EP-4735082-A1 - DEVICE AND METHODS FOR ADMINISTERING A THERAPEUTIC COMPOSITION TO THE PHARYNGEAL MUSCLE

Abstract

The present disclosure relates to devices and methods for administration of a therapeutic composition to the pharyngeal muscle. In particular, the devices and methods of the disclosure may be used in treatment or prevention of dysphagia, including dysphagia associated with oculopharyngeal muscular dystrophy (OPMD) in individuals suffering therefrom or predisposed thereto. Additionally, the present disclosure relates to devices and methods used to deliver modified adeno-associated virus (AAV) delivery vectors comprising 'silence and replace' DNA constructs, including compositions comprising same.

Inventors

• MUKADAM, Sophie
• BANKS, Jerel
• ST-GUILY, Jean Lacau

Assignees

• Benitec IP Holdings Inc.

Dates

Publication Date

20260506

Application Date

20240628

Claims (20)

1. 1. An injection needle comprising: a needle cannula comprising: a proximal portion having a proximal end, a distal portion having a distal end, a middle portion disposed between the proximal portion and distal portion, and a lumen extending through the proximal portion, the middle portion and the distal portion between the proximal end of the proximal portion and the distal end of the distal portion, the lumen opening at an outlet at or adjacent the distal end of the distal portion; wherein the proximal portion and the distal portion are each substantially straight and wherein the middle portion is curved such that the distal portion extends at an angle of between 75° and 105° relative to the proximal portion; and wherein the length of the proximal portion is shorter than the length of the distal portion.
2. 2. The injection needle of claim 1, wherein the distal portion extends at an angle of between about 85° and 95° relative to the proximal portion.
3. 3. The injection needle of claim 1, wherein the distal portion extends at an angle of about 90° relative to the proximal portion.
4. 4. The injection needle of claim 1 or claim 2, wherein the radius of curvature of the middle portion is between about 2.5mm and 3.1mm.
5. 5. The injection needle of any one of claims 1 to 4, wherein the proximal portion has a length that is less than 90%, less than 80%, less than 70%, or less than 60%, or less than 50% of a length of the distal portion.
6. 6. The injection needle of any one of claims 1 to 5, wherein the length of the distal portion is greater than the sum of the length of the proximal portion and a length of the middle portion.
7. 7. The injection needle of any one of claims 1 to 6, wherein the total length of the needle cannula is between about 10mm and 27mm.
8. 8. The injection needle of any one of claims 1 to 7, wherein the length of the distal portion is between about 7mm and about 15mm.
9. 9. The injection needle of any one of claims 1 to 8, wherein the length of the middle portion is between about 3 mm and about 6mm.
10. 10. The injection needle of any one of claims 1 to 9, wherein the length of the proximal portion is between about 2mm and about 6mm.
11. 11. The injection needle of any one of claims 1 to 10, wherein: the distal portion extends at an angle of between about 85° and 95° relative to the proximal portion; and a radius of curvature of the middle portion is between about 2.5mm and 3.1mm.
12. 12. The injection needle of any one of claims 1 to 11, wherein: the proximal portion has a length that is less than 70% of a length of the distal portion; the length of the distal portion is greater than the sum of the length of the proximal portion and the length of the middle portion, optionally an arc length of the middle portion; and the total length of the needle cannula is between about 10mm and 27mm.
13. 13. The injection needle of any one of claims 1 to 12, wherein: the distal portion extends at an angle of between about 85° and 95° relative to the proximal portion; the length of the distal portion is between about 7mm and 15mm; and the length of the proximal portion is between about 2mm and 6mm.
14. 14. The injection needle of any one of claims 1 to 13, wherein the needle cannula is a 26- 28 Gauge.
15. 15. The injection needle of any one of claims 1 to 14, wherein an outer diameter of the needle cannula is between about 0.3mm and about 0.5mm.
16. 16. The injection needle of any one of claims 1 to 15, wherein an inner diameter of the needle cannula is between about 0.1mm and about 0.3mm.
17. 17. The injection needle of any one of claims 1 to 16, wherein a thickness of a wall of the needle cannula is between about 0.03mm and about 0.17mm.
18. 18. The injection needle of any one of claims 1 to 17, wherein the needle cannula comprises a dead volume of between about 0.5pL/25.4mm and about 1.5pL/25.4mm.
19. 19. The injection needle of any one of claims 1 to 18, wherein the needle cannula comprises an outlet that is at or adjacent the distal end of the distal portion.
20. 20. The injection needle of any one of claims 1 to 19, wherein the needle cannula comprises a bevel formed at a distal end of the needle, wherein the bevel includes a bevelled edge that faces away from an inner bend side of the needle cannula.

