Patent Description:
<CIT> discloses an electroporation device for injecting a product into a ciliary muscle of the eye. This device enables a precise and stable positioning of electrode needles into said eye.

Further electroporation devices are known from prior art documents <CIT>, <CIT> and <CIT>.

However, each needle is inserted substantially tangentially to the surface of the eye. The impact of the needle when it hits the surface may therefore lead to a rotation of the eye, which hinders the insertion on the needles.

Clamps are known to maintain the eye. However, they are bulky and require an extra operator.

There is a need for a solution which would facilitate the insertion of the needles, without the above-mentioned drawbacks.

It is an object of the invention to answer to this need.

To this end, the invention proposes a device, preferably an electroporation device, comprising:.

Therefore, when the spherical contact surface is extending on the outside surface of the eye, the first and second tips compress the eye as they are being pushed on the outside surface of the eye.

As it will become clear in the following description, the compression action advantageously limits the risk of rotation of the eye during the insertion of the first and second needles. In addition, the compression of the eye may be simultaneous to the insertion of the tips inside the eye, so that both compression and insertion operations can be achieved by a single operator.

A device according to the invention may also have one or several of the following optional and preferred features:.

The "compression forces" corresponds to the forces applied by the needles on the surface of an eye when said needles are moving from the extracted position to the inserted position and push on said surface before piercing it.

The "insertion point" of a needle is the point where, in the piercing position, the insertion axis along which said needle extends crosses the virtual sphere bearing the contact surface.

Two needles are "aligned" when they extend on a same axis.

A "quadrant of a hemisphere" designates a quarter of the surface of this hemisphere obtained by cuts in two perpendicular planes that intersect along the main axis of the hemisphere.

"First" and "second", or "upper" and "lower", or "right-hand" and "left-hand" are used to distinguish corresponding elements, but do not limit the invention.

In the present description, unless otherwise stated, "comprise " does not involve an exclusivity.

Other features and advantages of the invention will become clear upon reading the non-limitative following detailed description and by examining the non-limitative attached drawings, in which:.

A device according to the invention is particularly well adapted for electroporation. In this application, it preferably comprises an electric generator <NUM> configured for electroporation of a pharmaceutical composition, a support <NUM>, and first and second combs 6a and 6b, which are mobile along a sliding direction Δ<NUM>.

The first and second combs 6a and 6b comprise first and second electrode needles 8a and 8b, respectively. All the electrode needles are electrically connected to a first terminal 9a of the electric generator <NUM>. Together, they define an invasive electrode.

The support <NUM> comprises a support base <NUM> and a plate electrode <NUM> fixed on the support base and electrically connected to a second terminal 9b of the electric generator, which has a polarity opposite to the polarity of the first terminal.

The electrical generator is therefore adapted to polarize differently the plate electrode and the invasive electrode so as to generate an electrical field enabling electroporation.

The support base <NUM> is preferably in a polymeric material. It is preferably in a material which is not electrically conductive. It is preferably made of a transparent material for a better observation by the user.

The support base defines a spherical base contact surface <NUM> which extends along a virtual sphere S having a radius of curvature R between <NUM> and <NUM>, preferably between <NUM> and <NUM>, preferably between <NUM> and <NUM>, and is preferably about <NUM>. The virtual sphere S corresponds to the outside surface of an eye O so that, in the service configuration, the base contact surface can bear on this outside surface.

The stability of the support on the eye is therefore greatly improved.

Preferably, the base contact surface <NUM> has a surface area of greater than <NUM><NUM>, preferably of greater than <NUM><NUM>, preferably of greater than <NUM><NUM>, preferably of greater than <NUM><NUM>, preferably of greater than <NUM><NUM>, preferably of greater than <NUM><NUM>, and/or of less than <NUM><NUM>, preferably of less than <NUM><NUM>. Preferably, the base contact surface <NUM> does not extend over more than one quadrant of a hemisphere.

Seen from the front, the contact surface <NUM> can have a substantially parallelepipedal contour, for example a rectangular contour, or a substantially trapezoidal contour.

Preferably, the support base <NUM> defines a circular rim <NUM> which partially defines the limit of the contact surface <NUM>, and extends in a rim plane P<NUM>.

