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CELL REPLACEMENT - SCHWANN CELL TRANSPLANTATION

  

The first step, generating all of the pre-clinical safety and efficacy data to justify the testing of Schwann cell transplantation in humans, has been completed.  The Miami Project to Cure Paralysis has submitted its Investigational New Drug (IND) application to the Food and Drug Administration (FDA) requesting permission to begin a Phase I clinical trial to evaluate the safety of autologous human Schwann cell transplantation a few weeks after a spinal cord injury has occurred.  The second step, now, is for the FDA to approve the application so we can start the trial.

 

That first step was a major undertaking, however.  The table on the previous page demonstrates how much work was involved in preparing the IND application.  It is not as simple as completing a loan application or even a grant application (yes, those are considered simple compared to an IND application).  There are four major components of an IND application, 1) the qualifications of the investigators, 2) the clinical protocol(s), 3) the chemistry, manufacturing, and control (CMC) information of the experimental drug or cell in question, and 4) the pharmacology and toxicology information about the drug or cell to be tested. 

 

The qualifications of the investigators, that’s the easy part.  We have many leaders in the spinal cord injury (SCI) research field right here at The Miami Project.  Dr. Mary Bartlett Bunge has been spearheading investigations to evaluate the ability of Schwann cells to repair spinal cord damage in animal models for many years.  Dr. Pat Wood has been leading the CMC studies for human Schwann cell manufacturing.  Dr. Damien D. Pearse has taken the lead on conducting the pharmacology and toxicology studies in rodent models, while Dr. James Guest has done the same with our pig model and non-human primate model.  Drs. Allan Levi, Diana Cardenas, and James Guest have taken their multi-disciplinary clinical expertise to develop the Phase I clinical trial.  Finally, Dr. Dalton Dietrich, our Scientific Director, has assumed responsibility for the entire clinical trial as the Sponsor.

 

The clinical protocol section describes the entire clinical trial that we have proposed.  As we have discussed many times over the last couple years, the first step in the clinical trials process is to conduct a Phase I trial, which is strictly focused on safety outcomes.  That is particularly important in our situation because of 2 factors, 1) we are talking about putting cells inside the spinal cord and 2) we are sticking a needle directly into the spinal cord in order to deliver the cells.  Those are two pretty risky things.  Therefore, we have designed a clinical trial that will minimize risk and maximize evaluation of safety.  We have proposed to enroll 8 participants with complete thoracic SCI.  A potential subject would have to agree to participate within 5 days after his/her injury, which is considered the acute phase.  At that point, he/she would have a biopsy of a nerve in one leg to obtain his or her own Schwann cells.  The Schwann cells then need to grow in a culturing facility for 3 to 5 weeks to multiply in number and undergo purification.  By the time the Schwann cells are actually transplanted into the site of spinal cord injury, the participant would actually be 26-40 days post-injury, which is considered the sub-acute phase.  All procedures would be conducted in Miami at The Miami Project, the University of Miami Hospital, and at Jackson Memorial Hospital.  We will be following participants for 1 year after the transplantation surgery and evaluating their neurologic status, medical status, pain symptoms, and muscle spasticity very closely.  We have written a second clinical protocol that will then monitor participants for an additional 4 years on a less frequent interval.  We have sought advice on these clinical protocols from members of our External Advisory Board and Data Safety Monitoring Board, whom are respected nationally and internationally and are leaders in the SCI research field.

 

The CMC section describes in very great detail every single thing we will do to the Schwann cells once the leg nerve has been removed from the participant.  Because the Schwann cells we obtain from the nerve biopsy are what will eventually be injected into the spinal cord, they have to be handled in accordance to Good Manufacturing Practices (GMP).  This is to ensure that the cells and every single thing that touches them are not contaminated with something that could be very dangerous after they are transplanted.  This is also to ensure that the cells do not become modified during the culturing process and gain characteristics that could become harmful, such as start to develop tumors.  A very special person has been leading a team of people, under the guidance of Dr. Wood, in performing all of the experiments that contributed to the CMC section and that person is Dr. Gagani Athauda.

 

The pharmacology and toxicology section contains all of the data we have generated not only in the past four years, but everything we have done prior to that demonstrating the safety and efficacy of Schwann cell transplantation into animal models of SCI.  The data we have collected in the past four years, however, specifically addresses toxicity, cell survival, migration of the cells to other body parts (biodistribution), and whether or not they formed tumors (tumorigenicity) in animals.  The pig model has also given us crucial information about the safest way to inject cells, the appropriate dose and volume of cells to inject, as well as short-term survival and biodistribution of the cells.  The non-human primate model has generated data demonstrating the feasibility of autologous transplantation, long-term safety, and significant functional benefit in a species very similar to humans.  These data are all collectively very important for the FDA to be able to properly evaluate the risk:benefit ratio of Schwann cells as a therapeutic.

 

Once the FDA receives the IND application, they have 30 days to respond.  Interestingly, if we hear no response, that actually means we are allowed to move forward with the clinical trial.  What happens more often than not, however, is that the FDA will issue a clinical hold.  They have the right to do so if they feel the information presented in the IND is insufficient for them to assess the risks that subjects would be exposed to in the trial.  It is important to remember that testing cellular therapies for spinal cord injury in humans is a very new field; there are only a small handful of trials ongoing.  Though Schwann cells are less risky than stem cells, there is always the possibility that the FDA will request specific additional safety data from us before they allow the clinical trial to proceed.  If that happens to be the case, we will answer their requests and not stop until we obtain approval!

 

 

 

 

 

 

 Components currently being translated:

Neuroprotection - Therapeutic hypothermia

Cell replacement - Schwann cell transplantation

Rehabilitation - SCI Boot Camp

Investigational New Drug Process

IND Submission

IND Approval

 

 
 
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