VP48 AOC 1001 demonstrates DMPK reduction and spliceopathy improvement in a phase 1/2 study in myotonic dystrophy type 1 (DM1) (MARINA)
DM1 is a rare, autosomal dominant, progressive neuromuscular disease with no approved therapies. DM1 is caused by a toxic CTG repeat expansion (>50) in the myotonic dystrophy protein kinase (DMPK) gene. Mutant DMPK expression leads to the accumulation of toxic gain-of-function mRNA in the nucleus where it sequesters splicing factors resulting in global splicing dysregulation. AOC 1001 is a humanized anti-transferrin receptor 1 (TfR1) antibody conjugated to a siRNA targeting the DMPK mRNA (siDMPK) designed to reduce DMPK mRNA in muscle tissue and correct mis-spliced events that are responsible for DM1 pathogenesis. (Source:...
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: Y. Zhu, T. Kwan, Q. Meng, L. Tai, H. Cho, M. Lee, H. Younis, A. Levin, M. Flanagan Source Type: research
P49 The efficacy and safety of Tideglusib in a randomized, placebo-controlled, double blind study in children and adolescents with congenital myotonic dystrophy (REACH CDM study)
Congenital Type 1 myotonic dystrophy (CDM1) is a severe, life-threatening disorder that affects approximately 1 in 40,000 children. It is caused by a genetic defect (i.e. excessive base pair repeats) in the region of the DMPK gene on chromosome 19. Affected youth experience a multitude of physiological problems, including muscle weakness, respiratory issues, gastrointestinal problems, and fatigue, while also experiencing cognitive challenges, speech and communication difficulties, as well as features of autism spectrum disorder. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: J. Horrigan, M. Snape, E. Fantelli Source Type: research
P50 A phase 1/2 randomized, placebo-controlled, multiple ascending dose study (ACHIEVE) of DYNE-101 in individuals with myotonic dystrophy type 1 (DM1)
DM1 is a severe neuromuscular disease caused by expanded CUG triplets in the dystrophia myotonica protein kinase (DMPK) RNA, which sequester splicing proteins into toxic nuclear foci resulting in a spliceopathy that drives disease progression. As there are no approved disease-modifying therapies, treatment of DM1 is limited to symptom management. The FORCE ™ platform was developed to overcome limitations of oligonucleotide delivery to muscle by harnessing the expression of transferrin receptor (TfR)1 on muscle cells. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: D. Wolf, C. Mix, B. Han, A. Dugar, W. Farwell Source Type: research
P51 Phase 1/2 study to evaluate AOC 1020 for adult patients with facioscapulohumeral muscular dystrophy: FORTITUDE trial design
The aim of the study is to evaluate the safety and tolerability of single and multiple ascending doses of AOC 1020 in participants with FSHD. FSHD is a rare, progressive, often asymmetric, genetic disease caused by aberrant expression of the transcription factor DUX4 in skeletal muscle, leading to a series of downstream events that result in degeneration and wasting. Strategies targeting DUX4 expression in skeletal muscle of individuals with FSHD via oligonucleotides are promising therapeutic approaches. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: A. Halseth, E. Ackermann, T. Brandt, C. Chen, H. Cho, M. Stahl, K. DiTrapani, S. Hughes, R. Tawil, J. Statland Source Type: research
P52 Experiences of parents/caregivers of children in the ASPIRO X-Linked myotubular myopathy (XLMTM) gene therapy clinical trial: a qualitative study
X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy characterized by profound muscle weakness and hypotonia at birth, along with severe respiratory insufficiency. We conducted semi-structured in-depth interviews with caregivers of children with XLMTM participating in the ASPIRO gene therapy clinical trial. ASPIRO (NCT03199469) is a first-in-human clinical trial of an adeno-associated virus (AAV)-mediated, muscle-directed gene replacement therapy (resamirigene bilparvovec; ie, AT132) in boys with ventilator-dependent XLMTM. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: C. Juando-Prats, K. Hodwitz, N. Kenneally, L. Alfano, M. Sarazen, J. Coats Source Type: research
P53 Inclusion body myositis treatment with Celution processed adipose derived regenerative cells
Inclusion Body Myositis (IBM) is a progressive, debilitating disease leading to proximal and distal muscle weakness, most prominently in the quadriceps and finger flexors. The Celution 800/CRS System is a closed, automated system intended to digest adipose tissue to further extract, wash, and concentrate stromal stem cells and other associated progenitor cells intended for autologous reimplantation in a real-time bedside manner. The primary objective of this study is to assess in IBM the safety of an autologous graft consisting of adipose-derived regenerative cells (ADRCs) derived from the Celution 800/CRS System. (Source:...