The rim <NUM> has the shape of an arc of a circle C<NUM> having an axis X and a radius R<NUM> of greater than <NUM>, preferably of greater than <NUM>, preferably of greater than <NUM>, and of less than <NUM>, preferably of less than <NUM>, preferably of less than <NUM>, preferably of less than <NUM>. Such a rim has a shape substantially corresponding to the limbus of the eye. It may be placed in contact with this limbus, so as to encircle partially said limbus.

The stability of the support is greatly improved when the rim <NUM> is designed to bear on the limbus of the eye.

Preferably, the rim extends laterally over an angle sector α<NUM> of greater than <NUM>°, preferably greater than <NUM>°, preferably greater than <NUM>°, preferably greater than <NUM>°, preferably greater than <NUM>°, preferably greater than <NUM>°, preferably greater than <NUM>°, and/or less than <NUM>°, preferably less than <NUM>°, preferably less than <NUM>°, preferably less than <NUM>°, preferably less than <NUM>° (see <FIG>).

The support base preferably may comprise a support handle to be gripped, for example, between a thumb and an index finger of one hand. However, preferably, support handles are alternatively provided on the combs.

The plate electrode <NUM> is fixed on the support base <NUM>. It defines a plate electrode contact surface <NUM> which is intended to bear on the outside surface of the eye in the service position. It therefore preferably extends along the virtual sphere S.

The surface area of the plate electrode contact surface is preferably greater than <NUM><NUM>, greater than <NUM><NUM>, greater than <NUM><NUM>, greater than <NUM><NUM>, greater than <NUM><NUM>, greater than <NUM><NUM>, greater than <NUM><NUM>, greater than <NUM><NUM>, greater than <NUM><NUM>, greater than <NUM><NUM>, and/or less than <NUM><NUM>, less than <NUM><NUM>, less than <NUM><NUM>, less than <NUM><NUM>.

Preferably, the plate electrode contact surface <NUM> does not extend over more than one quadrant of a hemisphere. Preferably, it extends within an angular sector α<NUM> around the axis X of the rim (see <FIG>) which is less than <NUM>°, preferably less than <NUM>°, preferably less than <NUM>°, preferably less than <NUM>°, preferably less than <NUM>°, preferably less than <NUM>°, and/or preferably greater than <NUM>°, preferably greater than <NUM>°, preferably greater than <NUM>°.

In a front view, the plate electrode contact surface has preferably a substantially rectangular shape.

The radius of curvature R is large relative to the surface area of the plate electrode contact surface, so that the plate electrode contact surface substantially extends in a general plate electrode plane P<NUM>.

Preferably, the distance between the rim <NUM> and any point of the plate electrode contact surface <NUM> is greater than <NUM>, preferably greater than <NUM>, preferably greater than <NUM>, preferably greater than <NUM>, preferably greater than <NUM>, and/or less than <NUM>, preferably less than <NUM>, preferably less than <NUM>.

The plate electrode <NUM> may be an electrically conductive layer partly covering the support base. Preferably, it is not integral with the support base, i.e. is a part which is initially independent of the support base, then mounted onto the support base.

The first and second combs 6a and 6b are very similar, or identical, and assembled in the same way on the support, or in a very similar way, so that only the first comb and its arrangement are described in detail hereafter.

The references of the second comb are the same as the references of the first comb, but are indexed with "b" instead of "a".

Preferably, all the first electrode needles have the same structure.

Preferably, the diameter of a first electrode needle, preferably of any first electrode needle is less than <NUM>, preferably less than <NUM>, preferably less than <NUM>. This characteristic is particularly advantageous when the electrode needle is inserted into the eye substantially tangentially to the surface of the eye, as in the preferred embodiment. For the same reason, the first tip 36a of a first electrode needle, preferably of any first electrode needle is preferably bevelled.

The first comb may comprise one or several, preferably three, four or five, preferably four, preferably parallel, preferably coplanar, and preferably rectilinear first electrode needles 8a. The distance between the axis of two adjacent parallel first electrode needles 8a is preferably greater than <NUM>, preferably greater than <NUM>, preferably greater than <NUM>, preferably greater than <NUM>, and/or less than <NUM>, preferably less than <NUM>, preferably less than <NUM>, preferably less than <NUM>, preferably less than <NUM>, preferably less than <NUM>.