Description

DEVICE AND METHODS FOR ADMINISTERING A THERAPEUTIC COMPOSITION TO THE PHARYNGEAL MUSCLE Cross-Reference to Related Applications The present application claims priority from United States Provisional Patent Application No 63/510,750 filed on 28 June 2023, the content of which is incorporated herein by reference in its entirety. Furthermore, the present applicant has recently disclosed therapeutic agents and compositions for the treatment of oculopharyngeal muscular dystrophy (OPMD) throughout the following applications: US Provisional No. 62/812,187, filed 28 February 2019; US Provisional No. 62/747,089, filed 17 October 2018; International Patent Application PCT/AU2019/051134, filed 17 October 2019; and International Patent Application PCT/AU2020/050182, filed 28 February 2020, the complete contents of which are incorporated by reference herein in their entirety. Technical Field The present disclosure relates to devices and methods for administration of a therapeutic composition to the pharyngeal muscle. In particular, the devices and methods of the disclosure may be used in treatment or prevention of dysphagia, including dysphagia associated with oculopharyngeal muscular dystrophy (OPMD) in individuals suffering therefrom or predisposed thereto Additionally, the present disclosure relates to devices and methods used to deliver modified adeno-associated virus (AAV) delivery vectors comprising ‘silence and replace’ DNA constructs, including compositions comprising same, for example. Background OPMD is a rare and slowly-progressing, late-onset muscular dystrophy that first manifests in midlife, advances with age, and is characterized by progressive ptosis, swallowing difficulties and proximal limb weakness. OPMD is caused by a specific mutation in the gene encoding PABPN1 on chromosome 14 (position ql 1 ,2-ql 3). As a result, a person with OPMD can find it increasingly difficult to swallow (dysphagia), putting them at risk of harm or death from choking, inhaling food or drinks into their lungs (aspiration), aspiration pneumonia, weight loss and malnutrition. The mutation that causes OPMD is an abnormal expansion of a (GCN)n trinucleotide repeat in the coding region of the poly(A) binding protein nuclear 1 (PABPN1) gene. The presence of the trinucleotide repeat leads to an expanded polyalanine tract at the N-terminus of the PABPN1 protein: 10 alanines are present in the normal protein, however an expansion of 11 to 18 alanines is present in the mutant form (expPABPNl). Intranuclear aggregates, designated as “intranuclear inclusions” comprise the primary histopathological hallmark of the disease. Misfolding of expanded PABPN1 protein results in the accumulation of insoluble polymeric fibrillar aggregates inside nuclei of affected cells, as PABPN1 is an aggregation prone protein. There are no medicinal products approved for the treatment of OPMD, and there are no medicinal products that have demonstrated significant alterations in the natural history of the disease. Palliative surgical interventions, such as cricopharyngeal myotomy, have been employed. Cricopharyngeal myotomy serves to release the tension on the cricopharyngeus (CP) muscle, and this surgical procedure can transiently reduce the impact of dysphagia in some patients. Direct injection of botulinum toxin (Botox) into the CP muscle has also been used to affect temporary improvements in swallowing via chemical-induced relaxation of the targeted muscle. Although both techniques can provide transient reductions in the dysphagia experienced by some patients, the oropharyngeal symptoms inevitably return and disease progression continues unabated. Repetitive dilatation of the upper esophageal sphincter has demonstrated some efficacy in OPMD patients with moderate dysphagia, however, additional clinical studies are required to corroborate results and characterize long-term outcomes. By way of background, under normal conditions, a food bolus leaves the oral cavity and is able to traverse the length of the pharynx, en route to the esophagus, via the propulsive activity of the coordinated constriction of the superior, middle, and inferior pharyngeal constrictor muscles. As the food bolus nears the opening of the upper esophagus, the subsequent relaxation of the cricopharyngeal muscle allows the bolus to enter the esophagus and travel to the stomach. In OPMD, the pharyngeal constrictor muscles are weakened and atrophic and, as a result, are unable to consistently exert the level of force required to support the food bolus propulsion that defines the normal swallowing process. Restoration of muscle fiber size and muscle force generation capacity in the weakened and atrophic pharyngeal constrictor muscles would be expected to meaningfully enhance the ability of those muscle groups to support food bolus propulsion through the pharynx and towards the esophagus. The pharyngeal constrictor muscles (inferior and middle) are, then, more relevant therapeutic targets,