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: A. Heim, R. Soder, D. Bhavsar, A. Ciersdorff, M. Pasnoor, O. Jawdat, D. Jabari, C. Farmakidis, S. Chandrashekhar, M. Dimachkie Source Type: research
P54 T-cell response to SRP-9001 dystrophin transgene in a patient treated with Delandistrogene Moxeparvovec: a case of immune-mediated myositis
This study had a single case of immune-mediated myositis (IMM) in a patient with a deletion of exons 3 –43 of the DMD gene. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: S. Khan, H. Haegel, A. Hollenstein, C. Wandel, K. Wagner, D. Asher, D. Griffin, R. Potter, I. Moeller, T. Singh, L. Rodino-Klapac Source Type: research
VP55 Topline data analysis of the phase 1/2 clinical trial evaluating AOC 1001 in adult patients with myotonic dystrophy type 1: MARINA
The primary objective of this study is to evaluate the safety and tolerability of single and multiple ascending doses of AOC 1001 in adults with myotonic dystrophy type 1 (DM1). DM1 is a rare, dominantly inherited, progressive neuromuscular disease caused by a toxic gain-of-function mutation in the DM1 protein kinase (DMPK) gene. Currently, no disease-modifying therapies exist. AOC 1001 is an antibody oligonucleotide conjugate (AOC ™) comprised of a DMPK siRNA conjugated to a humanized antibody targeting human transferrin receptor 1 (TfR1), designed for functional delivery to muscle cells, where it can reduce the toxic...
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: N. Johnson, J. Day, J. Hamel, C. Thornton, S. Subramony, P. Soltanzadeh, J. Statland, M. Wicklund, W. Arnold, M. Freimer, K. DiTrapani, C. Heusner, C. Chen, H. Cho, B. McEvoy, Y. Zhu, L. Tai, E. Ackermann Source Type: research
P56 Preliminary study of anti-AAVrh74 seroprevalence following gene transfer
The increasing number of gene therapy studies and exclusion of candidates from clinical trials highlights the potential importance of pre-existing antibodies targeting viral capsid. Viral antibodies block transduction and preclude expression of the transferred gene. Provoked immune response could also be a threat to safety. Testing patients for pre-existing antibodies, either neutralizing (Nabs) or total/binding (TAbs/BAbs), prior to gene transfer is a critical step in the initiation of a clinical trial. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: E. D'Ambrosio, L. Tong, B. Ozes Ak, K. Lehman, Z. Sahenk, J. Mendell Tags: THERAPIES FOR NEUROMUSCULAR DISORDERS Source Type: research
P57 ORAI1 inhibition as a preclinical therapy for tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK)
Tubular aggregate myopathy (TAM) is characterized by childhood-onset upper and lower limb muscle weakness, myalgia, and cramps. Most patients manifest additional multi-systemic signs including short stature, thrombocytopenia, and hyposplenism, and the full clinical picture is referred to as Stormorken syndrome (STRMK). TAM/STRMK is caused by mutations in STIM1 or ORAI1, both encoding key players in Ca2+ homeostasis. Ca2+ serves as a second messenger for various biological processes and is essentially stored in the reticulum. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: R. Silva-Rojas, L. P érez-Guàrdia, A. Simon, S. Djeddi, S. Treves, J. Laporte, J. Bohm Source Type: research
P58 WITHDRAWN Cardiomyocyte death after AAV gene transfer can be related to proteotoxicity or to transgene abnormal function or localization
Gene delivery technologies based on adeno-associated virus vectors (AAV) have yielded promising results for the treatment of monogenic diseases, leading in recent cases to marketing authorization in Europe and US. However, preclinical studies and clinical trials have highlighted that infusing high vector doses can trigger immune responses or induce cytotoxicity in a number of organs, leading in a few cases to the death of the patient. In the wake of signs of cardiac suffering in humans after gene transfer in SMA, DMD and MTM1, we investigated the consequences on the heart of administration of high doses of AAV vectors expr...
