610;(vvvvv) the sense strand comprises SEQ ID NO: 598, and the antisense strand comprises SEQ ID NO: 611;(wwwww) the sense strand comprises SEQ ID NO: 599, and the antisense strand comprises SEQ ID NO: 612;(xxxxx) the sense strand comprises SEQ ID NO: 600, and the antisense strand comprises SEQ ID NO: 613;(yyyyy) the sense strand comprises SEQ ID NO: 601, and the antisense strand comprises SEQ ID NO: 614;(zzzzz)the sense strand comprises SEQ ID NO: 602, and the antisense strand comprises SEQ ID NO: 615;(aaaaaa) the sense strand comprises SEQ ID NO: 603, and the antisense strand comprises SEQ ID NO: 616;(bbbbbb) the sense strand comprises SEQ ID NO: 604, and the antisense strand comprises SEQ ID NO: 617;(cccccc) the sense strand comprises SEQ ID NO: 605, and the antisense strand comprises SEQ ID NO: 618;(dddddd) the sense strand comprises SEQ ID NO: 606, and the antisense strand comprises SEQ ID NO: 619;(eeeeee) the sense strand comprises SEQ ID NO: 607, and the antisense strand comprises SEQ ID NO: 620;(ffffff) the sense strand comprises SEQ ID NO: 608, and the antisense strand comprisesSEQ ID NO: 621; or(gggggg) the sense strand comprises SEQ ID NO: 609, and the antisense strand comprises SEQ ID NO: 622.

[0012] In some embodiments, the TrkA RNAi agents described herein may include modified nucleotides. In some embodiments of the TrkA RNAi agents, at least one nucleotide of the antisense strand is a modified nucleotide. In some embodiments of the TrkA RNAi agents, each nucleotide of the sense strand is a modified nucleotide. In some embodiments of the TrkA RNAi agents, each nucleotide of the antisense strand is a modified nucleotide. In some embodiments of the TrkA RNAi agents, each nucleotide of the sense strand and each nucleotide of the antisense strand is a modified nucleotide.

[0013] In some embodiments of the TrkA RNAi agents, the modified nucleotide is a 2’ -fluoro modified nucleotide, 2’-O-methyl modified nucleotide, 2’ deoxy nucleotide (DNA), or 2’-O-Ci6 alkyl modified nucleotide. In some embodiments of the TrkA RNAi agents, the sense strand has three 2’-fluoro modified nucleotides at positions 9, 10, and 11 from the 5’ end of the sense strand. In some embodiments of the TrkA RNAi agents, nucleotides at positions other than positions 9, 10, and 11 of the sense strand are 2'-O-methyl modified nucleotides. In some embodiments of the TrkA RNAi agents, the sense strand has four 2’ -fluoro modified nucleotides at positions 7, 9, 10, and 11 from the 5’ end of the sense strand. In some embodiments of the TrkA RNAi agents, nucleotides at positions other than positions 7, 9, 10, and 11 of the sense strand are 2’-O-methyl modified nucleotides. In some embodiments of the TrkA RNAi agents, the antisense strand has three 2’ -fluoro modified nucleotides at positions 2, 14, and 16 from the 5’ end of the antisense strand. In some embodiments of the TrkA RNAi agents, nucleotides at positions other than positions 2, 14, and 16 from the 5’ end of the antisense strand are 2’-O-methyl modified nucleotides. In some embodiments of the TrkA RNAi agents, the antisense strand has three 2’-fluoro modified nucleotides at positions 2, 14, and 16 from the 5’ end of the antisense strand and two deoxyribonucleotides at positions 4 and 7 from the 5’ end of the antisense strand. In some embodiments of the TrkA RNAi agents, nucleotides at positions other than positions 2, 4, 7, 14, and 16 from the 5’ end of the antisense strand are 2’-O-methyl modified nucleotides.

[0014] In some embodiments of the TrkA RNAi agents, the sense strand has four 2’ -fluoro modified nucleotides at positions 7, 9, 10, and 11 from the 5’ end of the sense strand. In some embodiments of the TrkA RNAi agents, the nucleotides at positions other than positions 7, 9, 10, and 11 of the sense strand are 2’-O-methyl modified nucleotides. In some embodiments of the TrkA RNAi agents, the antisense strand has four 2’-fluoro modified nucleotides at positions2, 6, 14, and 16 from the 5’ end of the antisense strand. In some embodiments of the TrkA RNAi agents, nucleotides at positions other than positions 2, 6, 14 and 16 of the antisense strand are 2’-O-methyl modified nucleotides. In some embodiments of the TrkA RNAi agents, the sense strand has three 2’ -fluoro modified nucleotides at positions 9, 10, and 11 from the 5’ end of the sense strand. In some embodiments of the TrkA RNAi agents, nucleotides at positions other than positions 9, 10, and 11 of the sense strand are 2’-O-methyl modified nucleotides. In some embodiments of the TrkA RNAi agents, the antisense strand has five 2’- fluoro modified nucleotides at positions 2, 5, 7, 14, and 16 from the 5’ end of the antisense strand. In some embodiments of the TrkA RNAi agents, nucleotides at positions other than positions 2, 5, 7, 14, and 16 of the antisense strand are 2’-O-methyl modified nucleotides. In some embodiments of the TrkA RNAi agents, the antisense strand has five 2’ -fluoro modified nucleotides at positions 2, 5, 8, 14, and 16 from the 5’ end of the antisense strand. In some embodiments of the TrkA RNAi agents, nucleotides at positions other than positions 2, 5, 8, 14, and 16 of the antisense strand are 2'-O-methyl modified nucleotides. In some embodiments of the TrkA RNAi agents, the antisense strand has five 2’ -fluoro modified nucleotides at positions 2, 3, 7, 14, and 16 from the 5’ end of the antisense strand. In some embodiments of the TrkA RNAi agents, nucleotides at positions other than positions 2, 3, 7, 14, and 16 of the antisense strand are 2’-O-methyl modified nucleotides. In some embodiments of the TrkA RNAi agents, the antisense strand comprises three 2’ -fluoro modified nucleotides at positions 2, 14, and 16 from the 5’ end of the antisense strand. In some embodiments of the TrkA RNAi agents, nucleotides at positions other than positions 2, 14, and 16 of the antisense strand are 2’-O- methyl modified nucleotides.

[0015] In some embodiments of the TrkA RNAi agents, the sense strand and the antisense strand comprise one or more modified internucleotide linkages. In some embodiments of the TrkA RNAi agents, the modified intemucleotide linkage is a phosphorothioate linkage. In some embodiments of the TrkA RNAi agents, the sense strand has four or five phosphorothioate linkages. In some embodiments of the TrkA RNAi agents, the antisense strand has four or five phosphorothioate linkages. In some embodiments of the TrkA RNAi agents, the antisense strand has a phosphate analog at the 5’ end. In some embodiments of the TrkA RNAi agents, the phosphate analog is 5’-vinylphosphonate. In some embodiments of the TrkA RNAi agents, the sense strand or antisense strand comprises an abasic moiety or inverted abasic moiety. In some embodiments of the TrkA RNAi agents, the sense strand comprises an abasic moiety at its 5’ end.

[0016] Exemplary modified sense strand and modified antisense strand sequences of dsRNA targeting human TrkA mRNA are provided in Table 2A and Table 2B.

[0017] In some embodiments, the TrkA RNAi agents further comprise a delivery moiety (D) conjugated to the dsRNA. In some embodiments of the TRKA RNAi agents, the delivery moiety D delivers the TrkA RNAi agent to a DRG neuron.

[0018] On one aspect, the invention provides a TrkA RNAi agent of Formula (I): (R-L)n-D, wherein R is a dsRNA comprising a sense stand and an antisense strand described in any one embodiment; wherein L is a linker, or absent; and wherein D is a delivery moiety and wherein n=l, 2, or 3. In some embodiments of the TrkA RNAi agent of Formula (I), n=l. In some embodiments of the TrkA RNAi agent of Formula (I), D is a DRG delivery moiety.

[0019] In some embodiments of the TrkA RNAi agent of Formula (I), the dsRNA comprises a sense strand and an antisense strand wherein the dsRNA comprises a sense strand and an antisense strand targeting human TrkA mRNA as provided in Table 2A and Table 2B.

[0020] In some embodiments of the TrkA RNAi agent, the D is conjugated to the sense strand. In some embodiments of the TrkA RNAi agent, the D is conjugated to the 3’ end or the 5’ end of the sense strand. In some embodiments of the TrkA RNAi agent, the D is conjugated to the 3’ end of the sense strand.

[0021] In some embodiments of the TrkA RNAi agent, the D comprises or consists essentially of a bivalent antibody, a heterodimeric antibody, a monovalent antibody, an antibody fragment, or a VHH molecule each one binding to a target present on a DRG neuron. In some embodiments of the TrkA RNAi agent, wherein the D further comprises a half-life extender. In some embodiments of the TrkA RNAi agent, the half-life extender modification is an antibody or an antibody fragment binding Human Serum Albumin (AEB) binding, or an AEB binding VHH. In some embodiments of the TrkA RNAi agent, the ALB binding protein is an ALB binding VHH or an ALB binding Fab. In some embodiments of the TrkA RNAi agent, the halflife extender is an immunoglobulin Fc region, optionally the immunoglobulin Fc region is a modified human IgG4 Fc region.

[0022] In some embodiments of the TrkA RNAi agent, the D is a protein comprising a human TfR binding protein or LI CAM binding protein. In some embodiments of the TrkA RNAi agent, the human TfR binding protein is a human TfR binding protein VHH. In some embodiments of the TrkA RNAi agent, the human TfR binding protein is a monovalent human TfR binding protein. In some embodiments of the TrkA RNAi agent, the human TfR binding protein is a bivalent human TfR binding protein.

[0023] In some embodiments of the TrkA RNAi agent, the bivalent antibody, the heterodimeric antibody, the monovalent antibody or the VHH further comprises a heavy chain constant region comprising cysteine for conjugation to the dsRNA. In some embodiments of the TrkA RNAi agent, the cysteine is residue 124 according to the EU Index numbering.

[0024] In some embodiments of the TrkA RNAi agent, wherein the antibody or the antibody fragment binding Human Serum Albumin (ALB) binding, or the ALB binding VHH further comprises a heavy chain constant region comprising cysteine for conjugation to the dsRNA, e.g. a cysteine at residue 124 (according to the EU Index numbering).

[0025] In some embodiments of the TrkA RNAi agent, the human TfR binding protein further comprises a heavy chain constant region comprising cysteine for conjugation to the dsRNA, e.g. a cysteine at residue 124 (according to the EU Index numbering). In some embodiments, the sequences of the human TfR binding domains and proteins are provided in Table 4.

[0026] In some embodiments of the TrkA RNAi agent, L is a SMCC linker, an OD linker, or a MSPT linker. In some embodiments of the TrkA RNAi agent, L is a MSPT linker.

[0027] In another aspect, the invention provides a pharmaceutical composition comprising the TrkA RNAi agent of any one of the embodiments described herein and a pharmaceutically acceptable carrier.

[0028] In another aspect, the invention provides a method of treating pain in a subject in need thereof, the method comprising administering to the subject an effective amount of a TrkA RNAi agent of any one of the embodiments described herein, or a pharmaceutical composition comprising these TrkA RNAi agents.

[0029] In one aspect, the invention provides a method of treating a TrkA-mediated disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a TrkA RNAi agent of any one of the embodiments described herein, or a pharmaceutical composition comprising these TrkA RNAi agents. In some embodiments, the TrkA-mediated disease or disorder is pain.

[0030] In certain aspects, pain includes without limitation post-surgical pain, rheumatoid arthritis pain, neuropathic pain, osteoarthritis pain, or a combination thereof. In some embodiments, osteoarthritis pain includes non-radicular (non-neuropathic) pain. In some embodiments, neuropathic pain includes radicular pain CLBP, DNP, and LSR (which is also referred to as sciatica). In some embodiments, the pain is chronic pain, such as for example, chronic pain of both mucsculoskeletal and / or as neuropathic origin.

[0031] In some embodiments, the invention provides methods of treating pain comprising administering to a subject in need thereof a pharmaceutical composition of the present invention. In some embodiments, pain includes without limitation post-surgical pain, rheumatoid arthritis pain, neuropathic pain, osteoarthritis pain. In some embodiments, osteoarthritis pain includes non-radicular (non-neuropathic) pain. In some embodiments, neuropathic pain includes radicular pain CLBP, DNP, and LSR (which is also referred to as sciatica). In some embodiments, the pain is chronic pain. In some embodiments, the pain is chronic pain, such as for example, chronic pain of both mucsculoskeletal and / or neuropathic origin. In some embodiments, the pain is chronic pain, such as for example, chronic pain of both mucsculoskeletal and / or neuropathic origin.

[0032] In some embodiments of the methods, the TrkA RNAi agent or a pharmaceutical composition comprising the same is administered to a subject in need thereof intravenously, epidurally, or subcutaneously.

[0033] In another aspect, the invention provides a TrkA RNAi agent of any of the embodiments described herein, or a pharmaceutical composition comprising the same, for use in a therapy, e.g. for treating pain. In one aspect, the invention provides a TrkA RNAi agent of any of the embodiments described herein, or a pharmaceutical composition comprising the same, for use in the treatment of a TrkA-mediated disease or disorder, optionally pain, and further optionally chronic pain. In one aspect the invention provides uses of the TrkA RNAi agent of any one of the embodiments described herein in the manufacture of a medicament for treating TrkA- mediated pain. In certain aspects, pain includes without limitation post-surgical pain, rheumatoid arthritis pain, neuropathic pain, osteoarthritis pain, or a combination thereof. Osteoarthritis pain includes non-radicular (non-neuropathic) pain. Neuropathic pain includes radicular pain CLBP, DNP, and LSR (which is also referred to as sciatica). In some embodiments, the pain is chronic pain, such as for example, chronic pain of both mucsculoskeletal and / or as neuropathic origin.DETAILED DESCRIPTION OF THE INVENTION

[0034] In certain aspects, the present disclosure provides an RNAi agent(s) for reducing tropomysin receptor kinase A (TrkA) mRNA and / or protein (a TrkA RNAi agent) expression, the RNAi agents comprising a sense strand and an antisense strand forming a double stranded RNA (dsRNA), compositions comprising such TrkA RNAi agents, and methods of their use in reducing TrkA (NTRK1) mRNA and / or protein levels for the treatment of pain, which maybeacute or chronic pain of nociceptive, inflammatory, neuropathic, nociplastic, or mixed etiologies.TrkA RNAi agents

[0035] In one aspect the present disclosure provides a TrkA RNAi agent for reducing TrkA (NTRK1) mRNA and / or protein expression, the RNAi comprising a sense strand and an antisense strand forming a double stranded RNA (dsRNA). Tn some embodiments, the antisense strand is 15 to 50 nucleotides in length. In some embodiments, the sense strand is 12 to 50 nucleotides in length. In some embodiments, the antisense strand is 18 to 23 nucleotides in length. In some embodiments, the sense strand is 12 to 21 nucleotides, 18 to 21 nucleotides in length. In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is 21 nucleotides in length. In some embodiments, the dsRNA comprises a region of complementarity that is at least 12, 13, 14, 15, 16, 17, or 18 nucleotides in length, optionally wherein the sense strand and the antisense strand form a dsRNA with 0, 1, 2, or 3 mismatches. In some embodiments, the dsRNA comprises a region of complementarity that is 12, 13, 14, 15, 16, 17, or 18 nucleotides in length, optionally wherein the sense strand and the antisense strand form a dsRNA with 0, 1, 2, or 3 mismatches over the 12, 13, 14, 15, 16, 17, or 18 nucleotides, optionally wherein the sense strand and the antisense strand form a dsRNA with 0 or 1 mismatches over the 12, 13, 14, 15, 16, 17, or 18 nucleotides.

[0036] In some embodiments, an RNAi agent for reducing TrkA (NTRK1) mRNA and / protein levels comprises a sense strand and an antisense strand forming a double stranded RNA (dsRNA) with 0, 1, 2, or 3 mismatches, wherein the antisense strand comprises a nucleotide sequence comprising 15-30, 15-23, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 contiguous nucleotides from one of the antisense sequences listed in any one of Table 1 A, Table IB, Table 1C, Table 2A, and Table 2B, and wherein the sense strand comprises a nucleotide sequence comprising at least 15-30, 15-23, at least 14-30, 14-23, 14-21, at least 12-30, at least 12-23, at least 14-21, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19 , at least 20 , or at least 21 contiguous nucleotides from a sense sequence from a paired set of sequences listed in any one of Table 1A, Table IB, Table 1C, Table 2A, and Table 2B, wherein optionally one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and wherein optionally one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. In certain embodiments, the dsRNA comprises an antisense strand comprising a nucleotide sequence comprising 15, 16, 17, 18, 19,20, 21, 22 or 23 contiguous nucleotides, with 0, 1, 2 or 3 mismatches to the sense strand. In certain embodiments, the dsRNA comprises a sense strand comprising a nucleotide sequence comprising 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides, with 0, 1, 2 or 3 mismatches to the antisense strand. In certain embodiments, the antisense strand comprises a nucleotide sequence comprising 15, 16, 17, 18, 19, 20, 21, 22 or 23 contiguous nucleotides, with 0 or 1 mismatches, and the sense strand comprises a nucleotide sequence comprising 14, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides, with 0, 1, 2 or 3 mismatches.

[0037] In one aspect, the invention provides, a TrkA RNAi agent comprising a sense strand and an antisense strand forming a double stranded RNA (dsRNA), wherein: the antisense strand comprises the nucleotides of any one of the antisense strands of Table 1 A and the sense strand comprises at least 14 to 18 nucleotides complementary to the nucleotides of the paired antisense stand of Table 1 A, wherein one or more nucleotides of the sense strand and one or more nucleotides of the antisense strand are independently modified nucleotides, and wherein optionally one or more internucleotide linkages of the sense strand and one or more intemucleotide linkages of the antisense strand are modified intemucleotide linkages.

[0038] In one aspect, the invention provides a TrkA RNAi agent comprising a sense strand and an antisense strand forming a double stranded RNA (dsRNA), wherein the antisense strand comprises the nucleotide sequence of any one of SEQ ID NO: 92-104 or 732-801 and the sense strand comprises at least 14 to 18 nucleotides complementary to the corresponding antisense strand sequence of any one of SEQ ID NO: 92-104 or 732-801 with 0, 1, 2, or 3 mismatches, wherein one or more nucleotides of the sense strand and one or more nucleotides of the antisense strand are independently modified nucleotides, and wherein optionally one or more intemucleotide linkages of the sense strand and one or more intemucleotide linkages of the antisense strand are modified intemucleotide linkages.

[0039] In some embodiments of the TrkA RNAi agent, one or more nucleotides of the sense strand and one or more nucleotides of the antisense strand are independently modified nucleotides, and wherein optionally one or more intemucleotide linkages of the sense strand and one or more intemucleotide linkages of the antisense strand are modified intemucleotide linkages. In some embodiments of the TrkA RNAi agent, the antisense strand further comprises a U nucleotide at its 5’ end. In some embodiments of the TrkA RNAi agent, the antisense strand further comprises one, two, three or four additional nucleotides at its 3’ end. In some embodiments of the TrkA RNAi agent, the antisense strand further comprises one, two, three or four additional nucleotides at its 3’ end, wherein the one, two, three and / or four additionalnucleotides are complementary to the target mRNA sequence. In some embodiments of the TrkA RNAi agent, each sense strand is 14, 15, 16, 17, 18, 19, 20 or 21 nucleotides long and each antisense strand is 18, 19, 20, 21, 22, or 23 nucleotides long.

