Summary: To behave Usher syndrome type 1F, a uncommon condition that causes deafness and liberal blindness, researchers have created a dual-gene treatment strategy. By separating the huge PCDH15 protein into two halves, delivering them via adeno-associated viruses, and reassembling them in cells, the remedy restored reading and stability in mice.
Testing in mortal eye organoids and animal corneas showed increased levels of protocadherin-15 in light-sensing cells, offering desire for perspective protection. This discovery provides a back gene therapy plan for Usher syndrome patients who have lost both their hearing and vision.
Important Information:
- In Usher illness mouse models, dual-AAV treatment restored balance and hearing.
- Macular tests suggest that humans and primates might be able to maintain perspective.
- If previous protein treatments fail, the counseling offers a second approach.
Origin: Harvard
Researchers at Harvard Medical School have made yet another important step in their quest to create a gene therapy for people who suffer from Usher syndrome type 1F, a unique situation that leads to progressive deafness and deafness.
A new way of delivering a corrected version of the faulty gene that causes Usher symptoms — , PCDH15 , — restored hearing in keyboard designs and showed potential in ocular organoids and nonhuman primates for improving eyesight, the crew reports , in the , Journal of Clinical Investigation.
The lab of David Corey, the Bertarelli Professor of Translational Medical Science at HMS, developed this second novel gene therapy for Usher syndrome. Earlier research showed that , a different gene-delivery strategy restored hearing , in mice.
If the first approach is deemed unsafe or ineffective in human testing, the new method offers a second option.
” Without a clinical trial in humans, we ca n’t know whether our first gene therapy restores normal function”, said , Corey, senior author of the study. In the event that the initial therapy fails, this new approach provides a backup. It might even turn out to be better than the first, once tested in patients”.
More strategies, more chances to cure
A central challenge in designing a therapy with the , PCDH15 , gene is that it’s too big to fit inside the hollowed-out shell of an adeno-associated virus, or AAV— the most common and safest vehicle used to carry genes into target cells.
The team’s earlier strategy involved trimming down , PCDH15 , into a mini gene that could fit in an AAV.
The new approach involves dividing the entire gene into two, putting each half into an AAV, and delivering the AAVs to the inner ear or eye. There, the halves rejoin and start instructing the cells to make the protein the gene codes for, protocadherin-15, correctly.
People with Usher syndrome type 1F are born without hearing or feeling in tune, and they eventually lose their vision. The mice’s hearing and balance were restored thanks to the new method.
The team was unable to determine whether existing mouse models ‘ vision improved because they do not go through the same process as Usher syndrome type 1F.
However, the dual-AAV therapy raised levels of protocadherin-15 in the light-sensing cells of human retinal organoids and nonhuman primate retinas. In those cells, the protein also migrated in the appropriate location. According to both findings, the treatment plan may one day help to preserve patients ‘ vision.
” These results are particularly exciting because, while cochlear implants can address hearing loss in human patients, there are currently no treatments for the vision dysfunction associated with Usher syndrome”, said first author , Maryna Ivanchenko, HMS instructor in neurobiology in the Corey Lab and an ophthalmologist.
Authorship, funding, disclosures
The Corey Lab collaborated with Swiss researchers at Basel’s Institute for Molecular and Clinical Ophthalmology and Basel University. Additional authors are Daniel M. Hathaway, Eric M. Mulhall, Kevin T. Booth, Mantian Wang, Cole W. Peters, Alex J. Klein, Xinlan Chen, Yaqiao Li, and Bence György.
Funding: This work was supported by the National Institutes of Health ( grants R01-DC016932 and R01-DC020190 and fellowship T32-GM007748 ), the Bertarelli Foundation, the Seamans Family, and the Swiss National Science Foundation ( grants PCEFP3_202756 and 310030_192665 ). The authors acknowledge the Usher 1F Collaborative’s ongoing support for the HMS MicRoN Microscopy Core and Electron Microscopy Facility.
U.S. Provisional Application No. 58 has been submitted by Harvard College President and Fellows. 18/025, 719, DUAL-AAV VECTOR DELIVERY OF PCDH15 AND USES THEREOF, with Corey, Mulhall, and Ivanchenko listed as inventors. The other authors have made it clear that there is no interest conflict.
About this genetics, vision, and auditory neuroscience research news
Author: Stephanie Dutchen
Source: Harvard
Contact: Stephanie Dutchen – Harvard
Image: The image is credited to Maryna Ivanchenko
Original Research: Open access.
“PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F Models” by Maryna Ivanchenko et al. Journal of Clinical Investigation
Abstract
PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F Models
Usher syndrome type 1F ( USH1F), resulting from mutations in the protocadherin-15 (PCDH15 ) gene, is characterized by congenital lack of hearing and balance, and progressive blindness in the form of retinitis pigmentosa.
In this study, we explore an approach for , USH1F , gene therapy, exceeding the single AAV packaging limit by employing a dual adeno-associated virus ( AAV ) strategy to deliver the full-length , PCDH15 , coding sequence.
We demonstrate the effectiveness of this technique in mouse USH1F models, which successfully restores these animals ‘ hearing and balance.
Importantly, our method also succeeds in expressing PCDH15 protein in clinically relevant retinal organoids and non-human primate retinas, demonstrating effective photoreceptor targeting and proper protein expression in calyceal processes.
This research represents a major step toward advancing gene therapy for USH1F and the multiple challenges of hearing, balance, and vision impairment.