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: A. Biquand, E. Gicquel, J. Poupiot, A. Brureau, I. Richard Source Type: research
P59 Generation and characterization of a novel XMEA mouse model and pharmacological evaluation of autophagy antagonists
X-linked myopathy with excessive autophagy (XMEA) is a rare autophagic vacuolar myopathy, characterized by progressive proximal weakness, internalization of capillaries, muscle fiber splitting, high levels of serum creatine kinase and accumulation of cytoplasmic autophagic vacuoles. VMA21 pathogenic mutations reduce the efficiency of autolysosome to acidify proteins resulting in the accumulation of vacuolar inclusions in XMEA patients. The VMA21 protein maintains the V-ATPase protein pump, which is responsible for the acidification of lysosomes, and is disrupted in XMEA. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: M. Karuppasamy, K. English, V. Sanders, M. Lopez, G. Kaur, L. Worthey, L. Huang, J. Dowling, M. Alexander Source Type: research
P60 Developing a decision-making framework for expanded access to gene therapy in rare neuromuscular diseases
Expanded access (EA) to investigational medicines offers a potential lifeline for patients suffering from a serious or life-threatening disease, who have exhausted other comparable or satisfactory alternative therapeutic options and are not eligible to enter a clinical trial. The 21st Century Cures Act requires that a company developing investigational medicines should make a policy regarding EA public and readily available. Navigating through EA can be challenging due to a number of considerations, such as the stage of clinical development, the safety profile of the investigational medicine, commercialization plans and th...
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: C. Lawrence Source Type: research
P61 High dose localized muscle irradiation: Hedgehog pathway as a new therapeutic target
Acute localized irradiation accidents may evolve into a cutaneous radiation syndrome which leaves, in spite of a reference treatment, an important underlying muscle defect. Therefore, identification of new therapeutic targets to improve post-irradiation muscle regeneration is necessary. The effect of the pro-myogenic Hedgehog signaling pathway modulation by recombinant Sonic Hedgehog (rShh; agonist) or cyclopamine (antagonist) was studied in vitro on irradiated pre-myoblasts C2C12 (5 Gy, X-Rays). (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: E Rota Graziosi, S. Fran çois, J. Pâteux, M. Gauthier, M. Drouet, D. Riccobono, N. Jullien Source Type: research
P62 SIMPATHIC: accelerating drug repurposing for rare neurological, neurometabolic and neuromuscular disorders by exploiting SIMilarities in clinical and molecular PATHology
Drug repurposing can fill an important gap for rare disease patient groups with large unmet medical needs. In comparison to traditional drug development, drug repurposing reduces the time and costs for drug development, because safety data are mostly available. Yet, the road from initial discovery to regulatory approval and market authorization can be winding and long. We need to increase the efficiency of the drug repurposing pathway to provide broader access to new therapeutic modalities for larger groups of patients. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: P. 't Hoen, L. Benkemoun, A. Prigione, I. Boussaad, M. de Kort, A. Geille, H. Lochm üller, N. Voermans, B. van Engelen, C. van Karnebeek Source Type: research