[0040] In one aspect, the invention provides a TrkA RNAi agent comprising a sense strand and an antisense strand forming a double stranded RNA (dsRNA), wherein:(a) the antisense strand comprises the nucleotides of SEQ ID NO: 92 and the sense strand comprises the nucleotides of SEQ ID NO: 79, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(b) the antisense strand comprises the nucleotides of SEQ ID NO: 93 and the sense strand comprises the nucleotides of SEQ ID NO: 80, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(c) the antisense strand comprises the nucleotides of SEQ ID NO: 94 and the sense strand comprises the nucleotides of SEQ ID NO: 81, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(d) the antisense strand comprises the nucleotides of SEQ ID NO: 95 and the sense strand comprises the nucleotides of SEQ ID NO: 82, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1 , 2, or 3 mismatches to the sense strand;(e) the antisense strand comprises the nucleotides of SEQ ID NO: 96 and the sense strand comprises the nucleotides of SEQ ID NO: 83, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1 , 2, or 3 mismatches to the sense strand;(f) the antisense strand comprises the nucleotides of SEQ ID NO: 97 and the sense strand comprises the nucleotides of SEQ ID NO: 84, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(g) the antisense strand comprises the nucleotides of SEQ ID NO: 98 and the sense strand comprises the nucleotides of SEQ ID NO: 85, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(h) the antisense strand comprises the nucleotides of SEQ ID NO: 99 and the sense strand comprises the nucleotides of SEQ ID NO: 86, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(i) the antisense strand comprises the nucleotides of SEQ ID NO: 100 and the sense strand comprises the nucleotides of SEQ ID NO: 87, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(j) the antisense strand comprises the nucleotides of SEQ ID NO: 101 and the sense strand comprises the nucleotides of SEQ ID NO: 88, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1 , 2, or 3 mismatches to the sense strand;(k) the antisense strand comprises the nucleotides of SEQ ID NO: 102 and the sense strand comprises the nucleotides of SEQ ID NO: 89, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(l) the antisense strand comprises the nucleotides of SEQ ID NO: 103 and the sense strand comprises the nucleotides of SEQ ID NO: 90, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand; or(m)the antisense strand comprises the nucleotides of SEQ ID NO: 104 and the sense strand comprises the nucleotides of SEQ ID NO: 91, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(n) the antisense strand comprises the nucleotides of SEQ ID NO: 732 and the sense strand comprises the nucleotides of SEQ ID NO: 662, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(o) the antisense strand comprises the nucleotides of SEQ ID NO: 733 and the sense strand comprises the nucleotides of SEQ ID NO: 663, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(p) the antisense strand comprises the nucleotides of SEQ ID NO: 734 and the sense strand comprises the nucleotides of SEQ ID NO: 664, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(q) the antisense strand comprises the nucleotides of SEQ ID NO: 735 and the sense strand comprises the nucleotides of SEQ ID NO: 665, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(r) the antisense strand comprises the nucleotides of SEQ ID NO: 736 and the sense strand comprises the nucleotides of SEQ ID NO: 666, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1 , 2, or 3 mismatches to the sense strand;(s) the antisense strand comprises the nucleotides of SEQ ID NO: 737 and the sense strand comprises the nucleotides of SEQ ID NO: 667, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(t) the antisense strand comprises the nucleotides of SEQ ID NO: 738 and the sense strand comprises the nucleotides of SEQ ID NO: 668, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(u) the antisense strand comprises the nucleotides of SEQ ID NO: 739 and the sense strand comprises the nucleotides of SEQ ID NO: 669, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(v) the antisense strand comprises the nucleotides of SEQ ID NO: 740 and the sense strand comprises the nucleotides of SEQ ID NO: 670, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(w)the antisense strand comprises the nucleotides of SEQ ID NO: 741 and the sense strand comprises the nucleotides of SEQ ID NO: 671, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(x) the antisense strand comprises the nucleotides of SEQ ID NO: 742 and the sense strand comprises the nucleotides of SEQ ID NO: 672, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(y) the antisense strand comprises the nucleotides of SEQ ID NO: 743 and the sense strand comprises the nucleotides of SEQ ID NO: 673, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(z) the antisense strand comprises the nucleotides of SEQ ID NO: 744 and the sense strand comprises the nucleotides of SEQ ID NO: 674, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1 , 2, or 3 mismatches to the sense strand;(aa) the antisense strand comprises the nucleotides of SEQ ID NO: 745 and the sense strand comprises the nucleotides of SEQ ID NO: 675, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(bb) the antisense strand comprises the nucleotides of SEQ ID NO: 746 and the sense strand comprises the nucleotides of SEQ ID NO: 676, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(cc) the antisense strand comprises the nucleotides of SEQ ID NO: 747 and the sense strand comprises the nucleotides of SEQ ID NO: 677, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(dd) the antisense strand comprises the nucleotides of SEQ ID NO: 748 and the sense strand comprises the nucleotides of SEQ ID NO: 678, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(ee) the antisense strand comprises the nucleotides of SEQ ID NO: 749 and the sense strand comprises the nucleotides of SEQ ID NO: 679, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(ff) the antisense strand comprises the nucleotides of SEQ ID NO: 750 and the sense strand comprises the nucleotides of SEQ ID NO: 680, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(gg) the antisense strand comprises the nucleotides of SEQ ID NO: 751 and the sense strand comprises the nucleotides of SEQ ID NO: 681, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(hh) the antisense strand comprises the nucleotides of SEQ ID NO: 752 and the sense strand comprises the nucleotides of SEQ ID NO: 682, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1 , 2, or 3 mismatches to the sense strand;(ii) the antisense strand comprises the nucleotides of SEQ ID NO: 753 and the sense strand comprises the nucleotides of SEQ ID NO: 683, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(jj) the antisense strand comprises the nucleotides of SEQ ID NO: 754 and the sense strand comprises the nucleotides of SEQ ID NO: 684, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(kk) the antisense strand comprises the nucleotides of SEQ ID NO: 755 and the sense strand comprises the nucleotides of SEQ ID NO: 685, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(11) the antisense strand comprises the nucleotides of SEQ ID NO: 756 and the sense strand comprises the nucleotides of SEQ ID NO: 686, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(mm) the antisense strand comprises the nucleotides of SEQ ID NO: 757 and the sense strand comprises the nucleotides of SEQ ID NO: 687, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(nn) the antisense strand comprises the nucleotides of SEQ ID NO: 758 and the sense strand comprises the nucleotides of SEQ ID NO: 688, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(oo) the antisense strand comprises the nucleotides of SEQ ID NO: 759 and the sense strand comprises the nucleotides of SEQ ID NO: 689, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(pp) the antisense strand comprises the nucleotides of SEQ ID NO: 760 and the sense strand comprises the nucleotides of SEQ ID NO: 690, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1 , 2, or 3 mismatches to the sense strand;(qq) the antisense strand comprises the nucleotides of SEQ ID NO: 761 and the sense strand comprises the nucleotides of SEQ ID NO: 691, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(IT) the antisense strand comprises the nucleotides of SEQ ID NO: 762 and the sense strand comprises the nucleotides of SEQ ID NO: 692, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(ss)the antisense strand comprises the nucleotides of SEQ ID NO: 763 and the sense strand comprises the nucleotides of SEQ ID NO: 693, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(tt) the antisense strand comprises the nucleotides of SEQ ID NO: 764 and the sense strand comprises the nucleotides of SEQ ID NO: 694, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(uu) the antisense strand comprises the nucleotides of SEQ ID NO: 765 and the sense strand comprises the nucleotides of SEQ ID NO: 695, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(vv) the antisense strand comprises the nucleotides of SEQ ID NO: 766 and the sense strand comprises the nucleotides of SEQ ID NO: 696, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(ww) the antisense strand comprises the nucleotides of SEQ ID NO: 767 and the sense strand comprises the nucleotides of SEQ ID NO: 697, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(xx) the antisense strand comprises the nucleotides of SEQ ID NO: 768 and the sense strand comprises the nucleotides of SEQ ID NO: 698, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1 , 2, or 3 mismatches to the sense strand;(yy) the antisense strand comprises the nucleotides of SEQ ID NO: 769 and the sense strand comprises the nucleotides of SEQ ID NO: 699, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(zz) the antisense strand comprises the nucleotides of SEQ ID NO: 770 and the sense strand comprises the nucleotides of SEQ ID NO: 700, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(aaa) the antisense strand comprises the nucleotides of SEQ ID NO: 771 and the sense strand comprises the nucleotides of SEQ ID NO: 701, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(bbb) the antisense strand comprises the nucleotides of SEQ ID NO: 772 and the sense strand comprises the nucleotides of SEQ ID NO: 702, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(ccc) the antisense strand comprises the nucleotides of SEQ ID NO: 773 and the sense strand comprises the nucleotides of SEQ ID NO: 703, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(ddd) the antisense strand comprises the nucleotides of SEQ ID NO: 774 and the sense strand comprises the nucleotides of SEQ ID NO: 704, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(eee) the antisense strand comprises the nucleotides of SEQ ID NO: 775 and the sense strand comprises the nucleotides of SEQ ID NO: 705, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(fff) the antisense strand comprises the nucleotides of SEQ ID NO: 776 and the sense strand comprises the nucleotides of SEQ ID NO: 706, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1 , 2, or 3 mismatches to the sense strand;(ggg) the antisense strand comprises the nucleotides of SEQ ID NO: 777 and the sense strand comprises the nucleotides of SEQ ID NO: 707, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(hhh) the antisense strand comprises the nucleotides of SEQ ID NO: 778 and the sense strand comprises the nucleotides of SEQ ID NO: 708, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(iii)the antisense strand comprises the nucleotides of SEQ ID NO: 779 and the sense strand comprises the nucleotides of SEQ ID NO: 709, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(jjj)the antisense strand comprises the nucleotides of SEQ ID NO: 780 and the sense strand comprises the nucleotides of SEQ ID NO: 710, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(kkk) the antisense strand comprises the nucleotides of SEQ ID NO: 781 and the sense strand comprises the nucleotides of SEQ ID NO: 711, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(lll)the antisense strand comprises the nucleotides of SEQ ID NO: 782 and the sense strand comprises the nucleotides of SEQ ID NO: 712, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(mmm)the antisense strand comprises the nucleotides of SEQ ID NO: 783 and the sense strand comprises the nucleotides of SEQ ID NO: 713, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(nnn) the antisense strand comprises the nucleotides of SEQ ID NO: 784 and the sense strand comprises the nucleotides of SEQ ID NO: 714, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1 , 2, or 3 mismatches to the sense strand;(ooo) the antisense strand comprises the nucleotides of SEQ ID NO: 785 and the sense strand comprises the nucleotides of SEQ ID NO: 715, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(ppp) the antisense strand comprises the nucleotides of SEQ ID NO: 786 and the sense strand comprises the nucleotides of SEQ ID NO: 716, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(qqq) the antisense strand comprises the nucleotides of SEQ ID NO: 787 and the sense strand comprises the nucleotides of SEQ ID NO: 717, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(rrr) the antisense strand comprises the nucleotides of SEQ ID NO: 788 and the sense strand comprises the nucleotides of SEQ ID NO: 718, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(sss) the antisense strand comprises the nucleotides of SEQ ID NO: 789 and the sense strand comprises the nucleotides of SEQ ID NO: 71 , and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(ttt)the antisense strand comprises the nucleotides of SEQ ID NO: 790 and the sense strand comprises the nucleotides of SEQ ID NO: 720, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(uuu) the antisense strand comprises the nucleotides of SEQ ID NO: 791 and the sense strand comprises the nucleotides of SEQ ID NO: 721, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(vvv) the antisense strand comprises the nucleotides of SEQ ID NO: 792 and the sense strand comprises the nucleotides of SEQ ID NO: 722, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1 , 2, or 3 mismatches to the sense strand;(www) the antisense strand comprises the nucleotides of SEQ ID NO: 793 and the sense strand comprises the nucleotides of SEQ ID NO: 723, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(xxx) the antisense strand comprises the nucleotides of SEQ ID NO: 794 and the sense strand comprises the nucleotides of SEQ ID NO: 724, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(yyy) the antisense strand comprises the nucleotides of SEQ ID NO: 795 and the sense strand comprises the nucleotides of SEQ ID NO: 725, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(zzz) the antisense strand comprises the nucleotides of SEQ ID NO: 796 and the sense strand comprises the nucleotides of SEQ ID NO: 726, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(aaaa) the antisense strand comprises the nucleotides of SEQ ID NO: 797 and the sense strand comprises the nucleotides of SEQ ID NO: 727, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(bbbb) the antisense strand comprises the nucleotides of SEQ ID NO: 798 and the sense strand comprises the nucleotides of SEQ ID NO: 728, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(cccc) the antisense strand comprises the nucleotides of SEQ ID NO: 799 and the sense strand comprises the nucleotides of SEQ ID NO: 729, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand;(dddd) the antisense strand comprises the nucleotides of SEQ ID NO: 800 and the sense strand comprises the nucleotides of SEQ ID NO: 730, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1 , 2, or 3 mismatches to the sense strand;(eeee) the antisense strand comprises the nucleotides of SEQ ID NO: 801 and the sense strand comprises the nucleotides of SEQ ID NO: 731, and wherein the antisense strand comprises at least 18 to 23, at least 18 to 25, or at least 18 to 30 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand, wherein one or more nucleotides of the sense strand and one or more nucleotides of the antisense strand are independently modified nucleotides, and wherein optionally one or more intemucleotide linkages of the sense strand and one or more internucleotide linkages of the antisense strand are modified internucleotide linkages.

[0041] In some embodiments of the TrkA RNAi agent: a. the antisense strand is 23 nucleotides long and the sense strand is 14 nucleotides long; b. the antisense strand is 23 nucleotides long and the sense strand is 15 nucleotides long; c. the antisense strand is 23 nucleotides long and the sense strand is 16 nucleotides long; d. the antisense strand is 23 nucleotides long and the sense strand is 17 nucleotides long e. the antisense strand is 23 nucleotides long and the sense strand is 18 nucleotides long f. the antisense strand is 23 nucleotides long and the sense strand is 19 nucleotides long; g. the antisense strand is 23 nucleotides long and the sense strand is 20 nucleotides long; or h. the antisense strand is 23 nucleotides long and the sense strand is 21 nucleotides long.

[0042] In some embodiments of the TrkA RNAi agent: a. the antisense strand is 22 nucleotides long and the sense strand is 14 nucleotides long; b. the antisense strand is 22 nucleotides long and the sense strand is 15 nucleotides long;c. the antisense strand is 22 nucleotides long and the sense strand is 16 nucleotides long; d. the antisense strand is 22 nucleotides long and the sense strand is 17 nucleotides long e. the antisense strand is 22 nucleotides long and the sense strand is 18 nucleotides long f. the antisense strand is 22 nucleotides long and the sense strand is 19 nucleotides long; g. the antisense strand is 22 nucleotides long and the sense strand is 20 nucleotides long; or h. the antisense strand is 22 nucleotides long and the sense strand is 21 nucleotides long.

[0043] In some embodiments of the TrkA RNAi agent: a. the antisense strand is 21 nucleotides long and the sense strand is 14 nucleotides long; b. the antisense strand is 21 nucleotides long and the sense strand is 15 nucleotides long; c. the antisense strand is 21 nucleotides long and the sense strand is 16 nucleotides long; d. the antisense strand is 21 nucleotides long and the sense strand is 17 nucleotides long e. the antisense strand is 21 nucleotides long and the sense strand is 18 nucleotides long f. the antisense strand is 21 nucleotides long and the sense strand is 19 nucleotides long; g. the antisense strand is 21 nucleotides long and the sense strand is 20 nucleotides long; or h. the antisense strand is 21 nucleotides long and the sense strand is 21 nucleotides long.

[0044] In some embodiments of the TrkA RNAi agent: a. the antisense strand is 20 nucleotides long and the sense strand is 14 nucleotides long; b. the antisense strand is 20 nucleotides long and the sense strand is 15 nucleotides long; c. the antisense strand is 20 nucleotides long and the sense strand is 16 nucleotides long; d. the antisense strand is 20 nucleotides long and the sense strand is 17 nucleotides long; e. the antisense strand is 20 nucleotides long and the sense strand is 18 nucleotides long; f. the antisense strand is 20 nucleotides long and the sense strand is 19 nucleotides long; or g. the antisense strand is 20 nucleotides long and the sense strand is 20 nucleotides long.

[0045] In some embodiments of the TrkA RNAi agent: a. the antisense strand is 19 nucleotides long and the sense strand is 14 nucleotides long; b. the antisense strand is 19 nucleotides long and the sense strand is 15 nucleotides long; c. the antisense strand is 19 nucleotides long and the sense strand is 16 nucleotides long; d. the antisense strand is 19 nucleotides long and the sense strand is 17 nucleotides long; e. the antisense strand is 19 nucleotides long and the sense strand is 18 nucleotides long; or f. the antisense strand is 19 nucleotides long and the sense strand is 19 nucleotides long.

[0046] In some embodiments of the TrkA RNAi agent, wherein: a. the antisense strand is 18 nucleotides long and the sense strand is 14 nucleotides long; b. the antisense strand is 18 nucleotides long and the sense strand is 15 nucleotides long;c. the antisense strand is 18 nucleotides long and the sense strand is 16 nucleotides long; d. the antisense strand is 18 nucleotides long and the sense strand is 17 nucleotides long; or e. the antisense strand is 18 nucleotides long and the sense strand is 18 nucleotides long.

[0047] In one aspect, the invention provides, a TrkA RNAi agent comprising a sense strand and an antisense strand fonning a double stranded RNA (dsRNA), wherein: the antisense strand comprises the nucleotides of any one of the antisense strands of Table IB and the sense strand comprises at least 14 to 21 nucleotides complementary to the nucleotides of the paired antisense stand of Table IB, and wherein the antisense strand comprises 23 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand, wherein one or more nucleotides of the sense strand and one or more nucleotides of the antisense strand are independently modified nucleotides, and wherein optionally one or more intemucleotide linkages of the sense strand and one or more intemucleotide linkages of the antisense strand are modified intemucleotide linkages.

[0048] In one aspect, the invention provides, a TrkA RNAi agent comprising a sense strand and an antisense strand fonning a double stranded RNA (dsRNA), wherein: the antisense strand comprises the nucleotides of any one of the antisense strands of Table 1C and the sense strand comprises at least 14 to 21 nucleotides complementary to the nucleotides of the paired antisense stand of Table 1C, and wherein the antisense strand comprises at least 18 to 23 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand, wherein one or more nucleotides of the sense strand and one or more nucleotides of the antisense strand are independently modified nucleotides, and wherein optionally one or more intemucleotide linkages of the sense strand and one or more intemucleotide linkages of the antisense strand are modified intemucleotide linkages.

[0049] In one aspect, the invention provides a TrkA RNAi agent comprising a sense strand and an antisense strand forming a double stranded RNA (dsRNA), wherein:(a) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 2, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 15,(b) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 3, and the antisense strand comprises a sequence which has atleast 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 16,(c) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 17,(d) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 5, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 18,(e) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 6, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 19,(f) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 7, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 20,(g) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 21,(h) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 22,(i) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 10, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 23,(j) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 11, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 24,(k) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 12, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 25,(l) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 13, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 26,(m)the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 14, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 27,(n) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 109,(o) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 105, and the antisense strand comprises a sequence which has atleast 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 21,(p) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 105, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 109,(q) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 105, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 110,(r) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 21,(s) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 109,(t) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 110,(u) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 21,(v) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 109,(w)the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 110,(x) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 111,(y) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 21,(z) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 110,(aa) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 111,(bb) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 126, and the antisense strand comprises a sequence which has atleast 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 184,(cc) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 127, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 185,(dd) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 128, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 186,(ee) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 129, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 187,(ff) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 130, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 188,(gg) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 131 , and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 189,(hh) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 132, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 190,(ii) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 133, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 191,(jj) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 134, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 192,(kk) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 135, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 193,(11) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 136, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 194,(mm) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 137, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 195,(nn) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 138, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 196,(oo) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 139, and the antisense strand comprises a sequence which has atleast 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 197,(pp) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 140, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 198,(qq) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 141, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 199,(rr) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 142, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 200,(ss)the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 143, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 201,(tt) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 144, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 202,(uu) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 145, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 203,(vv) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 146, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 204,(ww) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 147, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 205,(xx) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 148, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 206,(yy) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 149, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 207,(zz) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 150, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 208,(aaa) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 151, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 209,(bbb) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 152, and the antisense strand comprises a sequence which has atleast 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 210,(ccc) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 153, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 211,(ddd) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 154, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 212,(eee) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 155, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 213,(fff) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 156, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 214,(ggg) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 157, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 215,(hhh) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 158, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 216,(iii)the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 159, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 217,(jjj)the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 160, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 218,(kkk) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 161, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 219,(lll)the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 162, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 220,(mmm) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 163, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 221,(nnn) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 164, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 222,(ooo) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 165, and the antisense strand comprises a sequence which has atleast 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 223,(ppp) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 166, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 224,(qqq) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 167, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 225,(rrr) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 168, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 226,(sss) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 169, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 227,(ttt)the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 170, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 228,(uuu) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 171, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 229,(vvv) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 172, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 230,(www) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 173, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 231,(xxx) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 174, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 232,(yyy) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 175, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 233,(zzz) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 176, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 234,(aaaa) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 177, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 235,(bbbb) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has atleast 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 236,(cccc) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 237, (xx) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 238,(dddd) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 239,(eeee) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 178, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 22,(ffff) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 179, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 22,(gggg) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 180, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 22,(hhhh) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 181, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 22,(iiii) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 240,(jjjj) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 241,(kkkk) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 242,(1111) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 243,(mmmm) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 244,(nnnn) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has atleast 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 245,(oooo) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 246,(pppp) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 247,(qqqq) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 182, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 21,(rrrr) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 248,(ssss) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 183, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 17,(tttt) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 7, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 249,(uuuu) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 250, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 260,(vvvv) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 260,(wwww) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 261,(xxxx) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 251, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 261,(yyyy) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 7, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 249,(zzzz) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 111,(aaaaa) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has atleast 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 109,(bbbbb) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 263,(ccccc) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 252, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 263,(ddddd) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 252, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 21,(eeeee) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 264,(fffff) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 265,(ggggg) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 253, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 265,(hhhhh) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 254, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 264,(iiiii) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 255, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 266,(jjjjj) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 256, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 266,(kkkkk) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 256, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 267,(11111) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 257, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 267,(mmmmm) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 257, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 268,(nnnnn) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 258, and the antisense strand comprises a sequence which has atleast 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 20,(ooooo) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 258, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 268,(ppppp) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 258, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 269,(qqqqq) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 259, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 267,(rrrrr) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 259, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 268,(sssss) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 259, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 269,(ttttt) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 262,(uuuuu) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 597, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 610,(vvvvv) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 598, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 611,(wwwww) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 599, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 612,(xxxxx) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 600, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 613,(yyyyy) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 601, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 614,(zzzzz) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 602, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 615,(aaaaaa) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 603, and the antisense strand comprises a sequence which has atleast 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 616,(bbbbbb) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 604, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 617,(cccccc) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 605, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 618,(dddddd) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 606, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 619,(eeeeee) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 607, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 620,(ffffff) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 608, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 621, or(gggggg) the sense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 609, and the antisense strand comprises a sequence which has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 622.

