TREATMENT OF LIMB SPASTICITY

摘要

The present invention relates to a modified botulinum neurotoxin A (BoNT/A) for use in treating limb spasticity, wherein the modified BoNT/A is administered by intramuscular injection to a plurality of affected muscles of a subject, wherein the modified BoNT/A is administered by way of a unit dose of 53 Units to 948 Units of modified BoNT/A at the plurality of affected muscles, and wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the plurality of affected muscles are selected from: a first group comprising: the flexor digitorum superficialis, the flexor digitorum profundus, the flexor carpi radialis, the flexor carpi ulnaris, the brachioradialis, the pronator teres, the biceps brachii, the gastrocnemius medial head, the gastrocnemius lateral head, the flexor digitorum longus, the flexor hallucis longus, the gastrocnemius, the deltoid, the levator scapulae, the pronator quadratus, the flexor policis longus, the adductor policis, the flexor policis brevis, the palmaris longus, the lumbricales, the opponens policis, the adductor magnus, the adductor longus, the adductor brevis, the gracilis, the medial hamstrings, the lateral hamstrings, the tensor fascia lata, the rectus femoris, the vastus lateralis, the vastus medialis, the vastus intermedius, the gluteus maximus, the tibialis anterior, the flexor digitorum brevis, the extensor hallucis longus, and the flexor hallucis brevis; and a second group comprising: the triceps brachii (long head), the subscapularis, the pectoralis (e.g. the pectoralis major), the latissimus dorsi, the biceps brachii, the brachialis, the soleus, the tibialis posterior, the brachioradialis, the teres major, the iliopsoas, and the gastrocnemius; and wherein a single unit dose is administered at an affected first group muscle and/or multiple unit doses are administered at an affected second group muscle, and wherein the total dose administered during the treatment is up to 14,220 Units, and wherein the modified BoNT/A comprises: a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, wherein the modification is selected from: i. substitution of an acidic surface exposed amino acid residue with a basic amino acid residue; ii. substitution of an acidic surface exposed amino acid residue with an uncharged amino acid residue; iii. substitution of an uncharged surface exposed amino acid residue with a basic amino acid residue; iv. insertion of a basic amino acid residue; and v. deletion of an acidic surface exposed amino acid residue; or wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (Hc domain). Also provided are corresponding methods of treatment and uses, as well as unit dosage forms, and kits.