Gene therapy: Novel targets for congenital blindness

Date:
September 2, 2020
Source:
Ludwig-Maximilians-Universita"t Mu"nchen
Summary:
Retinitis pigmentosa is the most prevalent form of congenital
blindness.

Using a retinitis pigmentosa mouse model, researchers have now
shown that targeted activation of genes of similar function can
compensate for the primary defect.



FULL STORY ========================================================================== Retinitis pigmentosa is the most prevalent form of congenital
blindness. Using a retinitis pigmentosa mouse model, researchers from Ludwig-Maximilians Universitaet (LMU) in Munich have now shown that
targeted activation of genes of similar function can compensate for the
primary defect.


==========================================================================
As many as 40,000 people in Germany suffer from retinitis pigmentosa. This hereditary disorder is characterized by loss of photoreceptors in the
retina, and can be caused by mutations in many different genes. Depending
on the nature of the underlying genetic defect, the severity of the
condition can vary between night blindness and progressive visual
field loss that can ultimately result in total blindness. The first
gene therapies for the disease have recently been approved. However,
these approaches have certain disadvantages, which limit their range
of application. A research team led by PD Dr. Elvir Becirovic at the
Department of Pharmacology of Natural Sciences (Head: Prof.

Dr. Martin Biel) has developed a new strategy in collaboration with
Prof. Dr.

Stylianos Michalakis of the Opthalmology Clinic in the LMU Medical
Center. This approach is designed to compensate for the causative
hereditary defect by activating genes with similar functions that are
normally repressed in the affected tissues, and utilizes a variant of
the CRISPR/Cas9 technology that was first described in 2015. In the
online journal Science Advances, the team describes the first successful application of this method in the context of gene therapy.

Currently, two strategies are being used in the development of gene
therapies: In the context of gene supplementation, an attempt is made
to replace the defective gene with an intact version. However, this is currently only possible for relatively small genes. The second strategy
aims to correct disease-causing mutations, but this usually has to be
tailored to each individual mutation. In view of the high effort and the associated development costs, a broad application of this strategy is
therefore not possible. "To overcome these limitations, we have developed
a new strategy," says Becirovic.

Many genes in the human genome fall into families, whose members fulfill similar functions in different cell types, or are activated at different
stages during the differentiation of a particular cell type. "Our idea
was to compensate for the mutant gene's loss of function by specifically activating genes that have a similar function but are normally not
expressed in retinal cells," says Becirovic. "To do so, we delivered a
system called Cas9-VPR into the affected retinal cells." The Cas9-VPR
system is a derivative of the CRISPR/ Cas9 technology that is widely
used for the targeted modification of genes.

Akin to the classical CRISPR/Cas9 system, Cas9-VPR utilizes the same
targeting principle to guide an activating protein to the particular
gene of interest.

Becirovic and colleagues made use of a mouse model for retinitis
pigmentosa to test the activation approach. These mice lack the
light-sensitive rhodopsin protein that is normally expressed exclusively
in the rod cells of the retina, which are required for dim light and
night vision. The researchers delivered the Cas9-VPR system into the rod
cells with the aid of a harmless virus. By introducing Cas9-VPR into the
rods of the mice, the scientists switched on genes closely related to the rhodopsin gene, which are normally active in the cones responsible for
color and daylight vision. "In this way, we were able to compensate for
the lack of rhodopsin function in the rod cells, to attenuate the rate
of retinal degeneration and improve retinal function without detectable side-effects," says Becirovic.

The authors believe that a similar strategy can be applied to a wide
range of genes and genetic diseases, and offers a number of significant advantages over existing strategies. "Given the growing importance of
gene therapy and its potential benefits for patients, we are convinced
that our approach could soon be used in initial clinical feasibility
studies," says Becirovic.


========================================================================== Story Source: Materials provided by
Ludwig-Maximilians-Universita"t_Mu"nchen. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Sybille Bo"hm, Victoria Splith, Lisa Maria Riedmayr, Rene' Dominik
Ro"tzer, Gilles Gasparoni, Karl J. V. Nordstro"m, Johanna Elisabeth
Wagner, Klara Sonnie Hinrichsmeyer, Jo"rn Walter, Christian
Wahl-Schott, Stefanie Fenske, Martin Biel, Stylianos Michalakis,
Elvir Becirovic. A gene therapy for inherited blindness using
dCas9-VPR-mediated transcriptional activation. Science Advances,
2020; 6 (34): eaba5614 DOI: 10.1126/sciadv.aba5614 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200902095134.htm

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