[0050] In one aspect, the invention provides, a TrkA RNAi agent comprising a sense strand and an antisense strand forming a double stranded RNA (dsRNA), wherein: the antisense strand comprises the nucleotides of any one of the antisense strands of Table 2 A and the sense strand comprises at least 14 to 21 nucleotides complementary to the nucleotides of the paired antisense stand of Table 2A, and wherein the antisense strand comprises 23 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand.

[0051] In one aspect, the invention provides, a TrkA RNAi agent comprising a sense strand and an antisense strand forming a double stranded RNA (dsRNA), wherein: the antisense strand comprises the nucleotides of any one of the antisense strands of Table 2B and the sense strand comprises at least 14 to 21 nucleotides complementary to the nucleotides of the paired antisense stand of Table 2B, and wherein the antisense strand comprises at least 18 to 23 consecutive nucleotides with 0, 1, 2, or 3 mismatches to the sense strand.

[0052] In certain embodiments, the antisense strand comprises the first 18, 19, 20, 21, 22 or 23 consecutive nucleotides within an antisense strand from any one of duplex dsRNA NO: 1-528. In certain embodiments, the antisense strand is any one of the antisense strands from duplex dsRNA NO: 1-528. In certain embodiments, the sense strand is a complementary strand comprising nucleotides from any one of the sense strands from duplex dsRNA NO: 1-528. In certain embodiments, the antisense sense strand is any one of the sense strands from duplex dsRNA NO: 1-528 and the sense strand is the paired sense strands from duplex dsRNA NO: 1- 528. In certain embodiments, the sense strand and the antisense strand comprise nucleotide sequences of the paired sense strand and antisense strand of a duplex selected from duplex dsRNA NO: 14-51, 66-80, 180-194, 195-446, and 447-528.

[0053] In certain embodiments, the antisense strand comprises a nucleic acid sequence having at least 80%, at least 85%, at least 90%, and at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to the first 18, 19, 20, 21 , 22 or 23 consecutive nucleotides within an antisense strand from any one of duplex dsRNA NO: 1- 528. In certain embodiments, the sense strand comprises a nucleic acid sequence having at least 80%, at least 85%, at least 90%, and at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to a complementary strand comprising nucleotides from any one of the sense strands from duplex dsRNA NO: 1-528.

[0054] In certain embodiments, the sense strand comprises a nucleic acid sequence having at least 80%, at least 85%, at least 90%, and at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to any one of the sense strands fromduplex dsRNA NO: 1-528 and the antisense strand comprises a nucleic acid sequence having at least 80%, at least 85%, at least 90%, and at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to the paired antisense strands from duplex dsRNA NO: 1-528.

[0055] In certain embodiments, the sense strand comprises a nucleic acid sequence having at least 80%, at least 85%, at least 90%, and at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to a sense strand and the antisense strand comprises a nucleic acid sequence having at least 80%, at least 85%, at least 90%, and at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to an antisense strand, wherein the sense strand and antisense strand comprise nucleotide sequences of the paired sense strand and antisense strand of a duplex selected from duplex dsRNA NO: 14-51, 66-80, 180-194, 195-446, and 447-528.

[0056] In certain embodiments, the sense and / or antisense strand comprised in the dsRNA include various modifications. In certain embodiments of the RNAi agents, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, which means that individual nucleotides within the sense strand and the antisense strand can have different modified nucleotides. In certain embodiments, one or more internucleotide linkages of the sense strand and of the antisense strand are modified internucleotide linkages

[0057] In certain embodiments, the RNAi agent comprises any one of dsRNA NO: 14-51, 66- 80, 180-194, 195-446, and 447-528.

[0058] In certain embodiments, the present disclosure provides a TrkA RNAi agent comprising dsRNA wherein the antisense strand comprises a 3’ overhang of two nucleotides. In some embodiments, the sense and antisense strands each comprise one or more modified nucleotides. In some embodiments, the one or more modified nucleotides is a 2’ fluoro modified nucleotide or a 2’ O-methyl modified nucleotide.

[0059] In some embodiments, the present disclosure provides TrkA dsRNA agent wherein the sense and antisense strands each comprise one or more modified intemucleotide linkages. In some embodiments, one or more modified internucleotide linkages are phosphorothioate linkages.

[0060] In some embodiments, the antisense strand further comprises an abasic or inverted abasic moiety of Structure (I) or (II). In some embodiments, the antisense sense strand further comprises an inverted abasic moiety. In some embodiments, the inverted abasic structure is comprised of the following Structure (I):

[0061] The modifications can be made to one or more nucleotides of the sense and / or antisense strand or to the intemucleotide linkages, which are the bonds between two nucleotides in the sense or antisense strand. For example, some 2" -modifications of ribose or deoxyribose can increase RNA or DNA stability and half-life. Such 2’ -modifications can be 2’ -fluoro, 2’-O- methyl (i.e., 2’-methoxy), or 2'-O-alkyl (e.g., 2’-O-Ci6 alkyl).

[0062] In some embodiments, one or more nucleotides of the sense strand and / or the antisense strand are independently modified nucleotides, such that the sense strand and the antisense strand can have different modified nucleotides. In some embodiments, each nucleotide of the sense strand is a modified nucleotide. In some embodiments, each nucleotide of the antisense strand is a modified nucleotide. In some embodiments, the modified nucleotide is a 2’ -fluoro modified nucleotide, 2’-O-methyl modified nucleotide, or 2’-O-alkyl (e.g., 2’-O-Ci6 alkyl) modified nucleotide. In some embodiments, each nucleotide of the sense strand and the antisense strand is independently a modified nucleotide, e.g., a 2’-fluoro modified nucleotide, 2’-O-methyl modified nucleotide, or 2’-O-alkyl (e.g., 2’-O-Ci6 alkyl) modified nucleotide. In some embodiments, the modified nucleotide is selected from the 2’-O-methoxy, 2’-O-methyl, 2’ -fluoro, phosphorothioate, 2’ -deoxy, abasic moiety, inverted abasic moiety, glycol nucleic acid (GNA), extended nucleic acid (exNA), R-PrON (that is PrON in which the branched methyl of the internucleotide linkage is in the R configuration), and S-PrON (that is, PrON in which the branched methyl of the intemucleotide linkage is in the S configuration).

[0063] In some embodiments, the sense strand has four 2’ -fluoro modified nucleotides, e.g., at positions 7, 9, 10, 11 from the 5’ end of the sense strand. In some embodiments, the other nucleotides of the sense strand are 2-O-methyl modified nucleotides. In some embodiments, the antisense strand has four 2-fluoro modified nucleotides, e.g., at positions 2, 6, 14, 16 from the 5’ end of the antisense strand. In some embodiments, the other nucleotides of the antisense strand are 2-O-methyl modified nucleotides.

[0064] In some embodiments, the sense strand has four 2’ -fluoro modified nucleotides, e.g., at positions 7, 9, 10, 11 from the 5’ end of the sense strand. In some embodiments, the other nucleotides of the sense strand are 2’-O-methyl modified nucleotides. In some embodiments,the antisense strand has six 2’ -fluoro modified nucleotides, e.g., at positions 2, 6, 8, 9, 14, 16 from the 5’ end of the antisense strand. In some embodiments, the other nucleotides of the antisense strand are 2’-O-methyl modified nucleotides.

[0065] In some embodiments, the sense strand has three 2’-fluoro modified nucleotides, e.g., at positions 9, 10, 11 from the 5' end of the sense strand. In some embodiments, the other nucleotides of the sense strand are 2’-O-methyl modified nucleotides. In some embodiments, the antisense strand has five 2’ -fluoro modified nucleotides, e.g., at positions 2, 5, 7, 14, 16 from the 5’ end of the antisense strand. In some embodiments, the antisense strand has five 2’- fluoro modified nucleotides, e.g., at positions 2, 5, 8, 14, 16 from the 5’ end of the antisense strand. In some embodiments, the antisense strand has five 2’-fluoro modified nucleotides, e.g., at positions 2, 3, 7, 14, 16 from the 5’ end of the antisense strand. In some embodiments, the other nucleotides of the antisense strand are 2’-O-methyl modified nucleotides. In some embodiments, the antisense strand has three 2’-fluoro modified nucleotides, e.g., at positions 2, 14, 16 from the 5’ end of the antisense strand. In some embodiments, the other nucleotides of the antisense strand are 2’-O-methyl modified nucleotides.

[0066] In some embodiments, the sense strand has three 2’ -fluoro modified nucleotides, e.g., at positions 9, 10, 11 from the 5’ end of the sense strand. In some embodiments, the other nucleotides of the sense strand are 2’-O-methyl modified nucleotides. In some embodiments, the antisense strand has three 2’ -fluoro modified nucleotides, e.g., at positions 2, 14, 16 from the 5’ end of the antisense strand and two DNA nucleotides, e.g., at positions 4 and 7 from the 5’ end of the antisense strand. In some embodiments, the other nucleotides of the antisense strand are 2’-O-methyl modified nucleotides.

[0067] In some embodiments, the 5" end of the antisense strand has a phosphate analog, e.g., 5’-vinylphosphonate (5’-VP). In some embodiments, the sense strand comprises one or more 2’-O-MOE-5-methyl cytidine modified nucleotides. In some embodiments, the sense strand comprises two 2’-O-MOE-5-methyl cytidine modified nucleotides at the 5’ end of the sense strand.

[0068] In some embodiments, the sense strand or the antisense strand comprises an abasic moiety (abasic), e.g. of Structure (I), or inverted abasic moiety (iAb), e.g. of Structure (II). In the structure “5”’ and “3”’ indicate the 5’ to 3’ direction of the sequences. In some embodiments, *iAb is at 5’ end of sense strand.

[0069] In some embodiments, the sense strand and / or the antisense strand comprises butadiol. As used herein, “butadiol” or “bd” nucleotides are butadiol moieties that can be incorporated into one or more nucleotides and / or nucleosides by replacing one or more sugar moieties. The modified nucleotides can be incorporated into an oligonucleotide, such as an AGT RNAi agent, as a destabilizing agent in the RNAi agent. The butadiol moiety can be represented by the compounds of Structures (III), (IV), and (V).Structure (III): Butadiol, wherein B is a nucleobase.Structure (IV): (R,S) - Butadiol, wherein B is a nucleobase.Structure (V): (S,S)-Butadiol, wherein B is a nucleobase.

[0070] The butadiol moiety can comprise a mixture of the (R,S) and (S,S) diastereomers (Structure (III)), the (R,S) diastereomer (Structure (IV)), or the (S,S) diastereomer (Structure(V)). In some embodiments, the butadiol moiety can comprise the (R,R), (R.S), (S,S), and / or the (S,R) diastereomers.

[0071] In some embodiments, the dsRNA comprises a nucleotide termed (“PrON”) comprising a “2-propyl” intemucleotide linkage, as described in Structure (VI). In non-limiting embodiments, a “PrON” is incorporated in RNA sequence such that the properties of the RNA sequence are improved. In non-limiting embodiments, PrONs are stability enhancing modification, which extend the half-life and / or reduce degradation of the oligonucleotide comprising these. When PrON is incorporated into an oligonucleotide, it may be incorporated with random or intentional stereochemistry (that is, R or S, determined as rPrON and sPrON). In some instances, multiple PrONs may be included in a single oligonucleotide. An exemplary PrON nucleotide comprises the following structure:Structure (VI)

[0072] wherein “5”’ and “3”’ indicate the 5’ to 3’ direction of the sequences; wherein B is a nucleobase, and wherein R1is selected from the group consisting of H, OR2, NH2, SR2, F, and Cl, wherein R2is selected from the group consisting of H and C1-C20 alkyl.

[0073] Non-limiting embodiments of sPrON and rPrON nucleotides are structures as follows, wherein “5”’ and “3”’ indicate the 5’ to 3’ direction of the sequences:Structure (VII) and Structure (VIII)

[0074] In some embodiments, the dsRNA comprises a nucleotide termed (“UNA”) comprising of an unlocked nucleic acid, as described in Structure (IX). In non-limiting embodiments, a “UNA” is incorporated in RNA sequence such that the properties of the RNA sequence are improved. In some instances, multiple UNAs may be included in a single oligonucleotide. An exemplary UNA nucleotide comprises an oligonucleotide of the formula:Structure (IX) wherein “5”' and “3”’ indicate the 5’ to 3" direction of the sequences; wherein B is a nucleobase.

[0075] In some embodiments, the sense strand and the antisense strand have one or more modified internucleotide linkages. In some embodiments, the modified intemucleotide linkage is phosphorothioate linkage. In some embodiments, the sense strand has four or five phosphorothioate linkages. In some embodiments, the antisense strand has four or five phosphorothioate linkages. In some embodiments, the sense strand and the antisense strand each has four or five phosphorothioate linkages. In some embodiments, the sense strand has four phosphorothioate linkages and the antisense strand has five phosphorothioate linkages.

[0076] In some embodiments, the dsRNA comprises a sense strand that comprises a sequence that has 1, 2, or 3 differences from a sense stand sequence in Table 1 A, Table IB, Table 1C, Table 2A, and Table 2B. In some embodiments, the dsRNA comprises an antisense strand that comprises a sequence that has 1 , 2, or 3 differences from an antisense stand sequence in Table 1 A, Table IB, Table 1C, Table 2A, and Table 2B.

[0077] Exemplary modified sense strand and modified antisense strand sequences of dsRNA targeting human TrkA (NTRK1) mRNA are provided in Table 2A and Table 2B.Delivery moieties and conjugates comprising TrkA dsRNAs

[0078] In some aspects, the present disclosure provides a conjugate comprising an RNAi agent further comprising a delivery moiety D. In some embodiments, the delivery moiety D is conjugated to dsRNA of the RNAi agent. In some embodiments, the delivery moiety D delivers the dsRNA to dorsal root ganglion (DRG) neurons. In some embodiments the deliver moiety is a bivalent antibody, a heterodimeric antibody, a monovalent antibody, a Fab, a scFv, or a VHH binding to a target present on a DRG neuron.

[0079] In some embodiments, the delivery moiety D is an antibody, e.g., a monoclonal antibody. In some embodiments, the delivery moiety D is an antibody fragment, e.g., Fab, scFv, Fv, or scFab (single chain Fab). In some embodiments, the delivery moiety D is a Fab which further comprises a VHH that binds to human serum albumin (HSA). In some embodiments, the delivery moiety D is a VHH. In some embodiments, the delivery moiety D is a VHH whichfurther comprises a VHH that binds to human serum albumin, i.e., VHH-albVHH. In some embodiments, the delivery moiety D is a peptide.

[0001] In one embodiment, the delivery moiety D is a transferrin receptor binding protein (TBP). In some embodiments, the TBPs described herein bind to human transferrin receptor with high specificity, affinity, and with reduced immunogenicity risk. In some embodiments, the TBPs described herein may be used for targeting tissues and / or cells that express the transferrin receptor (TfR). In some embodiments, the TBPs described herein may be used to deliver a molecular payload to a target cell or tissue (e.g., a cell or tissue that expresses transferrin receptor).

[0002] In some embodiments, the human TfR binding proteins described herein comprise one or more engineered cysteine residues for conjugation. The approach of including engineered cysteines as a means for conjugation has been described in WO 2018 / 232088.-In some embodiments, the TBP comprises a cysteine at position 124 of the heavy chain.

[0003] In one aspect, the invention provides a TrkA RNAi agent of Formula (I): (R-L)n-D, wherein R is a dsRNA comprising a sense stand and an antisense strand described in any one embodiment; wherein L is a linker, or absent; and wherein D is a delivery moiety conjugated to the dsRNA, and wherein n=l, 2, or 3. In some embodiments of the TrkA RNAi agent of Formula (I), n=l. In some embodiments of the TrkA RNAi agent of Formula (I), D is DRG delivery moiety.

[0080] In some embodiments of the TrkA RNAi agent of Formula (I), the dsRNA comprises a sense strand and an antisense strand for example as described in e.g. Table 1 A, Table IB, Table 1C, Table 2 A and Table 2B.

[0081] In some embodiments, the anti-TfR antibody or antigen binding fragment thereof (TBP) comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR comprises heavy chain complementarity determining regions (HCDR) HCDR1, HCDR2, and HCDR3, and the LCVR comprises light chain complementarity determining regions (LCDR) LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 803, HCDR2 comprises SEQ ID NO: 804, HCDR3 comprises SEQ ID NO: 805, LCDR1 comprises SEQ ID NO: 806, LCDR2 comprises SEQ ID NO: 807, and LCDR3 comprises SEQ ID NO: 808.

[0082] In some embodiments, the TfR binding proteins of the present disclosure include a VH and a VL, and wherein VH comprises a sequence having at least 95% sequence identity to SEQ ID NO: 809 and VL comprises a sequence having at least 95% sequence identity to SEQID NO: 810. In some embodiments of the TBP, the HC comprises HCVR of SEQ ID NO: 809 and LC comprises LCVR of SEQ ID NO: 810. In some embodiments, the TBP comprises HC of SEQ ID NO: 811 and LC of SEQ ID NO: 812. In some embodiments, the TBP is an IgGl 124C Fab-albumin binding VHH (referred to as C3.08). Exemplary sequences of human TfR binding domains and proteins are shown in Table 4.

[0083] The TrkA RNAi agents of Formula (I) described herein can be made by a variety of procedures known to one of ordinary skill in the art, some of which are illustrated in the preparations and examples herein. One of ordinary skill in the art recognizes that the specific synthetic steps for each of the routes described may be combined in different ways, or in conjugation with steps from different schemes, to prepare conjugates. The product of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are readily available to one of ordinary skill in the art.

[0084] A delivery moiety D including any one of the TfR binding proteins described herein can be recombinantly produced in a host cell, for example, using an expression vector. For example, an expression vector may include a sequence that encodes one or more signal peptides that facilitate secretion of the polypeptide(s) from a host cell. Expression vectors containing a polynucleotide of interest encoding a delivery moiety D (e.g., a polynucleotide encoding a heavy chain or light chain of a delivery moiety D) may be transferred into a host cell by well- known methods. Additionally, expression vectors may contain one or more selection markers, e.g., tetracycline, neomycin, and dihydrofolate reductase, to aide in detection of host cells transformed with the desired polynucleotide sequences.

[0085] A host cell includes cells stably or transiently transfected, transformed, transduced or infected with one or more expression vectors expressing all or a portion of a delivery moiety D described herein. According to some embodiments, a host cell may be stably or transiently transfected, transformed, transduced or infected with an expression vector expressing HC polypeptides and / or an expression vector expressing LC polypeptides, an expression vector encoding a scFv of a delivery moiety D described herein. The TfR binding proteins may be produced in mammalian cells such as CHO, NS0, HEK293 or COS cells, or any other suitable expression system according to techniques well known in the art.