Preferably, the first electrode needles 8a extend in a first needle plane P<NUM> which defines with the rim plane P<NUM> of the rim <NUM> an angle which is greater than <NUM>°, greater than <NUM>°, preferably greater than <NUM>°, and/or less than <NUM>°, preferably less than <NUM>°, preferably less than <NUM>°, preferably less than <NUM>°.

The first needle plane P<NUM> is preferably substantially perpendicular to a median radial plane Pm<NUM> of the rim (angle θ of <NUM>° in <FIG>), i.e. a plane including the axis X and including the point at mid-length of the rim. Put differently, the first electrode needles are coplanar and preferably each extends substantially parallel to the plane P<NUM> of the rim.

The first electrode needles preferably each extend substantially parallel to the plate electrode <NUM>. The angle between the first needle plane P<NUM> and the plate electrode plane P<NUM> is preferably less than <NUM>°, preferably less than <NUM>°, preferably less than <NUM>° or less than <NUM>°. The first needle plane P<NUM> is preferably substantially parallel to the plate electrode plane P<NUM>.

The distance δ between these two planes is preferably between <NUM> and <NUM>, preferably between <NUM> and <NUM>, preferably between <NUM> and <NUM>. mm, preferably about <NUM>.

Each first electrode needle 8a is mobile and guided, by the sliding of a first guiding rod 32a in a guide of the support base <NUM>, between an extreme (i.e. limited by an abutment) first inserted position and a first extracted position in which it is protruding and not protruding, respectively, inside the virtual sphere S.

Preferably, in the first inserted position, any first electrode needle defines, with the outside surface of the eye, an angle ω that is less than <NUM>°, preferably less than <NUM>°, preferably less than <NUM>°. The first electrode needles therefore substantially penetrate tangentially into the eye.

Preferably, the length of the first electrode needles is determined so that, in the inserted position, in a front view, i.e. when observed perpendicularly to the first needle plane P<NUM>, the first electrode needles 8a appear to substantially completely cross the plate electrode contact surface (i.e. substantially extend from one side to the opposite side of the plate electrode contact surface).

Preferably, the first comb 6a comprises a first comb handle 38a extending substantially parallelly to the median radial plane of the rim, and preferably substantially perpendicular to the first needle plane P<NUM>, so that the operator may push on the first comb 6a toward the support without being disturbed by the nose of a patient.

Preferably, the force which is required to move the first comb against the spring 34a is greater than <NUM> Newton, preferably greater than <NUM> Newton, and/or less than <NUM> Newton, preferably less than <NUM> Newton. Advantageously, the spring 34a limits the risk of injury when the operator manipulates the device.

The second comb is similar, and preferably substantially identical to the first comb. Preferably, the second comb base is configured so that, in the inserted position of the first and second needles, it is substantially symmetric with the first comb base relative to median radial plane of the rim.

The second electrode needles extend in a second needle plane which is parallel to the first needle plane, preferably identical to the first needle plane. To avoid collision between first and second electrode needles, their respective axis must then be offset. Preferably, they are interlaced with each other, i.e. in the needle plane, first electrode needles alternate with second needles, as represented in <FIG>.

Preferably, as represented in <FIG>, the second comb 6b comprises a second comb handle 38b, preferably parallel to the first comb handle 38a. The convergence of the two combs toward the support, i.e. the movement in which the combs are pushed toward the support, is made easier and is possible with a single hand.

According to the invention, the two combs are slidable relative to the support so that, in a piercing position in which the plate electrode contact surface <NUM> bear on the outside surface of the eye, the rim <NUM> bears on the limbus of the eye, and the tips of the first and second electrode needles are bearing on the outside surface of the eye, said first and second tips can compress the eye when the first and second combs are simultaneously pushed toward the support <NUM>.

In the piercing position, the first and second electrode needles extend along first and second insertion axis Δ8a and Δ8b and bear on the virtual sphere S on first and second insertion points M8a and M8b.

All the first tips 36a of the first electrode needles exert, together, a first compression force F36a, acting on a first compression point M36a, along a first compression axis Δ36a.

All the second tips 36b of the second electrode needles exert, together, a second compression force F36b, acting on a second compression point M36b, along a second compression axis Δ36b.

