Preclinical Development and Safety of Laterally Spreading Dual AAV.SPR-MYO7A Vectors for the Treatment of…

Abstract

Usher syndrome type 1B (USH1B), caused by mutations in MYO7A, is the most severe form of Usher syndrome and accounts for more than 50% of USH1 cases. Affected patients are born profoundly deaf with vestibular dysfunction and develop progressive retinitis pigmentosa, for which no approved treatment exists. The MYO7A coding sequence exceeds the packaging capacity of adeno-associated virus (AAV), the gold standard vector for retinal gene therapy. To overcome this, we developed dual AAV hybrid and overlap platforms to reconstitute full-length MYO7A expression in photoreceptors and retinal pigment epithelium. Modification of cDNA split points, and reduction of non-coding sequence yielded optimized vector pairs that produced higher full-length MYO7A levels with substantially reduced truncated protein. Packaging in the laterally spreading AAV.SPR capsid enabled supraphysiological MYO7A expression in cynomolgus macaques at macular and distal retinal sites without requiring foveal detachment, an important safety consideration for USH1B patients with remaining central vision. A six-month GLP toxicology study confirmed that ATSN-301, an AAV.SPR-based dual vector reconstituting MYO7A driven by the smCBA promoter, was well tolerated at all doses, with a No Observed Adverse Effect Level established at 1.2E11 vg/eye, supporting its clinical advancement for USH1B.

Cortical dynamics in Angelman syndrome: novel insights from a preclinical mouse model
Manuel Scorrano, Elena Montagni, Abenezer Tarekegne Legesse +5
Translational Psychiatry29 Aug 2026Peer-reviewedCC BY-NC-ND 4.0Full textGenetics & genomicsPMC
Gene expression analysis of Fmr1-KO mouse caudate putamen reveals new preclinical biomarkers for fragile X syndrome
Shirin Sharghi, Stefanie Flunkert, Magdalena Daurer +3
Frontiers in Neuroscience23 Oct 2026Peer-reviewedCC BY 4.0Full textGenetics & genomicsCrossrefDOAJ
Computational modeling and preclinical evaluation support targeting somatic instability for Huntington’s disease treatment
Bryan P. Simpson, Paul T. Ranum, David E. Leib +14
Nature Communications28 Oct 2026Peer-reviewedCC BY-NC-ND 4.0Full textNeuroscienceCrossrefEurope PMCPMC
DDU384: A new preclinical candidate for the treatment of Tuberculosis
Simon R. Green, Kirsteen I. Buchanan, Helena I. M. Boshoff +31
bioRxiv26 Oct 2026PreprintCC BYFull textMicrobiologybioRxivPMC
Drug-Development Potential of Muntingia calabura L.: A Systematic Review of Ethnopharmacological Use, Pharmacological Potency, Preclinical Evidence, and Plant-Mediated Nanotechnology
Raden M Febriyanti, Aalbrecht A Irawan, Zelika Mega Ramadhania +4
Drug Design, Development and Therapy27 Oct 2026Peer-reviewedCC BY-NC 4.0Full textPlant biologyPMC

Cite

BibTeX RIS

BibTeX

@misc{calabro2026preclinical,
  title = {{Preclinical Development and Safety of Laterally Spreading Dual AAV.SPR-MYO7A Vectors for the Treatment of Usher Syndrome Type 1B}},
  author = {K. R. Calabro and E. Andres-Mateos and C. Kozlowski and P. S. Nemec and E. M. Xu and S. M. Crosson and D. Fajardo and H. L. Friend and J. J. Peterson and W. Li and H. Zhang and H. L. Sweeney and V. Stevenson and H. Rind and M. Leahy and R. F. Boyd and S. L. Boye and S. E. Boye},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.24.760972},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.24.760972v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Preclinical Development and Safety of Laterally Spreading Dual AAV.SPR-MYO7A Vectors for the Treatment of Usher Syndrome Type 1B
AU  - K. R. Calabro
AU  - E. Andres-Mateos
AU  - C. Kozlowski
AU  - P. S. Nemec
AU  - E. M. Xu
AU  - S. M. Crosson
AU  - D. Fajardo
AU  - H. L. Friend
AU  - J. J. Peterson
AU  - W. Li
AU  - H. Zhang
AU  - H. L. Sweeney
AU  - V. Stevenson
AU  - H. Rind
AU  - M. Leahy
AU  - R. F. Boyd
AU  - S. L. Boye
AU  - S. E. Boye
PY  - 2026
DA  - 2026/10/24
PB  - bioRxiv
DO  - 10.64898/2026.10.24.760972
UR  - https://www.biorxiv.org/content/10.64898/2026.10.24.760972v1
AB  - Usher syndrome type 1B (USH1B), caused by mutations in MYO7A, is the most severe form of Usher syndrome and accounts for more than 50% of USH1 cases. Affected patients are born profoundly deaf with vestibular dysfunction and develop progressive retinitis pigmentosa, for which no approved treatment exists. The MYO7A coding sequence exceeds the packaging capacity of adeno-associated virus (AAV), the gold standard vector for retinal gene therapy. To overcome this, we developed dual AAV hybrid and overlap platforms to reconstitute full-length MYO7A expression in photoreceptors and retinal pigment epithelium. Modification of cDNA split points, and reduction of non-coding sequence yielded optimized vector pairs that produced higher full-length MYO7A levels with substantially reduced truncated protein. Packaging in the laterally spreading AAV.SPR capsid enabled supraphysiological MYO7A expression in cynomolgus macaques at macular and distal retinal sites without requiring foveal detachment, an important safety consideration for USH1B patients with remaining central vision. A six-month GLP toxicology study confirmed that ATSN-301, an AAV.SPR-based dual vector reconstituting MYO7A driven by the smCBA promoter, was well tolerated at all doses, with a No Observed Adverse Effect Level established at 1.2E11 vg/eye, supporting its clinical advancement for USH1B.
ER  -

Abstract

Related

Cite