[0086] Assignment of amino acid residues to the CDRs may be done according to the well- known schemes, including those described in Kabat (Kabat et al., “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (1991)), Chothia(Chothia et al., “Canonical structures for the hypervariable regions of immunoglobulins", Journal of Molecular Biology, 196, 901-917 (1987); Al-Lazikani et al., “Standard conformations for the canonical structures of immunoglobulins”, Journal of Molecular Biology, 273, 927-948 (1997)), North (North et al., “A New Clustering of Antibody CDR Loop Conformations”, Journal of Molecular Biology, 406, 228-256 (2011)), or IMGT (the international ImMunoGeneTics database available at IMGT webpage; see Lefranc et al., Nucleic Acids Res. 1999; 27:209-212).

[0087] Medium, into which a delivery moiety D, e.g. a TfR binding protein, has been secreted, may be purified by conventional techniques, such as mixed-mode methods of ion-exchange and hydrophobic interaction chromatography. For example, the medium may be applied to and eluted from a Protein A or G column using conventional methods; mixed-ode methods of ion exchange and hydrophobic interaction chromatography may also be used. Soluble aggregate and multimers may be effectively removed by common techniques, including size exclusion, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. Various methods of protein purification may be employed, and such methods are known in the art and described, for example, in Deutscher, Methods in Enzymology 182: 83-89 (1990) and Scopes, Protein Purification: Principles and Practice, 3rdEdition, Springer, NY (1994).Linkers

[0088] In some embodiments, the dsRNA is linked to the delivery moiety D through a linker. In some embodiments, the linker is a Mal-Tet-TCO linker, SMCC linker, or GDM linker (structures of these linkers shown in Table 3).

[0089] In some embodiments, the dsRNA is linked to the human TfR binding protein through a linker. In some embodiments, the linker is a Mal-Tet-TCO linker, a SMCC linker, a MSPT, an OD or a GDM linker (structures of these linkers shown in Table 3).Pharmaceutical Compositions

[0090] In certain aspects the present disclosure provides a pharmaceutical composition comprising any one of the TrkA RNAi agents or a conjugate comprising any one of the TrkA RNAi agents of the present disclosure and a pharmaceutical earner.Methods of Treatment and Therapeutic Use

[0091] In certain aspects the present disclosure provides a method of treating a disease or disorder that benefits from reduction of TrkA (NTRK1) mRNA and / or protein level, comprising administering to an individual in need of such treatment an amount of a TrkA RNAiagent or a conjugate comprising a TrkA RNAi agent in an amount sufficient to effect such reduction of TrkA (NTRK1) mRNA and / or protein level. In non-limiting embodiments the amount administered is a therapeutically effective amount.

[0092] In certain aspects the present disclosure provides a method of treating a disease or disorder that benefits from reduction of TrkA (NTRK1) mRNA and / or protein level, comprising administering to an individual in need of such treatment an amount of a TrkA RNAi agent or a conjugate comprising a TrkA RNAi agent in an amount sufficient to effect such reduction of TrkA (NTRK1) mRNA and / or protein level, wherein the disease or disorder is pain, including without limitation chronic pain, that may present with different levels of severity, and is associated with a variety of pathologies, such as back injury or degenerative disk disease, migraine headaches, arthritis, diabetic neuropathy, cancer, and pain associated with other diseases.

[0093] The amount may be adjusted to a dosage to provide the optimum desired response(e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. The dosage may vary with the type and severity of the condition to be alleviated. It is further understood that for any particular subject, specific dosage should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[0094] Pharmaceutical compositions comprising the RNAi agents of the invention are delivered via any suitable route of administering. Non-limiting embodiments of routes of administering a pharmaceutical composition are readily optimized by a skilled person in the art, and include without limitation intravenous, subcutaneous, intrathecal or epidural delivery.

[0095] Nucleotide sequence of the human NTRK1 gene NM_002529.4 (SEQ ID NO: 1). ggaggcctgg cagctgcagc tgggagcgca cagacggctg ccccgcctga gcgaggcggg cgccgccgcg atgctgcgag gcggacggcg cgggcagctt ggctggcaca gctgggctgc ggggccgggc agcctgctgg cttggctgat actggcatct gcgggcgccg caccctgccc cgatgcctgc tgcccccacg gctcctcggg actgcgatgc acccgggatg gggccctgga tagcctccac cacctgcccg gcgcagagaa cctgactgag ctctacatcg agaaccagca gcatctgcag catctggagc tccgtgatct gaggggcctg ggggagctga gaaacctcac catcgtgaag agtggtctcc gtttcgtggc gccagatgcc ttccatttca ctcctcggct cagtcgcctg aatctctcct tcaacgctct ggagtctctc tcctggaaaa ctgtgcaggg cctctcctta caggaactgg tcctgtcggg gaaccctctg cactgttctt gtgccctgcg ctggctacag cgctgggagg aggagggact gggcggagtg cctgaacaga agctgcagtg tcatgggcaa gggcccctgg cccacatgcc caatgccagc tgtggtgtgcccacgctgaa ggtccaggtg cccaatgcct cggtggatgt gggggacgac gtgctgctgc ggtgccaggt ggaggggcgg ggcctggagc aggccggctg gatcctcaca gagctggagc agtcagccac ggtgatgaaa tctgggggtc tgccatccct ggggctgacc ctggccaatg tcaccagtga cctcaacagg aagaacgtga cgtgctgggc agagaacgat gtgggccggg cagaggtctc tgttcaggtc aacgtctcct tcccggccag tgtgcagctg cacacggcgg tggagatgca ccactggtgc atccccttct ctgtggatgg gcagccggca ccgtctctgc gctggctctt caatggctcc gtgctcaatg agaccagctt catcttcact gagttcctgg agccggcagc caatgagacc gtgcggcacg ggtgtctgcg cctcaaccag cccacccacg tcaacaacgg caactacacg ctgctggctg ccaacccctt cggccaggcc tccgcctcca tcatggctgc cttcatggac aaccctttcg agttcaaccc cgaggacccc atccctgtct ccttctcgcc ggtggacact aacagcacat ctggagaccc ggtggagaag aaggacgaaa caccttttgg ggtctcggtg gctgtgggcc tggccgtctt tgcctgcctc ttcctttcta cgctgctcct tgtgctcaac aaatgtggac ggagaaacaa gtttgggatc aaccgcccgg ctgtgctggc tccagaggat gggctggcca tgtccctgca tttcatgaca ttgggtggca gctccctgtc ccccaccgag ggcaaaggct ctgggctcca aggccacatc atcgagaacc cacaatactt cagtgatgcc tgtgttcacc acatcaagcg ccgggacatc gtgctcaagt gggagctggg ggagggcgcc tttgggaagg tcttccttgc tgagtgccac aacctcctgc ctgagcagga caagatgctg gtggctgtca aggcactgaa ggaggcgtcc gagagtgctc ggcaggactt ccagcgtgag gctgagctgc tcaccatgct gcagcaccag cacatcgtgc gcttcttcgg cgtctgcacc gagggccgcc ccctgctcat ggtctttgag tatatgcggc acggggacct caaccgcttc ctccgatccc atggacctga tgccaagctg ctggctggtg gggaggatgt ggctccaggc cccctgggtc tggggcagct gctggccgtg gctagccagg tcgctgcggg gatggtgtac ctggcgggtc tgcattttgt gcaccgggac ctggccacac gcaactgtct agtgggccag ggactggtgg tcaagattgg tgattttggc atgagcaggg atatctacag caccgactat taccgtgtgg gaggccgcac catgctgccc attcgctgga tgccgcccga gagcatcctg taccgtaagt tcaccaccga gagcgacgtg tggagcttcg gcgtggtgct ctgggagatc ttcacctacg gcaagcagcc ctggtaccag ctctccaaca cggaggcaat cgactgcatc acgcagggac gtgagttgga gcggccacgt gcctgcccac cagaggtcta cgccatcatg cggggctgct ggcagcggga gccccagcaa cgccacagca tcaaggatgt gcacgcccgg ctgcaagccc tggcccaggc acctcctgtc tacctggatg tcctgggcta gggggccggc ccaggggctg ggagtggtta gccggaatac tggggcctgc cctcagcatc ccccatagct cccagcagcc ccagggtgat ctcaaagtat ctaattcacc ctcagcatgt gggaagggac aggtgggggc tgggagtaga ggatgttcct gcttctctag gcaaggtccc gtcatagcaa ttatatttat tatcccttgTable 1A. Sense and antisense strand 18mers.Table IB. Exemplary unmodified sense and antisense strands of TrkA RNAi agents.Table 1C. Exemplary unmodified sense and antisense strands with sequence length modificationsTable 2A. Exemplary modified sense and antisense strands of TrkA RNAi agents.Abbreviations - “P” indicates 5’ phosphate; “VP” indicates vinyl phosphate; “m” indicates 2’-OMe; “f” indicated 2'-fluoro; indicates phosphorothioate linkage; “PrON” indicates racemic 2-propyl-o- uridine; “rPron” indicates PrON with R stereocenter in the intemucleotide linkage; “sPron” indicates PrON with S stereocenter in the internucleotide linkage; “e” indicates 2 '-methoxy ethyl; “[iAb]” indicates inverted abasic; “d” indicates 2’-deoxy; “UNA” indicates unlocked nucleic acid; “rsbd” indicates R,S- butadiol; “ssbd” indicates S,S-butadiol; “sg” indicates GNA; “hmp” indicates propanediol; “s” means the sense strand; “as” means the antisense strand.Table 2B. Exemplary modified sense and antisense strands of TrkA RNAi agents.Abbreviations - “P” indicates 5’ phosphate; “VP” indicates vinyl phosphate; “m” indicates 2’-OMe; “f” indicated 2’-fluoro; indicates phosphorothioate linkage; “PrON” indicates racemic 2-propyl-o- uridine; “rPron” indicates PrON with R stereocenter in the intemucleotide linkage; “sPron” indicates PrON with S stereocenter in the internucleotide linkage; “e” indicates 2'-methoxyethyl; “[iAb]” indicates inverted abasic; “d” indicates 2’-deoxy; “UNA” indicates unlocked nucleic acid; “rsbd” indicates R,S-butanediol; “ssbd” indicates S,S-butanediol; “sg” indicates GNA; “limp” indicates propanediol; “s” means the sense strand; “as” means the antisense strand.

[0096] Non-limiting embodiments of delivery agents (D):

[0097] TfR 0X26 Ab: HC (SEQ ID NO: 120)QVQLQQPGAALVRPGASMRLSCKASGYSFTTYWMNWVKQRPGQGLELIGMIHPSDSEVRLNQKFKDKATLTVDTSSSTAYMQLNSPTSEDSAVYYCARFGLDYWGQGTTLTVSSASTKGPCVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0098] TfR 0X26 Ab: LC (SEQ ID NO: 121)DIVITQSPSSLSASLGDTILITCHASQNINVWLSWFQQKPGNAPKLLIYKASNLHTGVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQGQSYPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0099] Exemplary L1CAM binding protein sequences are as follows:

[0100] L1CAM Ab: HC (SEQ ID NO: 122)

[0101] EVQLVESGGGVVQPGRSLRLSCAASGFTFSRFGMHWVRQAPGKGLEWVAFISNDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCARGRAYGSGSLFDPWGQGTLVTVSSASTKGPCVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFLLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[0102] L1CAM Ab: LC (SEQ ID NO: 123)

[0103] DIQMTQSPSSLSASVGDRVTITCKASQGISRFLSWFQQKPGKAPKSLIYAVSSLV DGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCVQYNSYPYGFGGGTKVEIKRTVAAPS VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0104] L1CAM Ab: HCVR (SEQ ID NO: 124)

[0105] EVQLVESGGGVVQPGRSLRLSCAASGFTFSRFGMHWVRQAPGKGLEWVAFISN DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCARGRAYGSGSLFDP WGQGTLVTVSS

[0106] L1CAM Ab: LCVR (SEQ ID NO: 125)

[0107] DIQMTQSPSSLSASVGDRVTITCKASQGISRFLSWFQQKPGKAPKSLIYAVSSLV DGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCVQYNSYPYGFGGGTKVEIKTable 3. Linkers for conjugating the dsRNAs to the delivery moiety D.

[0108] In one embodiment, the dsRNA is conjugated to a delivery moiety D via linker 1. In one embodiment, the dsRNA is conjugated to a delivery moiety D via linker 2. In one embodiment, the dsRNA is conjugated to a delivery moiety D via linker 3. In one embodiment, the dsRNA is conjugated to a delivery moiety D via linker 4. In one embodiment, the dsRNA is conjugated to a delivery moiety D via linker 5. In one embodiment, the dsRNA is conjugated to a delivery moiety D via linker 6. In one embodiment, the dsRNA is conjugated to a delivery moiety D via linker 7. In this table, each linker is shown as conjugated to a TBP, which TBP is one nonlimited embodiment of a delivery moiety D. In structures in this table “X” is O or S.Table 4. Exemplary sequences of human TfR binding domains and proteins.Definitions

[0109] As used herein, the terms “a,” “an,” “the,” and similar terms used in the context of the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

[0110] The term “antigen binding domain”, as used herein, refers to a portion of an antibody or antibody fragment that binds an antigen or an epitope of the antigen.

[0111] “Antibody,” as used herein, refers to a molecule that binds an antigen. Embodiments of an antibody include a monoclonal antibody, polyclonal antibody, human antibody, humanized antibody, chimeric antibody, heterodimeric antibody, bispecific or multispecific antibody, monovalent antibody, bivalent antibody, or conjugated antibody. The antibodies can be of any class (e.g., IgG, IgE, IgM, IgD, IgA), and any subclass (e.g., IgGl, IgG2, IgG3, IgG4).

[0112] An immunoglobulin G (IgG) type antibody comprised of four polypeptide chains: two heavy chains (HC) and two light chains (LC) that are cross-linked via inter-chain disulfide bonds. The amino-terminal portion of each of the four polypeptide chains includes a variable region of about 100-125 or more amino acids primarily responsible for antigen recognition. The carboxyl-terminal portion of each of the four polypeptide chains contains a constant region primarily responsible for effector function. Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region. Each light chain is comprised of a lightchain variable region (VL) and a light chain constant region. The IgG isotype may be further divided into subclasses (e.g., IgGl, IgG2, IgG3, and IgG4).

[0113] The VH and VL regions can be further subdivided into regions of hyper-variability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). The CDRs are exposed on the surface of the protein and are important regions of the antibody for antigen binding specificity. Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxylterminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Herein, the three CDRs of the heavy chain are referred to as “HCDR1, HCDR2, and HCDR3” and the three CDRs of the light chain are referred to as “LCDR1, LCDR2 and LCDR3”. The CDRs contain most of the residues that form specific interactions with the antigen. Assignment of amino acid residues to the CDRs may be done according to the well-known schemes, including those described in Kabat (Kabat et al., “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (1991)), Chothia (Chothia et al., “Canonical structures for the hypervariable regions of immunoglobulins”, Journal of Molecular Biology, 196, 901-917 (1987); ALLazikani et al., “Standard conformations for the canonical structures of immunoglobulins”, Journal of Molecular Biology, 273, 927-948 (1997)), North (North et al., “A New Clustering of Antibody CDR Loop Conformations”, Journal of Molecular Biology, 406, 228-256 (2011)), or IMGT (the international ImMunoGeneTics database available on at www.imgt.org; see Lefranc et al., Nucleic Acids Res. 1999; 27:209-212).

[0114] Embodiments of the present disclosure also include antibody fragments or antigenbinding fragments that, as used herein, comprise at least a portion of an antibody retaining the ability to specifically interact with an antigen or an epitope of the antigen, such as Fab, Fab’, F(ab’)2, Fv, scFv, scFab, disulfide -linked Fvs (sdFv), or Fd.

[0115] As used herein, “antisense strand” means a single-stranded oligonucleotide that is complementary to a region of a target sequence. Likewise, and as used herein, “sense strand” means a single-stranded oligonucleotide that is complementary to a region of an antisense strand.

[0116] The terms “bind” and “binds” as used herein are intended to mean, unless indicated otherwise, the ability of a protein or molecule to form a chemical bond or attractive interaction with another protein or molecule, which results in proximity of the two proteins or molecules as determined by common methods known in the art.

[0117] As used herein, “complementary” means a structural relationship between two nucleotides (e.g., on two opposing nucleic acids or on opposing regions of a single nucleic acid strand, e.g., a hairpin) that permits the two nucleotides to form base pairs with one another. For example, a purine nucleotide of one nucleic acid that is complementary to a pyrimidine nucleotide of an opposing nucleic acid may base pair together by forming hydrogen bonds with one another. Complementary nucleotides can base pair in the Watson-Crick manner or in any other manner that allows for the formation of stable duplexes. Likewise, two nucleic acids may have regions of multiple nucleotides that are complementary with each other to form regions of complementarity, as described herein.

[0118] An “effective amount” refers to an amount necessary (for periods of time and for the means of administration) to achieve the desired therapeutic result. An effective amount of a protein or conjugate may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the protein or conjugate to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the protein or conjugate are outweighed by the therapeutically beneficial effects. A “therapeutically effective amount” is an amount of a pharmaceutical composition that is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired treatment regimen.

[0119] As referred to herein, the term “epitope” refers to the amino acid residues, of an antigen, that are bound by an antibody, an antibody fragment or an antigen binding polypeptide or antibody. An epitope can be a linear epitope, a conformational epitope, or a hybrid epitope. The term “epitope” may be used in reference to a structural epitope. A structural epitope, according to some embodiments, may be used to describe the region of an antigen which is covered by an antibody or antigen binding protein. In some embodiments, a structural epitope may describe the amino acid residues of the antigen that are within a specified proximity (e.g., within a specified number of Angstroms) of an amino acid residue of the antibody or antigen binding protein. The term “epitope” may also be used in reference to a functional epitope. A functional epitope, according to some embodiments, may be used to describe amino acid residues of the antigen that interact with amino acid residues of the antibody or antigen binding protein in a manner contributing to the binding energy between the antigen and the antibody or antigen binding protein.

[0120] An epitope can be determined according to different experimental techniques, also called “epitope mapping techniques.” It is understood that the determination of an epitope mayvary based on the different epitope mapping techniques used and may also vary with the different experimental conditions used, e.g., due to the conformational changes or cleavages of the antigen induced by specific experimental conditions. Epitope mapping techniques are known in the art (e.g., Rockberg and Nilvebrant, Epitope Mapping Protocols: Methods in Molecular Biology, Humana Press, 3rded. 2018), including but not limited to, X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, site-directed mutagenesis, species swap mutagenesis, alanine-scanning mutagenesis, hydrogen-deuterium exchange (HDX) and cross-blocking assays.

[0121] The term “Fc region” as used herein refers to a polypeptide comprising the CH2 and CH3 domains of a constant region of an immunoglobulin, e.g., IgGl, IgG2, IgG3, or IgG4. Optionally, the Fc region may include a portion of the hinge region or the entire hinge region of an immunoglobulin, e.g., IgGl, IgG2, IgG3, or IgG4. In some embodiments, the Fc region is a human IgG Fc region, e.g., a human IgGl Fc region, human IgG2 Fc region, human IgG3 Fc region or human IgG4 Fc region. In some embodiments, the Fc region is a modified IgG Fc region with reduced or eliminated effector functions compared to the corresponding wild type IgG Fc region. The numbering of the residues in the Fc region is based on the EU index as described in Kabat (Kabat et al, Sequences of Proteins of Immunological Interest, 5th edition, Bethesda, MD: U.S. Dept, of Health and Human Services, Public Health Service, National Institutes of Health, 1991). The boundaries of the Fc region of an immunoglobulin heavy chain might vary, and the human IgG heavy chain Fc region is usually defined as the stretch from the N-terminus of the CH2 domain (e.g., the amino acid residue at position 231 according to the EU index numbering) to the C-terminus of the CH3 domain (or the C-terminus of the immunoglobulin) .

[0122] As used herein, “modified internucleotide linkage” means an intemucleotide linkage having one or more chemical modifications when compared with a reference internucleotide linkage having a phosphodiester bond. A modified internucleotide linkage can be a non- naturally occurring linkage. In some embodiments, the modified intemucleotide linkage is phosphorothioate linkage.