The first and second compression axis Δ36a and Δ36b are substantially parallel to the first and second insertion axis.

The angle between planes perpendicular to the first and second compression axis is preferably less than <NUM>°, preferably less than <NUM>°, preferably less than <NUM>°, preferably less than <NUM>°. The first and second compression axis are preferably parallel. Preferably, the distance between the first and second compression axis is less than <NUM>, preferably less than <NUM>, preferably less than <NUM>. Preferably, the first and second compression axis are aligned. The risk of a rotation of the eye during the insertion of the electrode needles is thereby highly reduced.

Preferably, the device comprises an injection needle <NUM>. The injection needle may in particular have one or several characteristics of the injection needle disclosed in <CIT>, <CIT>, or <CIT>. It preferably conventionally comprises an injection channel having an ejection orifice.

The injection needle is preferably not a first or a second electrode needle.

It is guided by the support base <NUM>, between retrieved and injection positions. The injection position is preferably an abutment position defined so that the ejection orifice is between the first needle plane P<NUM> and the plate electrode plane P<NUM>, preferably at mid-length between these planes, preferably so as to substantially face the centre of the plate electrode contact surface. In the injection position of the injection needle, the injection needle preferably extends parallel to the electrode needles.

Preferably, the injection needle is configured so that, when the plate electrode is extending in contact with the outside surface of the eye and the rim is extending on the limbus of the eye, and the injection needle is fully inserted, the ejection orifice of the injection needle opens in the ciliary muscle of the eye.

The injected product may be, in particular, any of the pharmaceutical compositions described in <CIT>, and in particular a therapeutic nucleic acid of interest, preferably a desoxyribonucleic acid (DNA) molecule (cDNA, gDNA, synthetic DNA, artificial DNA, recombinant DNA, etc.) or a ribonucleic acid (RNA) molecule (mRNA, tRNA, RNAi, RNAsi, catalytic RNA, antisens RNA, viral RNA, etc.). In an embodiment, the composition contains a circular piece of DNA.

In another particular embodiment, the electroporation device of the invention is particularly suitable for performing gene replacement. Accordingly, the nucleic acid may encode for a viable protein so as to replace the defective protein which is naturally expressed in the targeted tissue. Typically, defective genes that may be replaced include, but are not limited to, genes that are responsible for the diseases disclosed in <CIT>.

In accordance with the present invention, kits are envisioned. Such a kit comprises a device according to the invention and a pharmaceutical composition, and optionally instructions for use.

The pharmaceutical composition is preferably chosen among the pharmaceutical compositions which are described here above.

Within the kit, the components may be separately packaged or contained. Instructions can be in written, video, or audio form, and can be contained on paper, an electronic medium, or even as a reference to another source, such as a website or reference manual.

Other components such as excipients, carriers, other drugs or adjuvants, instructions for administration of the active substance or composition, and administration or injection devices can be supplied in the kit as well.

The device of the invention may be used for treating an ocular disease in a subject, a pharmaceutical composition being preferably chosen among the pharmaceutical compositions which are described here above.

To use the electroporation device an operator may proceed by the following steps:
First, the operator couples a reservoir filled with the pharmaceutical composition to the injection needle, and electrically connects the first electrode (all the electrode needles 8a and 8b) and the second electrode (plate electrode <NUM>) to the first and second terminals of the electrical generator <NUM>.

Initially, the first and second electrode needles are in the first and second extracted positions and are preferably partly within the support base <NUM>. The stiffness of the springs 34a and 34b is determined so that both first and second electrode needles are maintained in the extracted position, in particular, when the operator manipulates the device by the handles 38a and 38b.

To position the device, the operator places the rim <NUM> on the limbus of the eye O. The placement of the rim <NUM> on the edge of the cornea and the bearing of the spherical plate electrode contact surface <NUM> on the sclera guarantee a good stability of the device and a very precise positioning. The stabilisation is very important in the present specific application, since the angles between the electrode needles 8a and 8b, and/or injection needle <NUM> in one hand, and the spherical plate electrode contact surface in the other hand, are very low at the insertion points, i.e. the needles are inserted almost tangentially to this surface, which makes the insertion difficult.

