Towards Targeted Gene Therapy for Hair Cell Regeneration in the Inner Ear
Age-related deafness is caused by some mix of loss of sensory hair cells of the inner ear, and loss of connections between those cells and the brain. A range of potential approaches to restore those cells are under development, and the work here is an example of this sort of work. Researchers have constructed an AAV viral vector that has some specificity for hair cells and nearby supporting cells, and which can be used to deliver a gene therapy payload that converts those supporting cells into new hair cells.
Cells of the cochlea, such as hair cells (HCs) and supporting cells (SCs), are essential for hearing. While sensorineural hearing loss can result from genetic mutations in both HCs and SCs, non-genetic stresses, such as noise, ototoxic medicines, or aging, can also induce deafness through damaging HCs. In either case, these damages are irreversible in mammals who do not have the ability to regenerate cochlear cells. Notably, SCs have the potential to transdifferentiate into HC-like cells.
Gene therapies have emerged as important treatments for genetic diseases, and current progress also demonstrates their potential for treating hearing loss. Several genes, such as tmc1, clrn, and otof, when being delivered to cochleae, can restore hearing function in animal models. Adeno-associated viruses (AAVs) have been shown to possess high safety in both animal models and humans. Previously, we developed a synthetic AAV, AAV-ie, which targets SCs and HCs. AAV-ie can regenerate HC-like cells through delivering the transcription factor, Atoh1, which transdifferentiates SCs into HC-like cells. However, its targeting efficiencies for SCs or HCs need to be improved, especially in the basal region of cochleae.
In the present study, we performed mutational screening on the AAV-ie capsid. We generated a repertoire of mutants on the amino acid sequence of AAV-ie capsids to manipulate phosphorylation/ubiquitination of AAVs in cells. We demonstrated that a particular amino acid-mutant AAV-ie capsid, AAV-ie-K558R, can transduce SCs with high efficiency and is suitable for correcting dysfunctional genetic mutations or for HC-like regeneration.
Are there any timelines for human trials ?
I have heard of none. Pun intended...
Mutating AVV varients to try and find one more specific to a particular cell type does not seem like a promising approach to me. It seems possible, but slow, expensive, and not effective enough.
Perhaps Oisin's lipid nanoparticles could contain the LOCKR proteins invented by David Baker's lab to more specifically and effectively target certain cell types.
All the cells in an infected area would get a package delivered to them, but only in cells with certain combinations of internal proteins of mRNA would the treatment/gene therapy be activated.
https://www.fredhutch.org/en/news/spotlight/2022/02/ccg-lajoie-science.html
"Co-LOCKR stands for Colocalization-dependent Latching Orthogonal Cage/Key pRoteins. The system was designed by Drs. Lajoie, Boyken, and Salter, from the Baker and Riddell Labs, to lock onto cells following Boolean AND, OR, and NOT operators. Engineered proteins referred to as the "Cage" and "Key" can be created to recognize specific and distinct cell surface markers. The synthetic proteins are then mixed with heterogeneous populations of cells and Co-LOCKR is recruited to cells that display the matching combinations of markers and avoid cells that lack either of the markers. Once the Cage and Key co-localize on a cell's surface, they change shape to reveal a hidden segment of protein that can execute additional functions like fluorescing (glowing) or recruiting cytotoxic T-cells."
This bit of the article also stood out:
"Using Cages that fluoresce when active, the authors first showed that Co-LOCKR was only functional when bound to the cell surface rather than when floating untethered in solution. It was also capable of specifically labelling sub-populations of cells expressing distinct antigens in a heterogeneous pool. "
Imagine if the SENS RF or Methuselah foundation funded the Baker lab to create a fluorescent maker of senescent cells, so the senescent cell burden in skin tissue could be measured via a simple local injection? What gets measured gets done...