[0123] As used herein, “modified nucleotide” refers to a nucleotide having one or more chemical modifications when compared with a corresponding reference nucleotide selected from: adenine ribonucleotide, guanine ribonucleotide, cytosine ribonucleotide, uracil ribonucleotide, adenine deoxyribonucleotide, guanine deoxyribonucleotide, cytosine deoxyribonucleotide, and thymidine deoxyribonucleotide. A modified nucleotide can have, forexample, one or more chemical modification in its sugar, nucleobase, and / or phosphate group. Additionally, or alternatively, a modified nucleotide can have one or more chemical moieties conjugated to a corresponding reference nucleotide. In some embodiments, the modified nucleotide is a 2'-fluoro modified nucleotide, 2'-O-methyl modified nucleotide, or 2'-O-alkyl modified nucleotide. In some embodiments, the modified nucleotide has a phosphate analog. As used herein, “phosphate analog” means a chemical moiety that mimics the electrostatic and / or steric properties of a phosphate group. In some embodiments, a phosphate analog is positioned at the 5’ terminal nucleotide of an oligonucleotide in place of a 5’-phosphate, which is often susceptible to enzymatic removal. A 5’ phosphate analog can include a phosphatase- resistant linkage. Examples of phosphate analogs include 5’ methylene phosphonate (5 ’-MP) and 5’-(E)-vinylphosphonate (5’-VP). In some embodiments, the phosphate analog is 5’-VP. In some embodiments, the modified nucleotide has an abasic moiety or inverted abasic moiety.

[0124] The term “% sequence identity” or “percentage sequence identity” with respect to a reference nucleic acid sequence is defined as the percentage of nucleotides, nucleosides, or nucleobases in a candidate sequence that are identical with the nucleotides, nucleosides, or nucleobases in the reference nucleic acid sequence, after optimally aligning the sequences and introducing gaps or overhangs, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software programs, for example, those described in Current Protocols in Molecular Biology (Ausubel etaL, eds., 1987, Supp. 30, section 7.7.18, Table 7.7.1), and including BLAST, BLAST-2, ALIGN, Megahgn (DNASTAR), Clustal W2.0 or Clustal X2.0 software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Percentage of “sequence identity” can be determined by comparing two optimally aligned sequences over a comparison window, where the fragment of the nucleic acid sequence in the comparison window may comprise additions or deletions (e.g., gaps or overhangs) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage can be calculated by determining the number of positions at which the identical nucleotide, nucleoside, or nucleobase occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison,and multiplying the result by 100 to yield the percentage of sequence identity. The output is the percent identity of the subject sequence with respect to the query sequence.

[0125] The term “polypeptide” or “protein”, as used herein, refers to a polymer of amino acid residues. The term applies to polymers comprising naturally occurring amino acids and polymers comprising one or more non-naturally occurring amino acids. A polypeptide which extends the half-life of another polypeptide, e.g. without limitation the half-life of a TfR- binding antibody, antibody fragment or a TfR binding VHH polypeptide, is a “half-life extender.”

[0126] The term “TrkA” refers to tropomyosin receptor kinase A, also known as high affinity growth factor receptor, neurotropic tyrosine kinase receptor type 1, or TRK1 -transforming tyrosine kinase protein, and is encoded by the neurotrophic tyrosine kinase receptor 1 (NIKKI) gene. The nucleotide sequence of human NTRK1, transcript variant 2, can be found at NM_002529.4, and the protein sequence of human TrkA can be found at NP_002520.2. The TrkA RNAi agents disclosed herein may attenuate, inhibit, modulate, or reduce NTRK1 mRNA and / or TrkA protein expression in a cell.

[0127] In the context of the present disclosure, the term TfR is used to designate the TfRl homologue.

[0128] The following examples are offered to illustrate, but not to limit, the claimed present disclosures.ExamplesExample 1: TrkA dsRNA design and synthesis

[0129] Target sequences were identified in the NTRK1 nucleotide sequence of SEQ ID NO: 1. See Table 1A. In the RNA transcript corresponding to SEQ ID NO: 1, the T nucleotides are replaced by U nucleotides. The dsRNA comprises an antisense strand which forms a double stranded region with the sense strand and where one or more nucleotides and one or more intemucleotide linkages are optionally further modified as described herein.

[0130] Single strands (sense and antisense) of the dsRNA duplexes were synthesized on solid support via a K&A H-8 SE (K&A Labs GMBH). The sense strands were synthesized using phthalamido amino C6 Icaa CPG 500 A (Chemgenes), Cholesterol 3’-lcaa CPG (Chemgenes) or standard support (LGC Biosearch Technologies) whereas the antisense strands used standard support (LGC Biosearch Technologies). The oligonucleotides were synthesized via phosphoramidite chemistry at an appropriate scale for in-vitro or in-vivo experimentation. Theoligonucleotides were synthesized via phosphoramidite chemistry at either 5, 10, or 20 pmol scales.

[0131] Standard reagents were used in the oligo synthesis, where 0.1M xanthane hydride in pyridine was used as the sulfurization reagent and 20% DEA in ACN was used as an auxiliary wash post synthesis. All monomers were made at 0.1M in ACN and contained a molecular sieves trap bag. When necessary, inclusion of 10% volume equivalents of DMF was utilized to maintain amidite solubility (i.e. mU amidite).

[0132] The oligonucleotides were cleaved and deprotected (C / D) at 40 °C for 20 hours. The sense strands were C / D from the CFG using cold 50% (methylamine / ammonia hydroxide 28- 30%) at RT for 3 hrs, whereas 3% DEA in ammonia hydroxide (28-30%, cold) at 40 °C for 20 hours was used for the antisense strands. C / D was determined complete by IP-RP LCMS when the resulting mass data confirmed the identity of sequence. Dependent on scale, the CPG was filtered via 0.45 um PVDF syringeless filter, 0.22 um PVDF Steriflip® vacuum filtration or 0.22 um PVDF Stericup® Quick release. The CPG was rinsed with either 30% EtOH / RNAse free water then filtered through the same filtering device and combined with the first filtrate. This was repeated twice. The material was then divided evenly into 50 mL falcon tubes to remove organics via Genevac™. After concentration, the crude oligonucleotides were diluted back to synthesized scale with RNAse free water and filtered either by 0.45 pm PVDF syringeless filter, 0.22 pm PVDF Steriflip® vacuum filtration or 0.22 pm PVDF Stericup® Quick release.

[0133] The crude oligonucleotides were purified via AKTA™ Pure purification system using anion-exchange (AEX) or reverse-phase (RP) chromatography utilizing a gradient of Mobile Phase A (MPA) to Mobile Phase B as appropriate for the product. For AEX, an ES Industry Source™ 15Q column with MPA: 20mM NaH2PO4, 15% ACN, pH 7.4 and MPB: 20 mM NaH2PO4, IM NaBr, 15% ACN, pH 7.4. For RP, an ES Industry Source™ 15RPC with MPA: lOmM NaOAc 2% Acetonitrile and MPB: 80% Acetonitrile in water. Fractions were analyzed by IP-RP LCMS and those which contained a mass purity greater than 85% without impurities >5% were combined.

[0134] The purified oligonucleotides were typically desalted using 15 mL 3K MWCO centrifugal spin tubes at 3500xg for ~30 min. The oligonucleotides were rinsed with RNAse free water until the eluent conductivity reached < 100 usemi / cm. After desalting was complete, 2-3 mL of RNAse free water was added then aspirated lOx, the retainment was transferred to an appropriately sized conical tube, this was repeated until complete transfer of oligo by measuringconcentration of compound on filter via nanodrop. The final oligonucleotide was then typically nano filtered via 15 mL 100K MWCO centrifugal spin tubes at 3500xg for 2 min. The final desalted oligonucleotides were analyzed for concentration (nanodrop at A260). The molecular weight of the product was confirmed by LC-MS analysis using a Linear Ion Trap Mass Spectrometer (LTQ XL, Thermo Fisher), and purity was confirmed by UPLC analysis.

[0135] Oligonucleotide UPLC analysis was typically conducted under Ion-Pairing Reversed- Phase Ultra Performance Liquid Chromatography (IP-RP UPLC) conditions using a Waters™ ACQUITY™ UPLC Oligonucleotide BEH C18 Column 2.1x50 mm, 1.7 pm column. The gradient used Mobile Phase A (MPA) of 7 mM triethylamine with 100 mM hexafluoroisopropanol, and a Mobile Phase B (MPB) of 7:3 Methanol to Acetonitrile. Oligonucleotides with low lipophilicity were typically analyzed over a gradient of 0 to 25% MPB over 10 minutes while oligonucleotides with high lipophilicity were analyzed over a gradient of 5 to 90% MPB over 10 minutes.Oligonucleotide Synthesis ReagentsPhosphorami di tesLinker-functionaliz.ation ofTrkA ssRNA

[0136] A 15 mL Falcon tube was charged with TrkA-C6Am sense strand (29.5 mg, 1.5 mL, 4.12 |amol) and sodium bicarbonate (20 equiv., 6.92 mg). A solution of 2,5-dioxopyrrolidin-l- yl 2-(2-(2-(4-(5-(methylsulfonyl)-lH-tetrazol-l-yl)phenoxy)ethoxy)ethoxy)acetate (23.88 mg, 49.4 pmol) in ACN (1 .5 mL) was then added. The mixture was vortexed for one minute, then shook at lOOOrpm at 25 °C and monitored by LTQ-MS until the starting oligonucleotide was fully consumed. The solution was then diluted to 15 mL using RNAse free water to bring ACN concentration to < 10%. The solution was filtered using 20 mL 3K MWCO centrifugal spin tubes at 3900 rpm for ~30 minutes. The oligonucleotide was rinsed with RNAse free water three times. The retentate was quantitatively transferred from the spin tube to a 15 mL Falcon tube by adding 1 mL of RNAse free water, vortexing, and transferring to the Falcon tube. This was repeated until complete transfer of oligo by measuring concentration of compound on filter via nanodrop. The final oligonucleotide was analyzed for concentration (nano drop at A260),characterized by IP-RP, LCMS for mass purity, and UPLC for UV-purity. The optical density measurement of the product solution (average of 2 measurements) was 202.8 OD / mL, 0.96 mM, 3 mL, 21.7 mg. ES / MS (m / z): 7544.1 (M+H).Formation of linker-TrkA duplex

[0137] The nanodrop concentrations of aqueous solutions of each strand (average of 3x) were measure as SS = 1176 pM and AS = 1033pM. The sense strand and antisense strand are annealed to form a dsRNA. 2.9 mL of SS and 3.3 mL of AS are mixed. To anneal the strands, the mixture was incubated at 65°C for 10 minutes using a thermomixer (Eppendorf thermomixer C), and then slowly cooled to 22 °C over 40 minutes. The duplexed product was then transferred to a 100,000MWL centrifugation filter tube (Millipore) and spun at 3900 rpm for ~ 15 minutes to remove any potential endotoxins. Following endotoxin removal, the concentrated duplex solution was then transferred to a cryogenic storage vial (Corning) of the appropriate volume. The final concentration was then determined using the NanoPhotometer with OD260 measurements. The molecular weight of the product was confirmed by LC-MS analysis using a Linear Ion Trap Mass Spectrometer (LTQ XL, Thermo Fisher Scientific) equipped with a Vanquish HPLC system (Thermo Fisher Scientific). ES / MS (m / z): 7151.6, 7813.5 (M+H).Linker-functionalization ofTrkA dsRNA

[0138] A 15 mL Falcon tube was charged with TrkA-C6Am duplex (166.2 mg, 5 mL, 11.1 umol) and sodium bicarbonate (20 equiv., 18.6 mg). A freshly prepared solution of (2,5- dioxopyrrolidin-l-yl) 4-[(2,5-dioxopyrrol-l-yl)methyl]cyclohexanecarboxylate (40.56 mg, 133.31 umol) in ACN (5 mL) was then added. The mixture was vortexed for one minute, then shook at lOOOrpm at 25 °C and monitored by LTQ-MS until the starting oligonucleotide was fully consumed. The solution was then acidified to pH~4 with 20-30 drops of 5N HC1 and diluted using RNAse free water to bring ACN concentration to < 10%. The solution was filtered using 20 mL 3K MWCO centrifugal spin tubes at 3900 rpm for ~30 minutes. The oligonucleotide was rinsed with RNAse free water three times. The retentate was quantitatively transferred from the spin tube to a 15 mL Falcon tube by adding 1 mL of RNAse free water, vortexing, and transferring to the Falcon tube. This was repeated until complete transfer of oligo by measuring concentration of compound on filter via nanodrop. The final oligonucleotide was analyzed for concentration (nano drop at A260), characterized by IP-RP,LCMS for mass purity, and UPLC for UV-purity. The product was quickly frozen at -20 °C or below to prevent maleimide hydrolysis. The optical density measurement of the product solution (average of 2 measurements) was 144.4 OD / mL, 0.382 mM, 25 mF, 145 mg. ES / MS (m / z): 7370.6, 7813.5 (M+H).Example 2A: In vitro KD of human TrkA in SK-N-SH cells by TrkA RNAi agent comprising teg-cholesterol conjugated dsRNA by free delivery

[0139] A library of ChTeg siRNA molecules spanning the coding sequence (CDS) of NTRK1 was screened in a neuroblastoma cell line. Briefly, SK-N-SH cells (ATCC, #HTB-11, #CRL- 2273) were plated in a 96 well plate at a density of 5K cells / well in EMEM (ATCC, #30-2003) supplemented with 10% FBS (Corning, #1000052-147) and 1% pen-strep (Thermo Fisher, #15140-122). After a 24-hour incubation at 37 °C, TrkA (NTRK1) siRNA was free delivered to cells at a single concentration of 500 nM in Accell media (Horizon, B-005000-000). After a 72- hour incubation, cells were taken down by Cell to CT™ (Thermo Fisher, #4391851C) to collect total RNA. cDNA was then generated using fast advance RT reagents (Thermo Fisher, #A39110) for qPCR. Fast advance Taqman™ mastermix reagents (Thermo Fisher, #4444552F3) were used to quantify expression of NTRK1 (ThermoFisher, #hs01021012_ml, #hs010210! l_m l and #hs01021015_ml) against GAPDH as a calibrator gene (Thermo Fisher, hs99999905_ml) in a QS7 instrument. Relative expression of siRNA KD was normalized to non-treated media conditions and ranked by KD to select molecules for a subsequent CRC screen.

[0140] Selected molecules were tested in the same culture conditions for a CRC screen with an 8-point curve at a range of concentrations (1000, 200, 40, 8, 1.6, 0.32, 0.064, and 0.0128nM). Following the same RNA isolation and cDNA generation protocols, NTRK1 expression was quantified in a QS7 to calculate KD and IC50 in Graphpad PRISM by a 3 -point parameter curve fit. These data were then used to select hits based on performance parameters and transcript loci. IC50 data for the selected sequence hits is presented in Table 5A.Table 5A. Summary of IC50 (nM) mRNA KD for RNAi agents conjugated to teg-cholesterol in SK-N-SH cells.Example 2B: In vitro KD of human TrkA in SK-N-SH cells by transfection of TrkA RNAi agent comprising unconjugated dsRNA

[0141] A library of unconjugated siRNA molecules spanning the coding sequence (CDS) of NTRK1 was screened in a neuroblastoma cell line, SK-N-SH. Cells (ATCC, #HTB-11, #CRL- 2273) were plated in a 96 well plate at a density of 10K cells / well in EMEM (ATCC, #30-2003) supplemented with 10% FBS (Coming, #1000052-147) and 1 % pen-strep (ThermoFisher, #15140-122). After a 24-hour incubation at 37°C, 5% CO2, and 90% RH, TrkA (NTRK1) siRNA was forward transfected by RNAi Max (ThermoFisher, #13778075) at 8 concentrations spanning 50, 25, 5, 1, 0.2, 0.04, 0.004, and 0.0004nM. RNA was collected by Cell to CT™ (ThermoFisher, #4391851C) after 48-hr, followed by cDNA generation with fast advance RT reagents (ThermoFisher, #A39110). NTRK1 gene expression was quantified (ThermoFisher, #hs01021012_ml, #hs01021011_ml and #hs01021015_ml) by qPCR using Fast advance Taqman™ (ThermoFisher, #4444552F3) normalized to GAPDH (ThermoFisher, hs99999905_ml) on a QS7. IC50 was calculated in Graphpad PRISM by a 3-point parameter curve fit.Table 5B. Summary of IC50 (nM) mRNA KD and max KD (%) for unconjugated RNAi agents in SK-N-SH cells.Example 2C: Single Point In vitro KD of human TrkA in SK-N-SH cells by transfection of TrkA RNAi agent comprising unconjugated dsRNA

[0142] A library of unconjugated siRNA molecules spanning the coding sequence (CDS) of NTRK1 was screened in a neuroblastoma cell line, SK-N-SH. Cells (ATCC, #HTB-11, #CRL- 2273) were plated in a 96 well plate at a density of 10K cells / well in EMEM (ATCC, #30-2003) supplemented with 10% FBS (Coming, #1000052-147) and 1% pen-strep (ThermoFisher, #15140-122). After a 24-hour incubation at 37°C, 5% CO2, and 90% RH, TrkA (NTRK1) siRNA was forward transfected by RNAi Max (ThermoFisher, #13778075) at 2 concentrations1, and 0.1 nM. RNA was collected by Cell to CT™ (ThermoFisher, #4391851C) after 48-hr, followed by cDNA generation with fast advance RT reagents (ThermoFisher, #A39110). NTRK1 gene expression was quantified (ThermoFisher, #hs0102101 l_ml and #hs01021015_ml) by qPCR using Fast advance Taqman™ (ThermoFisher, #4444552F3) normalized to GAPDH (ThermoFisher, hs99999905_ml) on a QS7.Table 6. Summary of % mRNA remaining (1 nM) for unconjugated RNAi agents in SK-N-SH cells.Example 3: TrkA dsRNA Conjugation to a Delivery moiety (D)Expression and Purification:

[0143] The exemplified Delivery moiety D is an anti-TfR antibody 0x26 which was expressed and purified essentially as follows. Antibody 0x26 is expressed in an appropriate host cell, such CHO, either transiently or stably transfected with an expression system for secreting antibody using an optimal predetermined HC:LC vector ratio. The expression plasmids contains cDNA versions of the LC and HC genes for Antibody 0X26 (for example, a DNA sequence encoding a HC amino sequence of SEQ ID NO: 120 of exemplified Antibody 0x26, and a DNA sequence encoding a LC amino acid sequence of SEQ ID NO: 121); and are expressed from a commonly-used and suitable construct for this purpose, such as one based on human cytomegalovirus major immediate early promoters.

[0144] Medium, into which an antibody has been secreted, may be purified by conventional techniques, such as mixed-mode methods of ion-exchange and hydrophobic interaction chromatography. For example, the medium containing Antibody 0x26 may be applied to and eluted from a Protein A column (Cytiva) using conventional methods. Soluble aggregate, multimers, and fragments may be effectively removed by cation exchange chromatography using a POROS HS 50 column (Thermo Fisher Scientific) using conventional methods. The product may be immediately frozen, for example at -70°C, refrigerated, or may be lyophilized. Various methods of protein purification may be employed, and such methods are known in the art and described, for example, in 30 Deutscher, Methods in Enzymology 182: 83-89 (1990) and Scopes, Protein Purification: Principles and Practice, 3rd Edition, Springer, NY (1994). Antibody 0x26 may be immediately frozen at -70°C or stored at 2-8°C for several months, or may be lyophilized, or preserved in 4 °C for immediate use.

[0145] Site-specific engineered cysteine amino acid residues in the molecule were used to conjugate dsRNA. Cysteines can be engineered into the primary amino acid sequence of the TfR binding proteins. In one embodiment, Ser 124 Cys in EU numbering is the conjugation site.

[0146] The approach of introducing cysteines as a means for conjugation has been described in WO 2018 / 232088, which is both incorporated by reference in its entirety and incorporated specifically in relation to conjugation via cysteine residues. The Antibody 0x26 is first reduced with, for example, 10 molar equivalents reducing agent tris(2-carboxyethyl)phosphine (TCEP) at 37°C for one hour, followed by buffer exchange by, for example, a PD-10 desalting column (Cytiva) to remove reduction reagent. This is followed by re-oxidation of the Antibody 0x26 to reform the interchain disulfides with 20 molar equivalent dehydroascorbic acid (DHAA) incubation at room temperature for two hours. Buffer exchange was performed again to remove oxidizing agent.

[0147] Conjugation of dsRNA onto Antibody 0x26 was done using the SMCC-functionalized dsRNA. The prepared Antibody 0x26 was incubated with 0.5- 1.0 molar equivalents of the SMCC-dsRNA for conjugation for approximately 1 hour at room temperature.

[0148] Conjugation of dsRNA onto Antibody 0x26 was done using the tetrazole-functionalized dsRNA (MSPT linker). The prepared Antibody 0x26 was incubated with 0.5-1.0 molar equivalents of the tetrazole-dsRNA for conjugation for approximately 1 hour at 37C temperature.

