1. OBJECTIVES AND EXPECTED ACHIEVEMENTS
The cochlear implant (CI) has been the
“success story” of neuroprosthetic devices. Yet there remains a great
potential for improvement in cochlear implant outcomes. The major goal of
this program is to improve the outcomes of cochlear implantation still
further using drug application at the time of implantation to enhance the
responsiveness of the auditory nerve. This will be achieved by (1)
preventing neural degeneration during the traumatic procedure of
implantation, and (2) initiating a re-growth of the peripheral processes of
the auditory nerve towards the electrode array. Longer term goals are (1) to
better understand the role of these agents (and others) in preventing neural
degeneration; (2) develop safe technology to provide these agents in
patients with moderate hearing impairment to prevent its progress; and (3)
to provide data that may make the use of these agents practical in other
parts of the central nervous system (CNS). The main objectives are:
1. Clinical trial results of neurotrophin (NTF) treatment of the cochlea
during cochlear implantation.
Verification of the effectiveness of NTF in animal studies, and the safety
studies described in objective 3, will prepare their way for the first human
trials of the effectiveness of NTF in the human cochlea. The expected
achievement will be the execution of the first therapeutic intra-cochlear
drug delivery trials in humans, and an improvement of sound quality for the
patients involved in the study.
2. An increase in knowledge about degeneration of the auditory nerve during
deafness
This
will provide data describing the morphology of the auditory nerve and its
status prior to implantation, and the factors determining this status.
3.
Assessment of the safety and effectiveness of NTF and antioxidants (AO)
for promotion of SGC survival and re-growth, and establishment of the
acceptable dose range.
a. Definition of the dose-response efficacy and local
toxicity with GDNF.
b. Definition in-vivo of the combined effects of
delayed treatment with electrical stimulation (ES) and NTF on SGC
excitability, survival, and re-growth.
An
animal model of the typical clinical situation, incorporating a period of
deafness before CI implantation (“delayed treatment” model) will be
established.
4. Identify NTF receptors and
demonstrate NTF responsiveness of human SGC in culture; and assess the
efficacy of various NTF and AO in animal SGC in-vitro to identify optimal
NTF/AO candidates for survival and re-growth of the auditory nerve.
a. The establishment of a technique for culturing human
spiral ganglion cells (SGC)
b. The establishment of a cell line from
SGC of the immortomouse
5. A human implantable, fluid based drug delivery system and associated
technology;
Safe and effective delivery of drugs to the cochlea for a
few weeks after implantation requires careful adaptation of available
technology. The fluid-based system will consist of an implantable minipump
delivering GDNF at a constant, pre-determined rate through a catheter in the
implant electrode array, and thence into the cochlea. Preparatory work will
include the development of a suitable pump; flow and diffusion modeling and
experimental studies to ensure
delivery of the correct dose; design of the connection,
catheter system, and mechanisms for termination of drug flow, if needed.
6.
Develop a biopolymer coating suitable for cochlear implants which will
deliver NTF or antioxidants at the time of implantation.
In vivo and in vitro testing.
The use of a biopolymer
coating for delivery of drugs from the implant may offer advantages, as ease
and convenience of use. Bio-polymers are tested in vivo and in
vitro to assess possible fibrotization of cochlea alone and in
combination with NTF and AO. Biopolymers are also capable of delivering
drugs over an extended period of time, offering chronic treatment if
required. Such a system might allow long-term delivery of a variety of drugs
to inner ear.
