Phase I otoferlin gene therapy trial concludes this is “safe and efficacious as a novel treatment for children with autosomal recessive deafness 9”.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)02874-X/abstract
Otoferlin is one among more than 150 genes known to cause deafness in humans. Otoferlin is responsible for 1–8% of congenital, nonsyndromic hearing loss.
That was on the BBC news here yesterday. It’s a great treatment for those with the particular genetic condition. Hopefully it will lead to better research and more money put towards progressive SN losses too.
Yes - I thought of your post when I read this the other day. Great step forward for many.
Thanks for posting! I was a baby (well DECADES ago!) born with sensorineural deafness that runs in my family - which I think is one of the types of “autosomal recessive deafness” mentioned. It’s not WAY uncommon, according to the publication here:
<< Sensorineural hearing loss is one of the most common sensory deficits in humans, affecting one to two per 1000 newborns in developed countries [1]. Over the past 25 years since the discovery of the first deafness gene, more than 120 genes have been causally associated with non-syndromic hearing loss (https://hereditaryhearingloss.org/) and over 6000 disease-causing variants have been identified [2]. As most variants implicated in hearing loss are small insertions/deletions (indels) or single nucleotide variants [2], high-throughput sequencing is a well-suited method to rapidly allow for a deeper understanding of the spectrum of variants involved in deafness and their consequences on the auditory phenotype.>>
I wonder if I’m TOO OLD now for such a gene therapy treatment? It looks promising.
Whether this works probably mostly hinges on the question at what age re-expressing the misbehaving gene can still restore the problem. While AAV appears safe to use here as a vector, its cargo capacity is small (about 5 kbp, if I remember well), but it can still be used for more subtle gene corrections (CRISPR). It is rather fortunate that the inner ear is so small, relatively accessible and about identical in other mammals (so mouse studies are predictable). On the downside, there are indeed many types of mutations, and each cure will need to be trialled separately (so nothing will be done except for the most frequent mutations, and even then there will be cost/benefit issues). On the plus side, some genes (like neurotrophic factor) may also be used for acquired deafness (a huge market).
As you say, all well in the future…
That sounds encouraging! But the many types of variations in mutations seems daunting. I wonder if all mammals have that variation, or if it’s just us HUMANS. Oh, to be a MOUSE in the lab and have my cinderblock ears FIXED.
I suspect the genetics required to develop our hearing is very well conserved among all mammals as well (in sharp contrast with, say, our immune systems). Also, making transgenic mice (carrying the same mutations that cause deafness in humans) is fairly straightforward these days. So you can test if those defects can be corrected and restore hearing after birth in those animals. All feasible, but expensive. Pharmacoenomics (the bean counters in Pharma) are the biggest obstacle here…
Alternatively- once gene therapy in humans becomes standard (for the common forms), ethical commitees might approve trying to restore genetic defects in patients without going through the animal model pathway.
A recent survey in Iran listed mutations and their frequencies:
COOL! Instead of finding distant ancestors with 23ANDMe, I’d much rather know where my own defective gene(s) appear on the pie chart!
(Oh, if someone said Beethoven had the SAME defective gene, I’d feel flattered, even tho I’m no musician.)
Finding out the exact nature of a genetic defect that causes (non-syndromic) deafness is not very easy, though. What 23 and Me does is testing about 640,000 SNPs (single-nucleotide polymorphisms). They don’t sequence your entire genome (called WGS) but look at variations known to occur in the human population (many if which are non-coding, or synonymous, producing the same protein), so this is more like a fingerprint. If deafness runs in a family, investigators will usually first need to track down the particular chromosome that co-segregates with the condition, then narrow the gene down. In some cases, though, known defects (say a small mutation) is surrounded by known SNPs, and then 23 and Me may flag it.