[0001] Post conjugation of dsRNA to the TfR binding protein, the conjugated species was isolated by preparative AEX. Anion exchange, e.g., POROS™ XQ (ThermoFisher Scientific), was used with Buffer A: 20mM Tris pH 7, Buffer B: 20mM Tris pH 7 + IM NaCl. Separation was achieved with a 20 column volume gradient from 15-50% buffer B resulting in >95% purity of the conjugated species. The material was characterized for purity using analytical SEC and AEX chromatography.Example 4: In vivo rat model data: TrkA RNAi agent comprising dsRNA conjugated to a TfR binding Delivery moiety

[0149] The sense strand of dsRNA NO: 51 was conjugated via the SMCC linker to Cysl24 of the bivalent (BV) TfR binding antibody 0x26 essentially as described in Example 3. dsRNA NO: 51 TfR conjugate is rat cross-reactive and was tested in female Sprague Dawley rats (~200gm, Envigo). Rats (n=10 / group) were dosed IV with PBS or test articles, at a dose of 2mg / kg siRNA conjugated to 0x26 (TfR antibody shuttle). Fourteen days post IV injection, the animals were euthanized, blood was collected into K2EDTA BD Microtainer tubes (Becton Dickinson) for plasma isolation. Various tissues including lumbar DRGs were collected fromthe rats and frozen on dry ice and stored at -80C until processed for total TrkA protein and NTRK1 mRNA. Data are shown in Table 7A.

[0150] Human reactive sequences dsRNA NOs: 32, 33, 28, 30, 31 and 29 were tested in female humanized TrkA rats (custom line, Taconic). The sense strand of dsRNA NO: 32, 33, 28, 30, 31 and 29 was conjugated via the MSPT linker to Cysl24 of the bivalent (BV) TfR binding antibody 0x26 essentially as described in Example 3. Rats (n=8 / group) were dosed IV with PBS or test articles, at a dose of Img / kg siRNA conjugated to 0x26 (TfR antibody shuttle). Fourteen days post IV injection, the animals were euthanized, blood was collected into K2EDTA BD Microtainer tubes (Becton Dickinson) for plasma isolation. Various tissues including lumbar DRGs were collected from the rats and frozen on dry ice and stored at -80C until processed for total TrkA protein and NTRK1 mRNA. Data are shown in Table 7B.

[0151] For TrkA protein analysis, tissues were homogenized using a TissueLyser 2.0 in Cell lysis buffer (Cell Signaling) containing 2x Halt Protease and Phosphatase Inhibitor (ThermoFisher) and lx PMSF (Millipore Sigma). Total TrkA protein content was assessed using a custom MSD Assay (Meso Scale Discovery). Global protein content was assessed using the BCA method (ThermoFisher). Total TrkA protein was normalized by dividing by the global protein content per sample (Total TrkA / total protein, pg / ug).

[0152] For mRNA KD analysis: total RNA was extracted using Triazol and PurLink RNA miniprep Kit with the addition of Purelink DNAse I on column treatment according to the manufacturers protocol (ThermoFisher) and quantified on a NanoDrop (ThermoFisher). Equal amounts of RNA were reverse transcribed to cDNA using High-Capacity cDNA Reverse Transcription kit (ThermoFisher) on Mastercycler X50a (Eppendorf). Template cDNA was combined with Taqman Universal Master Mix and Assays on Demand primer / probe sets and RT-PCR is performed on the QuantStudio 7 Flex (ThermoFisher) A relative amount was calculated as follows: the CT value of rat Hprtl was subtracted from CT value of rat Ntrkl to obtain the delta CT value. Then the differential delta CT value was calculated by subtracting the delta CT value of the untreated sample (average of PBS control) from the delta CT value of each test sample. Percent mRNA knockdown (KD%) was calculated by subtracting test sample from the PBS control (=1), then multiplied by 100. Data is shown in Table 7A and Table 7B.Table 7A. % KD of TrkA mRNA and TrkA protein in lumbar DRG in female Sprague Dawley rats.Table 7B. % KD of TrkA mRNA and TrkA protein in lumbar DRG in female humanized TrkA rats.

[0153] These data show that TrkA RNAi is delivered to target DRG neurons and able to knock down TrkA mRNA and protein levels.Example 5: TrkA RNAi agent comprising dsRNA-cholesterol conjugates single point mRNA % KD determination

[0154] Human DRGs were harvested and plated into 96 well plates by Anabios Corporation (San Diego, CA) following their standard protocols using their proprietary culture media. Upon delivery of the DRG cells, 50% media change was performed using NbActiv4 (Transnetyx #NB4) supplemented with 25 ng / mL recombinant human GDNF (Alomone Labs #G-24), 25 ng / mL recombinant human NGF (Axol #axl39789), 10 ng / mL recombinant human NT-3 (Alomone Labs #N-260) and cells were incubated overnight.

[0155] 50% media change was performed with dsRNA-cholesterol conjugates were added to a final concentration of 300nM (3 wells / siRNA sequence) in the same NbActiv4 media as described above. After treatment, the plates were incubated for 3 days prior to qPCR. RNA was then extracted from cells harvested using RNAdvance Cell v2 Kit (Beckman Coulter Life Sciences).

[0156] An Agilent Technologies 4200 TapeStation was used to determine RIN and total RNA concentration. TaqMan qPCR was performed using standard techniques with a QuantStudio Pro 7 Real-time PCR system and relative gene expression determined by normalization to SNAP25housekeeping gene. The represented relative knockdown of TrkA mRNA expression was compared to PBS-treated control cells.Table 8. Single point % KD for TrkA RNAi agents conjugated to teg-cholesterol in human DRG primary culture.Example 6: In vivo Characterization of human Anti-TfR Antibody-TrkA dsRNA Conjugates in NHP

[0157] Human reactive sequences dsRNA NOs: 350 and 351 were tested in NHP cynomolgus macaque). The sense strand of dsRNA NO: 350 and 351 were conjugated via the MSPT linker to Ser 124 Cys at the EU numbering position of the Fab albVHH TfR C3.08. The Fab albVHH C3.08 was reduced as described in Example 3, omitting the re-oxidation step. The prepared Fab albVHH C3.08 was incubated with 0.8-1.0 molar equivalents of MSPT-dsRNA at room temperature for 2 hours. Following conjugation, the dsRNA-conjugated TfR-binding protein was purified by preparative AEX as described in Example 3. NHPs (n=4 / group) were dosed at day 0 and day 8 IV with PBS or test articles, at a dose of 0.5mg / kg or 30 mg / kg siRNA conjugated to C3.08 (TfR antibody shuttle). 28 days post the second IV injection, the animals were euthanized, blood was collected into K2EDTA BD Microtainer tubes (Becton Dickinson) for plasma isolation. Various tissues including lumbar DRGs were collected from the monkeysand frozen on dry ice and stored at -80C until processed for total TrkA protein and NTRK1 mRNA.

[0158] For TrkA protein analysis, tissues were homogenized using a TissueLyser 2.0 in Cell lysis buffer (Cell Signaling) containing 2x Halt Protease and Phosphatase Inhibitor (ThermoFisher) and lx PMSF (Millipore Sigma). Total TrkA protein content was assessed using a custom MSD Assay (Meso Scale Discovery). Global protein content was assessed using the BCA method (ThermoFisher). Total TrkA protein was normalized by dividing by the global protein content per sample (Total TrkA / total protein, pg / ug).

[0159] For mRNA KD analysis: total RNA was extracted using Triazol and PurLink RNA miniprep Kit with the addition of Purelink DNAse I on column treatment according to the manufacturers protocol (ThermoFisher) and quantified on a NanoDrop (ThermoFisher). Equal amounts of RNA were reverse transcribed to cDNA using High-Capacity cDNA Reverse Transcription kit (ThermoFisher) on Mastercycler X50a (Eppendorf). Template cDNA was combined with Taqman Universal Master Mix and Assays on Demand primer / probe sets and RT-PCR is performed on the QuantStudio 7 Flex (ThermoFisher) A relative amount was calculated as follows: the CT value of monkey Hprtl was subtracted from CT value of monkey Ntrkl to obtain the delta CT value. Then the differential delta CT value was calculated by subtracting the delta CT value of the untreated sample (average of PBS control) from the delta CT value of each test sample. Percent mRNA knockdown (KD%) was calculated by subtracting test sample from the PBS control (=1), then multiplied by 100.

[0160] Intravenous administration of the tested anti-TfR antibody-TrkA dsRNA conjugates at 0.5 and 30 mg / kg led to reductions of NTRK1 mRNA and TrkA protein in NHP DRGs, as shown in Table 9.Table 9. % KD of NTRK1 mRNA and TrkA protein in lumbar DRG in NHPs

Claims

CLAIMSWhat is claimed is:

1. A TrkA RNAi agent comprising a sense strand and an antisense strand forming a double stranded RNA (dsRNA), wherein:(a) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 2, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 15,(b) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 3, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 16,(c) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 17,(d) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 5, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 18,(e) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 6, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 19,(f) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 7, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 20,(g) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(h) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 22,(i) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 10, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 23,(j) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 11, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 24,(k) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 12, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 25,(l) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 13, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 26,(m) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 14, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 27,(n) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 109,(o) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 105, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(p) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 105, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 109,(q) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 105, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 110,(r) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(s) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 109,(t) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 110,(u) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(v) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 109,(w) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 110,(x) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 111,(y) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(z) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 110,(aa) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 111,(bb) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 126, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 184,(cc) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 127, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 185,(dd) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 128, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 186,(ee) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 129, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 187,(ff) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 130, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 188,(gg) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 131, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 189,(hh) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 132, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 190,(ii) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 133, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 191,(jj) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 134, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 192,(kk) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 135, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 193,(11) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 136, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 194,(mm) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 137, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 195,(nn) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 138, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 196,(oo) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 139, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 197,(pp) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 140, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 198,(qq) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 141, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 199,(rr) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 142, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 200,(ss) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 143, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 201,(tt) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 144, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 202,(uu) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 145, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 203,(vv) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 146, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 204,(ww) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 147, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 205,(xx) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 148, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 206,(yy) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 149, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 207,(zz) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 150, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 208,(aaa) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 151, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 209,(bbb) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 152, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 210,(ccc) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 153, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 211,(ddd) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 154, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 212,(eee) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 155, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 213,(fff) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 156, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 214,(ggg) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 157, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 215,(hhh) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 158, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 216,(iii) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 159, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 217,(jjj) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 160, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 218,(kkk) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 161, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 219,(111) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 162, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 220,(mmm) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 163, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 221,(nnn) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 164, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 222,(ooo) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 165, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 223,(ppp) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 166, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 224,(qqq) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 167, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 225,(rrr) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 168, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 226,(sss) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 169, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 227,(ttt) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 170, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 228,(uuu) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 171, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 229,(vvv) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 172, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 230,(www) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 173, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 231,(xxx) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 174, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 232,(yyy) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 175, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 233,(zzz) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 176, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 234,(aaaa) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 177, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 235,(bbbb) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 236,(cccc) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 237,(dddd) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 238,(eeee) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 239,(ffff) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 178, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 22,(gggg) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 179, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 22,(hhhh) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 180, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 22,(iiii) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 181, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 22,(jjjj) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 240,(kkkk) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 241,(1111) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 242,(mmmm) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 243,(nnnn) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 244,(oooo) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 245,(pppp) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 246,(qqqq) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 247,(rrrr) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 182, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(ssss) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 248,(tttt) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 183, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 17,(uuuu) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 7, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 249,(vvvv) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 250, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 260,(wwww) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 260,(xxxx) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 261,(yyyy) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 251, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 261,(zzzz) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 7, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 249,(aaaaa)the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 111,(bbbbb) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 109,(ccccc) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 263,(ddddd) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 252, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 263,(eeeee)the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 252, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(fffff) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 264,(ggggg) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 265,(hhhhh) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 253, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 265,(iiiii) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 254, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 264,(jjjjj) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 255, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 266,(kkkkk) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 256, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 266,(11111) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 256, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 267,(mmmmm) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 257, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 267,(nnnnn) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 257, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 268,(ooooo) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 258, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 20,(ppppp) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 258, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 268,(qqqqq) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 258, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 269,(rrrrr) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 259, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 267,(sssss) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 259, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 268,(ttttt) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 259, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 269,(uuuuu) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 262,(vvvvv) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 597, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 610,(wwwww) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 598, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 611,(xxxxx) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 599, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 612,(yyyyy) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 600, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 613,(zzzzz)the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 601, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 614,(aaaaaa) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 602, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 615,(bbbbbb) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 603, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 616,(cccccc) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 604, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 617,(dddddd) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 605, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 618,(eeeeee) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 606, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 619,(ffffff) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 607, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 620,(gggggg) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 608, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 621, or(hhhhhh) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 609, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 622.

2. The TrkA RNAi agent of claim 1, wherein:(a) the sense strand comprises SEQ ID NO: 2, and the antisense strand comprises SEQ ID NO: 15,(b) the sense strand comprises SEQ ID NO: 3, and the antisense strand comprises SEQ ID NO: 16,(c) the sense strand comprises SEQ ID NO: 4, and the antisense strand comprises SEQID NO: 17,(d) the sense strand comprises SEQ ID NO: 5, and the antisense strand comprises SEQ ID NO: 18,(e) the sense strand comprises SEQ ID NO: 6, and the antisense strand comprises SEQID NO: 19,(f) the sense strand comprises SEQ ID NO: 7, and the antisense strand comprises SEQ ID NO: 20,(g) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 21,(h) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 22,(i) the sense strand comprises SEQ ID NO: 10, and the antisense strand comprises SEQ ID NO: 23,(j) the sense strand comprises SEQ ID NO: 11, and the antisense strand comprises SEQ ID NO: 24,(k) the sense strand comprises SEQ ID NO: 12, and the antisense strand comprises SEQ ID NO: 25,(l) the sense strand comprises SEQ ID NO: 13, and the antisense strand comprises SEQ ID NO: 26,(m)the sense strand comprises SEQ ID NO: 14, and the antisense strand comprises SEQ ID NO: 27,(n) the sense strand comprises SEQ ID NO: 8 and the antisense strand comprises SEQ ID NO: 109;(o) the sense strand comprises SEQ ID NO: 105 and the antisense strand comprises SEQ ID NO: 21;(p) the sense strand comprises SEQ ID NO: 105 and the antisense strand comprises SEQ ID NO: 109;(q) the sense strand comprises SEQ ID NO: 105 and the antisense strand comprises SEQ ID NO: 110;(r) the sense strand comprises SEQ ID NO: 106 and the antisense strand comprises SEQ ID NO: 21;(s) the sense strand comprises SEQ ID NO: 106 and the antisense strand comprises SEQ ID NO: 109;(t) the sense strand comprises SEQ ID NO: 106 and the antisense strand comprises SEQ ID NO: 110;(u) the sense strand comprises SEQ ID NO: 107 and the antisense strand comprises SEQ ID NO: 21;(v) the sense strand comprises SEQ ID NO: 107 and the antisense strand comprises SEQ ID NO: 109;(w)the sense strand comprises SEQ ID NO: 107 and the antisense strand comprises SEQ ID NO: 110;(x) the sense strand comprises SEQ ID NO: 107 and the antisense strand comprises SEQ ID NO: 111;(y) the sense strand comprises SEQ ID NO: 108 and the antisense strand comprises SEQ ID NO: 21;(z) the sense strand comprises SEQ ID NO: 108 and the antisense strand comprises SEQ ID NO: 110; or(aa) the sense strand comprises SEQ ID NO: 108 and the antisense strand comprises SEQ ID NO: 111(bb) the sense strand comprises SEQ ID NO: 126, and the antisense strand comprises SEQ ID NO: 184,(cc) the sense strand comprises SEQ ID NO: 127, and the antisense strand comprises SEQ ID NO: 185,(dd) the sense strand comprises SEQ ID NO: 128, and the antisense strand comprises SEQ ID NO: 186,(ee) the sense strand comprises SEQ ID NO: 129, and the antisense strand comprises SEQ ID NO: 187,(ff) the sense strand comprises SEQ ID NO: 130, and the antisense strand comprises SEQ ID NO: 188,(gg) the sense strand comprises SEQ ID NO: 131, and the antisense strand comprises SEQ ID NO: 189,(hh) the sense strand comprises SEQ ID NO: 132, and the antisense strand comprises SEQ ID NO: 190,(ii) the sense strand comprises SEQ ID NO: 133, and the antisense strand comprises SEQ ID NO: 191,(jj) the sense strand comprises SEQ ID NO: 134, and the antisense strand comprises SEQ ID NO: 192,(kk) the sense strand comprises SEQ ID NO: 135, and the antisense strand comprises SEQ ID NO: 193,(11) the sense strand comprises SEQ ID NO: 136, and the antisense strand comprisesSEQ ID NO: 194,(mm) the sense strand comprises SEQ ID NO: 137, and the antisense strand comprises SEQ ID NO: 195,(nn) the sense strand comprises SEQ ID NO: 138, and the antisense strand comprises SEQ ID NO: 196,(oo) the sense strand comprises SEQ ID NO: 139, and the antisense strand comprises SEQ ID NO: 197,(pp) the sense strand comprises SEQ ID NO: 140, and the antisense strand comprises SEQ ID NO: 198,(qq) the sense strand comprises SEQ ID NO: 141, and the antisense strand comprises SEQ ID NO: 199,(rr) the sense strand comprises SEQ ID NO: 142, and the antisense strand comprises SEQ ID NO: 200,(ss)the sense strand comprises SEQ ID NO: 143, and the antisense strand comprises SEQ ID NO: 201,(tt) the sense strand comprises SEQ ID NO: 144, and the antisense strand comprises SEQ ID NO: 202,(uu) the sense strand comprises SEQ ID NO: 145, and the antisense strand comprises SEQ ID NO: 203,(vv) the sense strand comprises SEQ ID NO: 146, and the antisense strand comprises SEQ ID NO: 204,(ww) the sense strand comprises SEQ ID NO: 147, and the antisense strand comprises SEQ ID NO: 205,(xx) the sense strand comprises SEQ ID NO: 148, and the antisense strand comprises SEQ ID NO: 206,(yy) the sense strand comprises SEQ ID NO: 149, and the antisense strand comprises SEQ ID NO: 207,(zz) the sense strand comprises SEQ ID NO: 150, and the antisense strand comprises SEQ ID NO: 208,(aaa) the sense strand comprises SEQ ID NO: 151, and the antisense strand comprises SEQ ID NO: 209,(bbb) the sense strand comprises SEQ ID NO: 152, and the antisense strand comprises SEQ ID NO: 210,(ccc) the sense strand comprises SEQ ID NO: 153, and the antisense strand comprises SEQ ID NO: 211,(ddd) the sense strand comprises SEQ ID NO: 154, and the antisense strand comprises SEQ ID NO: 212,(eee) the sense strand comprises SEQ ID NO: 155, and the antisense strand comprises SEQ ID NO: 213,(fff) the sense strand comprises SEQ ID NO: 156, and the antisense strand comprises SEQ ID NO: 214,(ggg) the sense strand comprises SEQ ID NO: 157, and the antisense strand comprises SEQ ID NO: 215,(hhh) the sense strand comprises SEQ ID NO: 158, and the antisense strand comprises SEQ ID NO: 216,(iii)the sense strand comprises SEQ ID NO: 159, and the antisense strand comprises SEQ ID NO: 217,(jjj)the sense strand comprises SEQ ID NO: 160, and the antisense strand comprisesSEQ ID NO: 218,(kkk) the sense strand comprises SEQ ID NO: 161, and the antisense strand comprises SEQ ID NO: 219,(lll)the sense strand comprises SEQ ID NO: 162, and the antisense strand comprisesSEQ ID NO: 220,(mmm)the sense strand comprises SEQ ID NO: 163, and the antisense strand comprises SEQ ID NO: 221,(nnn) the sense strand comprises SEQ ID NO: 164, and the antisense strand comprises SEQ ID NO: 222,(ooo) the sense strand comprises SEQ ID NO: 165, and the antisense strand comprisesSEQ ID NO: 223,(ppp) the sense strand comprises SEQ ID NO: 166, and the antisense strand comprises SEQ ID NO: 224,(qqq) the sense strand comprises SEQ ID NO: 167, and the antisense strand comprises SEQ ID NO: 225,(rrr) the sense strand comprises SEQ ID NO: 168, and the antisense strand comprises SEQ ID NO: 226,(sss) the sense strand comprises SEQ ID NO: 169, and the antisense strand comprises SEQ ID NO: 227,(ttt)the sense strand comprises SEQ ID NO: 170, and the antisense strand comprisesSEQ ID NO: 228,(uuu) the sense strand comprises SEQ ID NO: 171, and the antisense strand comprises SEQ ID NO: 229,(vvv) the sense strand comprises SEQ ID NO: 172, and the antisense strand comprises SEQ ID NO: 230,(www) the sense strand comprises SEQ ID NO: 173, and the antisense strand comprises SEQ ID NO: 231,(xxx) the sense strand comprises SEQ ID NO: 174, and the antisense strand comprises SEQ ID NO: 232,(yyy) the sense strand comprises SEQ ID NO: 175, and the antisense strand comprises SEQ ID NO: 233,(zzz) the sense strand comprises SEQ ID NO: 176, and the antisense strand comprises SEQ ID NO: 234,(aaaa) the sense strand comprises SEQ ID NO: 177, and the antisense strand comprises SEQ ID NO: 235,(bbbb) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 236,(cccc) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 237,(dddd) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 238,(eeee) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 239,(ffff) the sense strand comprises SEQ ID NO: 178, and the antisense strand comprises SEQ ID NO: 22,(gggg) the sense strand comprises SEQ ID NO: 179, and the antisense strand comprises SEQ ID NO: 22,(hhhh) the sense strand comprises SEQ ID NO: 180, and the antisense strand comprises SEQ ID NO: 22,(iiii) the sense strand comprises SEQ ID NO: 181, and the antisense strand comprises SEQ ID NO: 22,Qjjjj) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 240,(kkkk) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 241,(1111) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 242,(mmmm) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 243,(nnnn) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 244,(oooo) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 245,(pppp) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 246,(qqqq) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 247,(rrrr) the sense strand comprises SEQ ID NO: 182, and the antisense strand comprises SEQ ID NO: 21,(ssss) the sense strand comprises SEQ ID NO: 4, and the antisense strand comprises SEQ ID NO: 248.(tttt) the sense strand comprises SEQ ID NO: 183, and the antisense strand comprises SEQ ID NO: 17,(uuuu) the sense strand comprises SEQ ID NO: 7, and the antisense strand comprises SEQ ID NO: 249,(vvvv) the sense strand comprises SEQ ID NO: 250, and the antisense strand comprises SEQ ID NO: 260,(wwww) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 260,(xxxx) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 261,(yyyy) the sense strand comprises SEQ ID NO: 251, and the antisense strand comprises SEQ ID NO: 262,(zzzz) the sense strand comprises SEQ ID NO: 106, and the antisense strand comprises SEQ ID NO: 111,(aaaaa)the sense strand comprises SEQ ID NO: 108, and the antisense strand comprises SEQ ID NO: 109,(bbbbb) the sense strand comprises SEQ ID NO: 8, and the antisense strand comprises SEQ ID NO: 263,(ccccc)the sense strand comprises SEQ ID NO: 252, and the antisense strand comprises SEQ ID NO: 263,(ddddd) the sense strand comprises SEQ ID NO: 252, and the antisense strand comprises SEQ ID NO: 21,(eeeee)the sense strand comprises SEQ ID NO: 4, and the antisense strand comprises SEQ ID NO: 264,(fffff) the sense strand comprises SEQ ID NO: 4, and the antisense strand comprises SEQ ID NO: 265,(ggggg) the sense strand comprises SEQ ID NO: 253, and the antisense strand comprises SEQ ID NO: 265,(hhhhh) the sense strand comprises SEQ ID NO: 254, and the antisense strand comprises SEQ ID NO: 264,(iiiii) the sense strand comprises SEQ ID NO: 255, and the antisense strand comprisesSEQ ID NO: 266,(jjjjj) the sense strand comprises SEQ ID NO: 256, and the antisense strand comprises SEQ ID NO: 266,(kkkkk) the sense strand comprises SEQ ID NO: 256, and the antisense strand comprises SEQ ID NO: 267,(11111) the sense strand comprises SEQ ID NO: 257, and the antisense strand comprises SEQ ID NO: 267,(mmmmm) the sense strand comprises SEQ ID NO: 257, and the antisense strand comprises SEQ ID NO: 268,(nnnnn) the sense strand comprises SEQ ID NO: 258, and the antisense strand comprises SEQ ID NO: 20,(ooooo) the sense strand comprises SEQ ID NO: 258, and the antisense strand comprises SEQ ID NO: 268,(ppppp) the sense strand comprises SEQ ID NO: 258, and the antisense strand comprises SEQ ID NO: 269,(qqqqq) the sense strand comprises SEQ ID NO: 259, and the antisense strand comprises SEQ ID NO: 267,(rrrrr) the sense strand comprises SEQ ID NO: 259, and the antisense strand comprises SEQ ID NO: 268,(sssss) the sense strand comprises SEQ ID NO: 259, and the antisense strand comprises SEQ ID NO: 269,(ttttt) the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 262;(uuuuu) the sense strand comprises SEQ ID NO: 597, and the antisense strand comprises SEQ ID NO: 610;(vvvvv) the sense strand comprises SEQ ID NO: 598, and the antisense strand comprises SEQ ID NO: 611;(wwwww) the sense strand comprises SEQ ID NO: 599, and the antisense strand comprises SEQ ID NO: 612;(xxxxx) the sense strand comprises SEQ ID NO: 600, and the antisense strand comprises SEQ ID NO: 613:(yyyyy) the sense strand comprises SEQ ID NO: 601, and the antisense strand comprises SEQ ID NO: 614;(zzzzz)the sense strand comprises SEQ ID NO: 602, and the antisense strand comprises SEQ ID NO: 615;(aaaaaa) the sense strand comprises SEQ ID NO: 603, and the antisense strand comprises SEQ ID NO: 616;(bbbbbb) the sense strand comprises SEQ ID NO: 604, and the antisense strand comprises SEQ ID NO: 617;(cccccc) the sense strand comprises SEQ ID NO: 605, and the antisense strand comprises SEQ ID NO: 618;(dddddd) the sense strand comprises SEQ ID NO: 606, and the antisense strand comprises SEQ ID NO: 619;(eeeeee) the sense strand comprises SEQ ID NO: 607, and the antisense strand comprises SEQ ID NO: 620;(ffffff) the sense strand comprises SEQ ID NO: 608, and the antisense strand comprises SEQ ID NO: 621; or(gggggg) the sense strand comprises SEQ ID NO: 609, and the antisense strand comprises SEQ ID NO: 622.

