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Comment by DiversityRules | Hacker News Reader

Does the strengthening of neural connections only work with people with that specific gene? Could this be extended to other cortical visual disorders, such as amblyopia?

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The protein, RPE65 [1][2] allows cells to produce a required pigment necessary for both rod and cone-mediated vision. Getting that sequence into the (correct cells in the) patient was the hard part. This particular protein helps prevent blindness in these patients precisely because their natural version of this protein is an ineffective variant of the canonical RPE65 (the sequence of the RPE65 they have is different or truncated from the sequence in [1]). The delivery via Adeno-associated virus works because the eye is special - immunologically privileged. So gene therapies work well for tissues that are immunologically privileged, or can be extracted from the body, affected, and then re-implanted (the eyes and T-cells respectively). This allows the therapy itself to avoid triggering your immune system and fighting the therapy. This is why most of the first gene therapies you will see here soon are targeted towards these two systems.

Different disorders will require addressing the truncations/deviations of different proteins. But if the delivery mechanism works properly, and the knowledge about which proteins are ineffective for particular diseases, this [gene therapy] is the mechanism for curing a whole host of diseases not caused by a foreign agent. At this point, the delivery is the significant technological hurdle. Combined with the effectiveness of Cas9-genomic targeting, and the past 20 years of reading genetic code, there is a lot here to watch.

[1] the 534 amino acids of RPE65 that are required - to the bit - in order to see:

  MSIQVEHPAGGYKKLFETVEELSSPLTAHVTGRIPLWLTGSLLRCGPGLFEVGSEPFYHLFDGQALLHKFDFKEGHVTYHRRFIRTDAYVRAMTEKRIVITEFGTCAFPDPCKNIFSRFFSYFRGVEVTDNALVNVYPVGEDYYACTETNFITKINPETLETIKQVDLCNYVSVNGATAHPHIENDGTVYNIGNCFGKNFSIAYNIVKIPPLQADKEDPISKSEIVVQFPCSDRFKPSYVHSFGLTPNYIVFVETPVKINLFKFLSSWSLWGANYMDCFESNETMGVWLHIADKKRKKYLNNKYRTSPFNLFHHINTYEDNGFLIVDLCCWKGFEFVYNYLYLANLRENWEEVKKNARKAPQPEVRRYVLPLNIDKADTGKNLVTLPNTTATAILCSDETIWLEPEVLFSGPRQAFEFPQINYQKYCGKPYTYAYGLGLNHFVPDRLCKLNVKTKETWVWQEPDSYPSEPIFVSHPDALEEDDGVVLSVVVSPGAGQKPAYLLILNAKDLSEVARAEVEINIPVTFHGLFKKS

[2] http://www.uniprot.org/uniprot/Q16518

Definitely strongly agree with delivery being the most significant hurdle. Many problems arise from difficulty delivering gene therapies via viral vectors, most notably treatment efficacy and treatment durability, which should never really be a problem because you're replacing the genes. There's also the much-feared off-target effects, which can and do rapidly and gruesomely kill people in the gene therapy clinical trials-- an eminently solvable problem given more research into the correct epitope targeting, I think.

Most of the current viral delivery vectors are shitty in a multitude of ways, but the kinks are being rapidly worked out for AAVs and lentiviruses. Crispr/Cas9 genome engineering is also a huge leap forward, as you mentioned. It's important to note that some groups were having luck with gene therapy even before Crispr, though-- imagine what they can do now, barely two years later. The door to de novo synthetic biology has been kicked open.

As someone with glaucoma and bilateral amblyopia (I had congenital cataracts in both eyes) the answer to this interests me greatly!

I'd also add:

Will this kind of gene therapy allow protection or regeneration of the optic nerve?

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