AMP-101 Shows Pharmacologic and Safety Promise for Neuromuscular Disorders in Preclinical Study

The Amplo Biotechnology gene therapy showed positive findings in mouse models, suggestive of the therapy’s development for use in a clinical setting. The AAV therapy delivers DOK7 gene, which has shown benefit in neuromuscular disorders.

Patricio Sepulveda, PhD, CEO of Amplo Biotechnology

Patricio Sepulveda, PhD

According to the findings of a pharmacology and safety analysis of AMP-101, Amplo Biotechnology’s investigational gene therapy for the treatment of neuromuscular junction disorders, the agent is a promising clinical candidate with a good safety profile.1

The data were presented by Patricio Sepulveda, PhD, CEO of Amplo Biotechnology, and colleagues in a poster at the 2023 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, March 19-22, in Dallas, Texas. The group noted that all of the findings of this analysis support the further development of AMP-101 for use in a clinical setting. Sepulveda et al wrote that, “AMP-101 can be consistently manufactured at high yields and purity” and that “the [treatment’s] potency is compatible with clinical experimentation.”

The treatment was developed based on literature showing that AAV delivery of DOK7 can be beneficial in neuromuscular disorders,2,3 and to date, mouse model studies of AMP-101 have suggested that a dose of 6 x1013 vg/kg can provide functional correction of the myasthenic phenotype and extend lifespan.4,5 It utilizes a recombinant AAV serotype rh74 that is designed to express the DOK7 protein via a muscle-restricted promoter. The therapy was licensed by Amplo from the University of Tokyo via an exclusive license agreement, which was announced in September 2019.6

READ MORE: Giant Axonal Neuropathy Gene Therapy Well-Tolerated With Some Clinical Benefit

The manufacturing data showed that the therapy can be produced at scale, with the yields showing an excess of 1e14 vg/L, and all vector batches reported a 91% or greater full-to-empty ratio.1 For the pharmacology evaluations, 4-day-old mice pups were injected with escalating doses of AMP-101, beginning with 2 x1013 and increasing to 6 x1013 and 1x 1014 vg/kg. The control wild-type littermates were injected with saline. Both groups were then assessed on weight and strength, the latter of which was measured via a hang test, grip test, and rotarod. After 3 months, electromyograms were performed.

The pharmacology data showed that 2 of the 3 doses tested rescued the DOK7-KI phenotype mice at a rate of approximately 45%, with those mice living longer than 10 days. Of those mice, 90% survived the full 3-month study period and, after strength tests, were deemed either equally strong or significantly stronger than controls. Comparatively, their untreated counterparts “have severe muscle weakness, are small, fail to thrive, and do not survive longer than 10 days,” Sepulveda et al wrote.

Additionally, the study suggested that so-called super synapses—enlarged neuromuscular junctions—were observed in the diaphragm of treated mice, with some displaying a 10-times greater postsynaptic area than wild-type controls.

Regarding the safety assessment, Sepulveda et al noted that there was no reported mortality, with all animals surviving to day 29/30 or day 183/184 necropsies. No AMP-101-related macroscopic findings were observed. Safety and toxicology studies included 10-week-old C57BL/6J male and female mice, which were injected with either 6 x1013 or 2 x1014 vg/kg doses of AMP-101. Blood and tissue analyses were collected at the 15-, 30-, and 180-day marks posttreatment end points.

Read more coverage of the 2023 MDA Conference here.

1. Sepulveda P, Hawkins A, Canzonetta C, et al. Pharmacology and safety profile of AMP-101, DOK7 gene therapy to stabilize the neuromuscular junction. Presented at: MDA Clinical & Scientific Conference; March 19-22, 2023; Dallas, TX. Poster 305.
2. Okada K, Inoue A, Okada M, et al. The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science. 2006 312(5781):1802-1805. doi:10.1126/science.1127142
3. Beeson D, Higuchi O, Palace J, et al. Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science. 313(5795):1975-1978. doi:10.1126/science.1130837.
4. Arimura S, Okada T, Tezuka T, et al. DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction. Science. 2014;345(6203):1505-8. doi:10.1126/science.1250744
5. Miyoshi S, Tezuka T, Arimura S, Tomono T, Okada T, Yamanashi Y. DOK7 gene therapy enhances motor activity and life span in ALS model mice. EMBO Mol Med. 2017;9(7):880-889. doi:10.15252/emmm.201607298
6. Amplo Licenses Aav-DOK7 for Congenital Myastenia From University of Tokyo. News release. Amplo Biotechnology. September 2019. Accessed March 21, 2023.
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