3. The TrkA RNAi agent of claim 1 or 2, wherein: a. the sense strand consists essentially of SEQ ID NO: 2, and the antisense strand consists essentially of SEQ ID NO: 15, b. the sense strand consists essentially of SEQ ID NO: 3, and the antisense strand consists essentially of SEQ ID NO: 16, c. the sense strand consists essentially of SEQ ID NO: 4, and the antisense strand consists essentially of SEQ ID NO: 17,d. the sense strand consists essentially of SEQ ID NO: 5, and the antisense strand consists essentially of SEQ ID NO: 18, e. the sense strand consists essentially of SEQ ID NO: 6, and the antisense strand consists essentially of SEQ ID NO: 19, f. the sense strand consists essentially of SEQ ID NO: 7, and the antisense strand consists essentially of SEQ ID NO: 20, g. the sense strand consists essentially of SEQ ID NO: 8, and the antisense strand consists essentially of SEQ ID NO: 21, h. the sense strand consists essentially of SEQ ID NO: 9, and the antisense strand consists essentially of SEQ ID NO: 22, i. the sense strand consists essentially of SEQ ID NO: 10, and the antisense strand consists essentially of SEQ ID NO: 23, j. the sense strand consists essentially of SEQ ID NO: 11, and the antisense strand consists essentially of SEQ ID NO: 24, k. the sense strand consists essentially of SEQ ID NO: 12, and the antisense strand consists essentially of SEQ ID NO: 25, l. the sense strand consists essentially of SEQ ID NO: 13, and the antisense strand consists essentially of SEQ ID NO: 26, m. the sense strand consists essentially of SEQ ID NO: 14, and the antisense strand consists essentially of SEQ ID NO: 27, n. the sense strand consists essentially of SEQ ID NO: 8 and the antisense strand consists essentially of SEQ ID NO: 109; o. the sense strand consists essentially of SEQ ID NO: 105 and the antisense strand consists essentially of SEQ ID NO: 21; p. the sense strand consists essentially of SEQ ID NO: 105 and the antisense strand consists essentially of SEQ ID NO: 109; q. the sense strand consists essentially of SEQ ID NO: 105 and the antisense strand consists essentially of SEQ ID NO: 110; r. the sense strand consists essentially of SEQ ID NO: 106 and the antisense strand consists essentially of SEQ ID NO: 21 ; s. the sense strand consists essentially of SEQ ID NO: 106 and the antisense strand consists essentially of SEQ ID NO: 109;t. the sense strand consists essentially of SEQ ID NO: 106 and the antisense strand consists essentially of SEQ ID NO: 110: u. the sense strand consists essentially of SEQ ID NO: 107 and the antisense strand consists essentially of SEQ ID NO: 21; v. the sense strand consists essentially of SEQ ID NO: 107 and the antisense strand consists essentially of SEQ ID NO: 109: w. the sense strand consists essentially of SEQ ID NO: 107 and the antisense strand consists essentially of SEQ ID NO: 110; x. the sense strand consists essentially of SEQ ID NO: 107 and the antisense strand consists essentially of SEQ ID NO: 111; y. the sense strand consists essentially of SEQ ID NO: 108 and the antisense strand consists essentially of SEQ ID NO: 21 ; z. the sense strand consists essentially of SEQ ID NO: 108 and the antisense strand consists essentially of SEQ ID NO: 110; aa. the sense strand consists essentially of SEQ ID NO: 108 and the antisense strand consists essentially of SEQ ID NO: 11 1; bb. the sense strand consists essentially of SEQ ID NO: 126 and the antisense strand consists essentially of SEQ ID NO: 184; cc. the sense strand consists essentially of SEQ ID NO: 127 and the antisense strand consists essentially of SEQ ID NO: 185; dd. the sense strand consists essentially of SEQ ID NO: 128 and the antisense strand consists essentially of SEQ ID NO: 186; ee. the sense strand consists essentially of SEQ ID NO: 129 and the antisense strand consists essentially of SEQ ID NO: 187; ff. the sense strand consists essentially of SEQ ID NO: 130 and the antisense strand consists essentially of SEQ ID NO: 188; gg. the sense strand consists essentially of SEQ ID NO: 131 and the antisense strand consists essentially of SEQ ID NO: 189; hh. the sense strand consists essentially of SEQ ID NO: 132 and the antisense strand consists essentially of SEQ ID NO: 190; ii. the sense strand consists essentially of SEQ ID NO: 133 and the antisense strand consists essentially of SEQ ID NO: 191;jj. the sense strand consists essentially of SEQ ID NO: 134 and the antisense strand consists essentially of SEQ ID NO: 192; kk. the sense strand consists essentially of SEQ ID NO: 135 and the antisense strand consists essentially of SEQ ID NO: 193;11. the sense strand consists essentially of SEQ ID NO: 136 and the antisense strand consists essentially of SEQ ID NO: 194; mm. the sense strand consists essentially of SEQ ID NO: 137 and the antisense strand consists essentially of SEQ ID NO: 195; nn. the sense strand consists essentially of SEQ ID NO: 138 and the antisense strand consists essentially of SEQ ID NO: 196; oo. the sense strand consists essentially of SEQ ID NO: 139 and the antisense strand consists essentially of SEQ ID NO: 197; pp. the sense strand consists essentially of SEQ ID NO: 140 and the antisense strand consists essentially of SEQ ID NO: 198; qq. the sense strand consists essentially of SEQ ID NO: 141 and the antisense strand consists essentially of SEQ ID NO: 199; rr. the sense strand consists essentially of SEQ ID NO: 142 and the antisense strand consists essentially of SEQ ID NO: 200; ss. the sense strand consists essentially of SEQ ID NO: 143 and the antisense strand consists essentially of SEQ ID NO: 201; tt. the sense strand consists essentially of SEQ ID NO: 144 and the antisense strand consists essentially of SEQ ID NO: 202; uu. the sense strand consists essentially of SEQ ID NO: 145 and the antisense strand consists essentially of SEQ ID NO: 203; vv. the sense strand consists essentially of SEQ ID NO: 146 and the antisense strand consists essentially of SEQ ID NO: 204; ww. the sense strand consists essentially of SEQ ID NO: 147 and the antisense strand consists essentially of SEQ ID NO: 205; xx. the sense strand consists essentially of SEQ ID NO: 148 and the antisense strand consists essentially of SEQ ID NO: 206; yy. the sense strand consists essentially of SEQ ID NO: 149 and the antisense strand consists essentially of SEQ ID NO: 207;zz. the sense strand consists essentially of SEQ ID NO: 150 and the antisense strand consists essentially of SEQ ID NO: 208: aaa. the sense strand consists essentially of SEQ ID NO: 151 and the antisense strand consists essentially of SEQ ID NO: 209; bbb. the sense strand consists essentially of SEQ ID NO: 152 and the antisense strand consists essentially of SEQ ID NO: 210: ccc. the sense strand consists essentially of SEQ ID NO: 153 and the antisense strand consists essentially of SEQ ID NO: 211; ddd. the sense strand consists essentially of SEQ ID NO: 154 and the antisense strand consists essentially of SEQ ID NO: 212; eee. the sense strand consists essentially of SEQ ID NO: 155 and the antisense strand consists essentially of SEQ ID NO: 213; fff. the sense strand consists essentially of SEQ ID NO: 156 and the antisense strand consists essentially of SEQ ID NO: 214; ggg. the sense strand consists essentially of SEQ ID NO: 157 and the antisense strand consists essentially of SEQ ID NO: 215; hhh. the sense strand consists essentially of SEQ ID NO: 158 and the antisense strand consists essentially of SEQ ID NO: 216; iii. the sense strand consists essentially of SEQ ID NO: 159 and the antisense strand consists essentially of SEQ ID NO: 217; jjj. the sense strand consists essentially of SEQ ID NO: 160 and the antisense strand consists essentially of SEQ ID NO: 218; kkk. the sense strand consists essentially of SEQ ID NO: 161 and the antisense strand consists essentially of SEQ ID NO: 219:

111. the sense strand consists essentially of SEQ ID NO: 162 and the antisense strand consists essentially of SEQ ID NO: 220; mmm. the sense strand consists essentially of SEQ ID NO: 163 and the antisense strand consists essentially of SEQ ID NO: 221; nnn. the sense strand consists essentially of SEQ ID NO: 164 and the antisense strand consists essentially of SEQ ID NO: 222; ooo. the sense strand consists essentially of SEQ ID NO: 165 and the antisense strand consists essentially of SEQ ID NO: 223;ppp. the sense strand consists essentially of SEQ ID NO: 166 and the antisense strand consists essentially of SEQ ID NO: 224; qqq. the sense strand consists essentially of SEQ ID NO: 167 and the antisense strand consists essentially of SEQ ID NO: 225; rrr. the sense strand consists essentially of SEQ ID NO: 168 and the antisense strand consists essentially of SEQ ID NO: 226; sss.the sense strand consists essentially of SEQ ID NO: 169 and the antisense strand consists essentially of SEQ ID NO: 227; ttt. the sense strand consists essentially of SEQ ID NO: 170 and the antisense strand consists essentially of SEQ ID NO: 228; uuu. the sense strand consists essentially of SEQ ID NO: 171 and the antisense strand consists essentially of SEQ ID NO: 229; vw. the sense strand consists essentially of SEQ ID NO: 172 and the antisense strand consists essentially of SEQ ID NO: 230; www. the sense strand consists essentially of SEQ ID NO: 173 and the antisense strand consists essentially of SEQ ID NO: 231; xxx. the sense strand consists essentially of SEQ ID NO: 174 and the antisense strand consists essentially of SEQ ID NO: 232; yyy. the sense strand consists essentially of SEQ ID NO: 175 and the antisense strand consists essentially of SEQ ID NO: 233; zzz. the sense strand consists essentially of SEQ ID NO: 176 and the antisense strand consists essentially of SEQ ID NO: 234; aaaa. the sense strand consists essentially of SEQ ID NO: 177 and the antisense strand consists essentially of SEQ ID NO: 235; bbbb. the sense strand consists essentially of SEQ ID NO: 9 and the antisense strand consists essentially of SEQ ID NO: 236; cccc. the sense strand consists essentially of SEQ ID NO: 9 and the antisense strand consists essentially of SEQ ID NO: 237; dddd. the sense strand consists essentially of SEQ ID NO: 9 and the antisense strand consists essentially of SEQ ID NO: 238; eeee. the sense strand consists essentially of SEQ ID NO: 9 and the antisense strand consists essentially of SEQ ID NO: 239;ffff. the sense strand consists essentially of SEQ ID NO: 178 and the antisense strand consists essentially of SEQ ID NO: 22; gggg. the sense strand consists essentially of SEQ ID NO: 179 and the antisense strand consists essentially of SEQ ID NO: 22; hhhh. the sense strand consists essentially of SEQ ID NO: 180 and the antisense strand consists essentially of SEQ ID NO: 22; iiii.the sense strand consists essentially of SEQ ID NO: 181 and the antisense strand consists essentially of SEQ ID NO: 22; jjjj. the sense strand consists essentially of SEQ ID NO: 9 and the antisense strand consists essentially of SEQ ID NO: 240; kkkk. the sense strand consists essentially of SEQ ID NO: 9 and the antisense strand consists essentially of SEQ ID NO: 241;1111. the sense strand consists essentially of SEQ ID NO: 8 and the antisense strand consists essentially of SEQ ID NO: 242; mmmm. the sense strand consists essentially of SEQ ID NO: 8 and the antisense strand consists essentially of SEQ ID NO: 243; nnnn. the sense strand consists essentially of SEQ ID NO: 8 and the antisense strand consists essentially of SEQ ID NO: 244; oooo. the sense strand consists essentially of SEQ ID NO: 8 and the antisense strand consists essentially of SEQ ID NO: 245; pppp. the sense strand consists essentially of SEQ ID NO: 8 and the antisense strand consists essentially of SEQ ID NO: 246; qqqq. the sense strand consists essentially of SEQ ID NO: 8 and the antisense strand consists essentially of SEQ ID NO: 247; rrrr. the sense strand consists essentially of SEQ ID NO: 182 and the antisense strand consists essentially of SEQ ID NO: 21 ; ssss. the sense strand consists essentially of SEQ ID NO: 4 and the antisense strand consists essentially of SEQ ID NO: 248; tttt.the sense strand consists essentially of SEQ ID NO: 183 and the antisense strand consists essentially of SEQ ID NO: 17; uuuu. the sense strand consists essentially of SEQ ID NO: 7 and the antisense strand consists essentially of SEQ ID NO: 249;vvvv. the sense strand consists essentially of SEQ ID NO: 250 and the antisense strand consists essentially of SEQ ID NO: 260: wwww. the sense strand consists essentially of SEQ ID NO: 9 and the antisense strand consists essentially of SEQ ID NO: 260; xxxx. the sense strand consists essentially of SEQ ID NO: 9 and the antisense strand consists essentially of SEQ ID NO: 261: yyyy. the sense strand consists essentially of SEQ ID NO: 251 and the antisense strand consists essentially of SEQ ID NO: 262; zzzz. the sense strand consists essentially of SEQ ID NO: 106 and the antisense strand consists essentially of SEQ ID NO: 111; aaaaa. the sense strand consists essentially of SEQ ID NO: 108 and the antisense strand consists essentially of SEQ ID NO: 109; bbbbb. the sense strand consists essentially of SEQ ID NO: 8 and the antisense strand consists essentially of SEQ ID NO: 263; ccccc. the sense strand consists essentially of SEQ ID NO: 252 and the antisense strand consists essentially of SEQ ID NO: 263; ddddd. the sense strand consists essentially of SEQ ID NO: 252 and the antisense strand consists essentially of SEQ ID NO: 21; eeeee. the sense strand consists essentially of SEQ ID NO: 4 and the antisense strand consists essentially of SEQ ID NO: 264; fffff. the sense strand consists essentially of SEQ ID NO: 4 and the antisense strand consists essentially of SEQ ID NO: 265; ggggg. the sense strand consists essentially of SEQ ID NO: 253 and the antisense strand consists essentially of SEQ ID NO: 265: hhhhh. the sense strand consists essentially of SEQ ID NO: 254 and the antisense strand consists essentially of SEQ ID NO: 264; iiiii. the sense strand consists essentially of SEQ ID NO: 255 and the antisense strand consists essentially of SEQ ID NO: 266; jjjjj. the sense strand consists essentially of SEQ ID NO: 256 and the antisense strand consists essentially of SEQ ID NO: 266; kkkkk. the sense strand consists essentially of SEQ ID NO: 256 and the antisense strand consists essentially of SEQ ID NO: 267;11111. the sense strand consists essentially of SEQ ID NO: 257 and the antisense strand consists essentially of SEQ ID NO: 267: mmmmm. the sense strand consists essentially of SEQ ID NO: 257 and the antisense strand consists essentially of SEQ ID NO: 268; nnnnn. the sense strand consists essentially of SEQ ID NO: 258 and the antisense strand consists essentially of SEQ ID NO: 20; ooooo. the sense strand consists essentially of SEQ ID NO: 258 and the antisense strand consists essentially of SEQ ID NO: 268; ppppp. the sense strand consists essentially of SEQ ID NO: 258 and the antisense strand consists essentially of SEQ ID NO: 269; qqqqq. the sense strand consists essentially of SEQ ID NO: 259 and the antisense strand consists essentially of SEQ ID NO: 267; rrrrr. the sense strand consists essentially of SEQ ID NO: 259 and the antisense strand consists essentially of SEQ ID NO: 268; sssss. the sense strand consists essentially of SEQ ID NO: 259 and the antisense strand consists essentially of SEQ ID NO: 269; ttttt. the sense strand consists essentially of SEQ ID NO: 9 and the antisense strand consists essentially of SEQ ID NO: 262; uuuuu. the sense strand consists essentially of SEQ ID NO: 597 and the antisense strand consists essentially of SEQ ID NO: 610; vvvvv. the sense strand consists essentially of SEQ ID NO: 598 and the antisense strand consists essentially of SEQ ID NO: 611; wwwww. the sense strand consists essentially of SEQ ID NO: 599 and the antisense strand consists essentially of SEQ ID NO: 612; xxxxx. the sense strand consists essentially of SEQ ID NO: 600 and the antisense strand consists essentially of SEQ ID NO: 613; yyyyy. the sense strand consists essentially of SEQ ID NO: 601 and the antisense strand consists essentially of SEQ ID NO: 614; zzzzz. the sense strand consists essentially of SEQ ID NO: 602 and the antisense strand consists essentially of SEQ ID NO: 615; aaaaaa.the sense strand consists essentially of SEQ ID NO: 603 and the antisense strand consists essentially of SEQ ID NO: 616;bbbbbb. the sense strand consists essentially of SEQ ID NO: 604 and the antisense strand consists essentially of SEQ ID NO: 617; cccccc.the sense strand consists essentially of SEQ ID NO: 605 and the antisense strand consists essentially of SEQ ID NO: 618; dddddd. the sense strand consists essentially of SEQ ID NO: 606 and the antisense strand consists essentially of SEQ ID NO: 619; eeeeee.the sense strand consists essentially of SEQ ID NO: 607 and the antisense strand consists essentially of SEQ ID NO: 620; ffffff. the sense strand consists essentially of SEQ ID NO: 608 and the antisense strand consists essentially of SEQ ID NO: 621; or gggggg. the sense strand consists essentially of SEQ ID NO: 609 and the antisense strand consists essentially of SEQ ID NO: 622.

