JAN WIJNHOLDS' CRB1 GENE THERAPY PROGRAM

Jan Wijnholds’ CRB1 gene therapy program

at LUMC, The Netherlands

Below are the answers to six key questions regarding Jan Wijnholds’ CRB1 gene therapy program.

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1.?Eligibility

Question:

If a patient has already lost a significant number of photoreceptors (i.e. rods and cones), is it possible that they might not have enough living photoreceptors for LUMC’s gene therapy to work??

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Answer:

From animal studies, it seems that only very few photoreceptors are needed to give substantial vision.?So, as long as there are some intact rods and cones, this gene therapy could work.?

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2.?Stopping vision deterioration

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Would LUMC’s gene therapy stop vision getting worse by protecting the remaining intact photoreceptors?

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Answer:

The aim is that the gene therapy product would permanently stop further retinal degeneration (i.e. loss of rods and cones) by maintaining structural interactions between different types of retinal cells (i.e. rods, cones and Muller glial cells).?Whether the gene therapy would indeed permanently stop rods and cones from dying needs to be explored in further experiments and through clinical studies. ?However, from previous studies, it can already be predicted that the gene therapy product would last for more than 10 years, thereby at least significantly delaying further retinal degeneration.

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3.?Improving vision

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Question:

Does LUMC’s gene therapy aim to improve vision by restoring dead or dying rods and cones?

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Answer:

The gene therapy would not restore dead photoreceptors.?However, it could improve vision by rescuing/restoring the function of disorganised (i.e. dying) photoreceptors through stimulating interaction and signalling between the disorganised rods, cones and Muller glial cells in the retina.?This in turn would stimulate transmission of signals from the photoreceptors to the inner retinal neurons, and then to the ganglion cells, and then to the visual cortex, resulting in improved vision. ?Experimental studies are underway to establish this hypothesis.

4.?Effect on retinal cells

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Could LUMC’s gene therapy program result in the creation of additional photoreceptors or Muller glial cells or any other helpful retinal cells??

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Answer:?

No, the CRB gene augmentation therapy program will help photoreceptor and Muller glial cells to adhere to each other, and thereafter allow proper formation of photoreceptor synapses and light sensitive photoreceptor outer segments, with functional Muller glial cells that nurture the photoreceptors. ?Only the existing living photoreceptors, Muller glial cells and retinal pigment epithelial cells will benefit. ?It is not likely that additional photoreceptors, Muller glial cells, or other retinal cells will be created.

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5.?LCA and RP differences

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With LUMC’s gene therapy, are there different factors to consider for LCA patients as compared with RP patients?

Answer:

In the case of RP patients, there is a relatively long period available for application of the gene therapy vector and subsequent potential functional recovery of the retina.?In the case of LCA in newborns, there is a relatively short period available for timely application of the gene therapy vector and therefore also less time for effective functional recovery of the retina.?Compounds/factors need to be identified that delay the serious disorganisation in LCA retina such that there is a relatively longer period available for timely application of the CRB gene therapy vector.

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6.?Significance of mutations

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Question:

Would the identity of a patient’s two mutations affect the outcome of LUMC’s gene therapy??

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Answer:

Mutations in CRB1 can cause RP, LCA and macular degeneration (MD). ?Surprisingly, people can have exactly the same two mutations (and so, the same genotypes) but develop either RP, LCA or MD (and so, different phenotypes).?It is likely that a combination of the patient’s other genes, the identity of the two mutations on the CRB1 gene copies and also non-genetic factors have an effect on phenotype and gene therapy outcome but the details are not clear.?Experimental studies on CRB1 disease mechanism are underway to provide more clarity.