The operator then pushes the first and second combs 6a and 6b toward each other, against the action of the first and second springs 34a and 34b, respectively, until the piercing configuration, where the electrode needles are in their respective piercing positions, their respective tips contacting the outside surface of the eye.

In the piercing configuration, if the operator continues pushing the first and second combs 6a and 6b toward each other, he applies a compression on the eye. This compression results from the action of the first electrode needles, which is a first compression force acting on the first compression point M36a, along a first compression axis Δ36a, with the counter action of the of the second electrode needles, which is a second compression force, acting on a second compression point M36b, along a second compression axis Δ36b.

The spring stiffness is determined so that the tips of both the first and second electrode needles come into contact with the outside surface of the eye before any of them pierces it. Preferably, the force applied by the first spring 34a on the first comb 6a is the same as the force applied by the second spring 34b on the second comb 6b, so that the tips of both the first and second electrode needles substantially simultaneously come into contact with the outside surface of the eye. In the piercing position, they, therefore, compress said surface, which efficiently prevents any rotation of the eye relative to the support base <NUM>.

The operator then continues to push the first and second comb 6a and 6b toward each other, until the electrode needles pierce the outside surface of the eye.

The guiding rods 32a and 32b are slidably mounted on the support base <NUM> to guide the movement of electrode needles until they reach their respective inserted positions.

The first and second electrode needles then together define a grid which extends substantially parallel to the plate electrode contact surface <NUM>, all along the length of the plate electrode contact surface <NUM>.

Preferably, the first and second electrode needles are interlaced, as represented in <FIG>.

The operator then inserts the injection needle in the corresponding insertion guide, until a corresponding injection position. The previous insertion of the electrode needles enables a very stable position of the support during the insertion of the injection needle.

The injection needle can comprises a needle stop to determine an injection position in which the ejection orifice(s) open in the ciliary muscle, in front of the grid of the electrode needles, preferably in front of the centre of the grid.

The operator can then inject the composition.

The device is then in the service configuration and the operator sends a suitable electrical signal, for example suitable electrical impulses, by means of the electrical generator, in such a way as to create, within the injection zone, an electrical field that promotes electroporation.

An electrical field constituted by one or more electrical pulse(s) can be applied, as described in <CIT>.

When the electroporation of the product has been completed, the operator electrically disconnects the electrodes and the generator.

As is now clear, the device according to the invention permits.

Of course, the invention is not limited to the embodiments described and shown, which have been provided by way of illustration.

Claim 1:
A device comprising:
- a support (<NUM>) comprising a support base (<NUM>) defining
- a spherical base contact surface (<NUM>) extending along a virtual sphere (S) having a radius (R) between <NUM> and <NUM> to match an outside surface of an eye, and
- a circular rim (<NUM>) extending in a rim plane (P<NUM>), having an axis X perpendicular to said rim plane (P<NUM>) and a radius of greater than <NUM> and of less than <NUM>, so as to match the limbus of the eye;
- a first needle and a second needle (8a;8b) having a first tip and a second tip (36a;36b), respectively, and being mobile on the support between
- first and second extracted positions, in which the first and second needles are outside said virtual sphere, respectively, and
- first and second inserted positions, in which the first and second needles are maximally inserted in the virtual sphere, respectively, via first and second intermediate piercing positions in which, respectively, the first and second needles extend along first and second insertion axis (Δ8a;Δ8b) and the first and second tips are located on first and second insertion points (M8a;M8b) belonging respectively to first and second hemispheres of the virtual sphere which are separated by a plane including the axis X and including a central point at mid-length of the rim, or "median radial plane of the rim" (Pm<NUM>), an angle (θ) between the median radial plane of the rim and any of the first and second insertion axis being greater than <NUM>° and less than <NUM>°, said device further comprising
- an electroporation generator (<NUM>) comprising first and second terminals (9a, 9b) with different polarities,
-
- a plate electrode (<NUM>) fixed on the support, connected to the second terminal, and defining a plate electrode contact surface (<NUM>) which extends along the virtual sphere, the dimensions of the plate electrode contact surface being preferably such that the plate electrode contact surface substantially extends in a general "plate electrode plane",
characterised in that an invasive electrode is electrically connected to the first terminal and comprises said first and second needles.