4. The TrkA RNAi agent of claim 1 or 2, wherein the sense strand comprises SEQ ID NO: 4, and the antisense strand comprises SEQ ID NO: 17.

5. The TrkA RNAi agent of claim 1 or 2, wherein the sense strand comprises SEQ ID NO: 9, and the antisense strand comprises SEQ ID NO: 22.

6. The TrkA RNAi agent of any one of claims 1-5, wherein each nucleotide of the sense strand is a modified nucleotide.

7. The TrkA RNAi agent of any one of claims 1-6, wherein each nucleotide of the antisense strand is a modified nucleotide.

8. The TrkA RNAi agent of any one of claims 1-7, wherein the modified nucleotide is a 2’- fluoro modified nucleotide, 2’-O-methyl modified nucleotide, 2’ deoxy nucleotide (DNA), or 2’-O-Ci6 alkyl modified nucleotide.

9. The TrkA RNAi agent of any one of claims 1-8, wherein the sense strand has three 2’- fluoro modified nucleotides at positions 9, 10, and 11 from the 5’ end of the sense strand.

10. The TrkA RNAi agent of claim 9, wherein nucleotides at positions other than positions 9, 10, and 1 1 of the sense strand are 2’-O-methyl modified nucleotides.

11. The TrkA RNAi agent of any one of claims 1-8, wherein the sense strand has four 2’ -fluoro modified nucleotides at positions 7, 9, 10, and 11 from the 5' end of the sense strand.

12. The TrkA RNAi agent of claim 11, wherein nucleotides at positions other than positions 7, 9, 10, and 11 of the sense strand are 2’-O-methyl modified nucleotides.

13. The TrkA RNAi agent of any one of claims 1-8, wherein the antisense strand has three 2’- fluoro modified nucleotides at positions 2, 14, and 16 from the 5’ end of the antisense strand.

14. The TrkA RNAi agent of a claim 13, wherein nucleotides at positions other than positions 2, 14, and 16 from the 5’ end of the antisense strand are 2’-O-methyl modified nucleotides.

15. The TrkA RNAi agent of any one of claims 1-8, wherein the antisense strand has three 2’- fluoro modified nucleotides at positions 2, 14, and 16 from the 5’ end of the antisense strand and two deoxyribonucleotides at positions 4 and 7 from the 5’ end of the antisense strand.

16. The TrkA RNAi agent of a claim 15, wherein nucleotides at positions other than positions 2, 4, 7, 14, and 16 from the 5’ end of the antisense strand are 2’-O-methyl modified nucleotides.

17. The TrkA RNAi agent of any one of claims 1-8, wherein the antisense strand has four 2’- fluoro modified nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand.

18. The TrkA RNAi agent of claim 17, wherein nucleotides at positions other than positions 2, 6, 14 and 16 of the antisense strand are 2’-O-methyl modified nucleotides.

19. The TrkA RNAi agent of any one of claims 1-8, wherein the antisense strand has five 2’- fluoro modified nucleotides at positions 2, 5, 7, 14, and 16 from the 5’ end of the antisense strand.

20. The TrkA RNAi agent of claim 19, wherein nucleotides at positions other than positions 2, 5, 7, 14, and 16 of the antisense strand are 2’-O-methyl modified nucleotides.

21. The TrkA RNAi agent of any one of claims 1-8, wherein the antisense strand has five 2’- fluoro modified nucleotides at positions 2, 5, 8, 14, and 16 from the 5’ end of the antisense strand.

22. The TrkA RNAi agent of claim 21, wherein nucleotides at positions other than positions 2, 5, 8, 14, and 16 of the antisense strand are 2’-0-methyl modified nucleotides.

23. The TrkA RNAi agent of any one of claims 1-8, wherein the antisense strand has five 2’- fluoro modified nucleotides at positions 2, 3, 7, 14, and 16 from the 5’ end of the antisense strand.

24. The TrkA RNAi agent of claim 23, wherein nucleotides at positions other than positions 2, 3, 7, 14, and 16 of the antisense strand are 2’-0-methyl modified nucleotides.

25. The TrkA RNAi agent of any one of claims 1-24, wherein the sense strand and the antisense strand comprise one or more modified internucleotide linkages.

26. The TrkA RNAi agent of claim 25, wherein the modified internucleotide linkage is a phosphorothioate linkage.

27. The TrkA RNAi agent of claim 26, wherein the sense strand has four or five phosphorothioate linkages.

28. The TrkA RNAi agent of claim 26, wherein the antisense strand has four or five phosphorothioate linkages.

29. The TrkA RNAi agent of any one of claims 1 -28, wherein the antisense strand has a phosphate analog at the 5’ end.

30. The TrkA RNAi agent of claim 29, wherein the phosphate analog is 5’-vinylphosphonate.

31. The TrkA RNAi agent of any one of claims 1-30, wherein the sense strand or antisense strand comprises an abasic moiety or inverted abasic moiety.

32. The TrkA RNAi agent of claim 31, wherein the sense strand comprises an abasic moiety at its 5’ end.

33. The TrkA RNAi agent of any one of claims 1-8, wherein the sense strand and the antisense strand comprise the sequences from any one of duplex dsRNA NOs. selected from 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77,78, 79, 80, 180, 181, 182, 183, 184, 185, 186, 187, 188. 189, 190, 191, 192, 193, 194, 195,196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213,214, 215, 216, 217, 218. 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230. 231,232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249,250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267,268, 269. 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285,286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297. 298, 299, 300, 301, 302, 303,304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321,322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339,340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357,358, 359, 360, 361, 362, 363, 364. 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375,376, 377, 378, 379, 380, 381, 382, 383, 384, 385. 386, 387, 388, 389, 390, 391, 392, 393,394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411,412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429,430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447,448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465,466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483,484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501,502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519,520, 521, 522, 523, 524, 525, 526. 527, 528, 542, 543, 544, 545, 546, 547, 548, 549, 550,551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, and 567.

34. The TrkA RNAi agent of any one of claims 1-8, wherein the sense strand and the antisense strand consist of the sequences from any one of duplex dsRNA NOs. selected from 14, 15, 16, 17, 18. 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33. 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213,214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225. 226, 227, 228, 229, 230, 231,232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249,250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267,268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285,286, 287, 288, 289, 290, 291, 292. 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303,304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321,322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339,340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357,358, 359, 360, 361, 362. 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374. 375,376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393,394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411,412, 413. 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429,430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441. 442, 443, 444, 445, 446, 447,448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465,466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483,484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501,502, 503, 504, 505, 506, 507, 508. 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519,520, 521, 522, 523, 524, 525, 526, 527, 528, 542. 543, 544, 545, 546, 547, 548, 549, 550,551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, and 567.

35. The TrkA RNAi agent of any one of claims 1-34, further comprising a delivery moiety (D) conjugated to the dsRNA.

36. The TrkA RNAi agent of claim 35, wherein the delivery moiety D delivers the TrkA RNAi agent to a dorsal root ganglion (DRG) neuron.

37. A TrkA RNAi agent of Formula (I): (R-L)n-D, wherein R is a dsRNA comprising a sense stand and an antisense strand forming a double stranded RNA (dsRNA), wherein:(a) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 2, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 15,(b) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 3, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 16,(c) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 17,(d) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 5, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 18,(e) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 6, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 19,(f) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 7, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 20,(g) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(h) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 22,(i) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 10, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 23,(j) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 11, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 24,(k) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 12, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 25,(l) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 13, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 26,(m)the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 14, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 27,(n) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 109,(o) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 105, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(p) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 105, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 109,(q) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 105, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 110,(r) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(s) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 109,(t) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 110,(u) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(v) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 109,(w)the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 110,(x) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 107, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 111,(y) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(z) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 110,(aa) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 111,(bb) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 126, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 184,(cc) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 127, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 185,(dd) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 128, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 186,(ee) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 129, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 187,(ff) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 130, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 188,(gg) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 131, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 189,(hh) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 132, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 190,(ii) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 133, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 191,(jj) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 134, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 192,(kk) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 135, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 193,(11) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 136, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 194,(mm) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 137, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 195,(nn) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 138, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 196,(oo) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 139, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 197,(pp) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 140, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 198,(qq) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 141, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 199,(rr) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 142, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 200,(ss)the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 143, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 201,(tt) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 144, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 202,(uu) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 145, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 203,(vv) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 146, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 204,(ww) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 147, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 205,(xx) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 148, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 206,(yy) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 149, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 207,(zz) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 150, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 208,(aaa) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 151, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 209,(bbb) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 152, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 210,(ccc) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 153, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 211,(ddd) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 154, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 212,(eee) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 155, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 213,(fff) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 156, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 214,(ggg) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 157, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 215,(hhh) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 158, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 216,(iii)the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 159, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 217,(jjj) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 160, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 218,(kkk) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 161, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 219,(lll)the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 162, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 220,(mmm) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 163, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 221,(nnn) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 164, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 222,(ooo) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 165, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 223,(ppp) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 166, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 224,(qqq) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 167, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 225,(rrr) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 168, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 226,(sss) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 169, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 227,(ttt)the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 170, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 228,(uuu) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 171, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 229,(vvv) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 172, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 230,(www) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 173, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 231,(xxx) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 174, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 232,(yyy) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 175, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 233,(zzz) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 176, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 234,(aaaa) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 177, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 235,(bbbb) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 236,(cccc) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 237,(dddd) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 238,(eeee) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 239,(ffff) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 178, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 22,(gggg) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 179, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 22,(hhhh) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 180, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 22,(iiii) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 181, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 22,(jjjj) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 240,(kkkk) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 241,(1111) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 242,(nininim) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 243,(nnnn) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 244,(oooo) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 245,(pppp) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 246,(qqqq) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 247,(rrrr) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 182, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(ssss) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 248,(tttt) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 183, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 17,(uuuu) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 7, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 249,(vvvv) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 250, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 260,(wwww) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 260,(xxxx) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 261,(yyyy) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 251, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 261,(zzzz) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 7, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 249,(aaaaa)the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 106, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 111,(bbbbb) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 108, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 109,(ccccc) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 8, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 263,(ddddd) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 252, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 263,(eeeee)the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 252, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 21,(fffff) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 264,(ggggg) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 4, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 265,(hhhhh) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 253, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 265,(iiiii) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 254, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 264,(jjjjj) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 255, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 266,(kkkkk) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 256, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 266,(11111) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 256, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 267,(mmmmm) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 257, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 267,(nnnnn) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 257, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 268,(ooooo) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 258, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 20,(ppppp) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 258, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 268,(qqqqq) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 258, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 269,(rrrrr) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 259, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 267,(sssss) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 259, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 268,(ttttt) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 259, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 269,(uuuuu) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 9, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 262,(vvvvv) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 597, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 610,(wwwww) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 598, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 611,(xxxxx) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 599, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 612,(yyyyy) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 600, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 613,(zzzzz)the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 601, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 614,(aaaaaa) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 602, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 615,(bbbbbb) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 603, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 616,(cccccc) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 604, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 617,(dddddd) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 605, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 618,(eeeeee) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 606, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 619,(ffffff) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 607, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 620,(gggggg) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 608, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 621, or(hhhhhh) the sense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 609, and the antisense strand comprises a sequence which has at least 95% identity to SEQ ID NO: 622; wherein L is a linker, or absent; and wherein D is a delivery moiety; and wherein n=l, 2, or 3.

38. A TrkA RNAi agent of Formula (I): (R-L)n-D, wherein R is a double stranded RNA (dsRNA); wherein L is a linker, or absent; wherein D is a delivery moiety; wherein n=I, 2, or 3; and wherein the dsRNA comprises a sense strand and an antisense strand forming any one of duplex dsRNA NOs. 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31. 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231. 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310. 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326. 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341 , 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370. 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 41 1, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472. 473, 474, 475, 476, 477, 478, 479, 480, 481. 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494,495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512,513, 514, 515, 516, 517. 518, 519, 520, 521, 522, 523, 524, 525, 526, 527528, 542, 543,544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561,562, 563, 564, 565, 566, and 567.

39. The TrkA RNAi agent of claim 38, wherein the dsRNA consists of a sense strand and an antisense strand forming any one of duplex dsRNA NOs. 14, 15, 16, 17, 18, 19, 20, 21, 22 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48. 49, 50, 51, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77.

78. 79, 80, 180, 181. 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248. 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336. 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403. 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, and 567.

40. The TrkA RNAi agent of claim 38 or 39, wherein the dsRNA NOs. comprise 28, 33, 350, and 351.

41. The TrkA RNAi agent of any one of claims 37-40, wherein the D is conjugated to the sense strand.

42. The TrkA RNAi agent of any one of claims 37-40, wherein the D is conjugated to the 3’ end or the 5’ end of the sense strand.

43. The TrkA RNAi agent of any one of claims 37-40, wherein the D is conjugated to the 3’ end of the sense strand.

44. The TrkA RNAi agent of any one of claims 37-43, wherein the D comprises or consists essentially of a bivalent antibody, a heterodimeric antibody, a monovalent antibody, an antibody fragment, or a VHH molecule each one binding to a target present on a DRG neuron.

45. The TrkA RNAi agent of any one of claims 37-44, wherein the D further comprises a halflife extender.

46. The TrkA RNAi agent of claim 45, wherein the half-life extender is an antibody or an antibody fragment binding Human Serum Albumin (ALB) binding, or an ALB binding VHH.

47. The TrkA RNAi agent of claim 46, wherein antibody fragment is an ALB binding Fab.

48. The TrkA RNAi agent of claim 46, wherein the half-life extender is an immunoglobulin Fc region, optionally the immunoglobulin Fc region is a modified human IgG4 Fc region.

49. The TrkA RNAi agent of any one of claims 37-48, wherein D is a protein comprising a human TfR binding protein or LI CAM binding protein.

50. The TrkA RNAi agent of claim 49, wherein the human TfR binding protein is a human TfR binding protein VHH.

51. The TrkA RNAi agent of claim 49 or 50, wherein the human TfR binding protein is a monovalent human TfR binding protein.

52. The TrkA RNAi agent of claim 49 or 50, wherein the human TfR binding protein is a bivalent human TfR binding protein.

53. The TrkA RNAi agent of any one of claims 44-48, wherein the bivalent antibody, the heterodimeric antibody, the monovalent antibody or the VHH further comprises a heavy chain constant region comprising cysteine for conjugation to the dsRNA.

54. The TrkA RNAi agent of claim 53, wherein the cysteine is residue 124 according to the EU Index numbering.

55. The TrkA RNAi agent of claim 46, wherein the antibody or the antibody fragment binding Human Serum Albumin (ALB) binding, or the ALB binding VHH further comprises a heavy chain constant region comprising cysteine for conjugation to the dsRNA, e.g. a cysteine at residue 124 (according to the EU Index numbering).

56. The TrkA RNAi agent of any one of claims 49-52, wherein the human TfR binding protein further comprises a heavy chain constant region comprising cysteine for conjugation to the dsRNA, e.g. a cysteine at residue 124 (according to the EU Index numbering).

57. The TrkA RNAi agent of any one of claims 49-56, wherein the human TfR binding protein comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR comprises heavy chain complementarity determining regions (HCDR) HCDR1, HCDR2, and HCDR3, and the LCVR comprises light chain complementarity determining regions (LCDR) LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 803, HCDR2 comprises SEQ ID NO: 804, HCDR3 comprises SEQ ID NO: 805, LCDR1 comprises SEQ ID NO: 806, LCDR2 comprises SEQ ID NO: 807, and LCDR3 comprises SEQ ID NO: 808.

58. The TrkA RNA agent of claim 57, wherein the human TfR protein comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises SEQ ID NO: 809 and the VL comprises SEQ ID NO: 810.

59. The TrkA RNAi agent of any one of claims 37-58, wherein L is a SMCC linker, an OD linker, or a MSPT linker.

60. The TrkA RNAi agent of any one of claims 37-59, wherein L is a MSPT linker.

61. The TrkA RNAi agent of any one of claims 37-60, wherein n=l.

62. A pharmaceutical composition comprising the TrkA RNAi agent of any one of claims 1-61 and a pharmaceutically acceptable carrier.

63. A method of treating a TrkA -mediated disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the TrkA RNAi agent of any one of claims 1-61, or the pharmaceutical composition of claim 62.

64. The method of claim 63, wherein the TrkA-mediated disease or disorder is pain.

65. The method of claim 64, wherein the pain is chronic pain.

66. The method of any one of claims 62-65, wherein the TrkA RNAi agent is administered to the subject intravenously, epidurally, or subcutaneously.

67. The TrkA RNAi agent of any one of claims 1-61, or the pharmaceutical composition of claim 62, for use in a therapy.

68. The TrkA RNAi agent of any one of claims 1-61, or the pharmaceutical composition of claim 62, for use in the treatment of a TrkA-mediated disease or disorder, wherein the TrkA-mediated disease or disorder is pain.

69. The TrkA RNAi agent of any one of claims 1-61, or the pharmaceutical composition of claim 62, for use in the treatment of a TrkA-mediated disease or disorder, wherein the TrkA-mediated disease or disorder is chronic pain.

70. Use of the TrkA RNAi agent of any one of claims 1-61 in the manufacture of a medicament for treating a TrkA-mediated pain.

71. The use of claim 70, wherein the manufacture is the manufacture of a medicament for treating a TrkA-mediated pain.

72. The use of claim 71, wherein the TrkA-mediated pain is chronic pain.