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Ask Dr. Carpenter: Episode 1

July 20, 2016

On July 11th we solicited questions on our blog for our Chief Scientific Officer, Randy Carpenter. A number of parents asked questions about their daughters’ symptoms and medications. Please note that Dr. Carpenter is not a Rett clinician and is not able to give medical advice on the website. Responses to the other questions are below.

What would a clinical trial for gene therapy or protein replacement look like? Would there be a Phase I stage (I imagine such therapies could not be first studied in healthy volunteers) or would the study start at Phase II? - Lena D.

The short answer is that the most appropriate population for initial trials in humans will ultimately be decided by a thorough risk-benefit analysis in collaboration with the regulatory agencies. Nevertheless, my expectation is that the majority of protein replacement therapeutics will first be tested in healthy volunteers while most, if not all, gene therapy trials will proceed directly into humans with Rett syndrome.

The primary objective of early-phase clinical trials, especially first-in-human trials, is an evaluation of safety and dosage. Protein replacement and gene therapy have unique risks compared with typical pharmaceutical drugs and special safety issues must also be addressed in the initial safety and tolerability studies. Further complicating the decision process is the fact that data from healthy volunteers may not be fully predictive of safety/efficacy in patients. Consequently, selection of the most appropriate study population (for example, the age of patients) for early-phase trials involves not only consideration of the potential risks, but also the potential for individual subject benefit and the ability of the study population to provide interpretable data.

Additional factors that may influence the design of initial studies in individuals with Rett syndrome include; disease stage or severity, the lack of other treatment options, and the additional safeguards that are required to permit enrollment of pediatric subjects in clinical investigations.

The bottom line is that gene therapy scientists, Rett clinicians, and regulators will need to work closely together to design the best possible trial. The first trial will likely be small, perhaps a handful of patients, and will inform next steps.

Dear Dr. Carpenter, as your post suggested you have immersed yourself in the RETT world for 4 months now. I would be interested to hear what you think will be the first significant treatment for RETT to reach us.........I know nothing can be guaranteed!!! Thanks very much. - Kate

Physicians and families caring for individuals with Rett syndrome clearly need better therapeutic options. During my short tenure, I have been particularly encouraged by breakthrough scientific advances that may ultimately enable therapeutics directly targeting the cause of Rett syndrome – insufficient MeCP2 protein (e.g., gene therapy, X-reactivation, protein replacement). Although these programs are still in relatively early stages and success will require additional scientific advances, the pace of progress is encouraging.

Equally impressive is the surge in interest from pharmaceutical and biotechnology companies. Because I have not been able to access study reports for most of these compounds, it is impossible for me to accurately assess which, if any, of the drugs in development are most likely to demonstrate meaningful efficacy.

Regardless, experiences in other disease areas suggest that encouraging efficacy data in model animals does not reliably predict meaningful efficacy in humans. Some of the failures are clearly because the drug does not have efficacy in humans. However, the lack of sensitive outcome measures may also be to blame for some of these failures. Specifically, trial participants improved in meaningful ways, but these improvements were not captured on the efficacy measures. It’s absolutely critical that we improve the effectiveness and efficiency of future clinical trials, and that’s why a primary focus of mine during these first three months has been to launch the Outcome Measures and Biomarker Development consortium. This is a key effort if we are to improve the translation of lab discoveries into medications your children can benefit from. In doing so we reduce drug development risks and encourage investment from industry. This is a major goal at RSRT.

On a cautionary note, if all of the interested companies actually move forward, recruitment demands of competing trials may soon exceed capacity of the existing clinical research infrastructure. I, therefore, believe it timely, for all of us in the Rett community to begin considering how best to prioritize trial participation. The dilemma, therefore, is whether and how we can best anticipate this possibility and work together to best serve individuals with Rett Syndrome and their families.

It is my sincere hope that we will be able to work together to accelerate the translation of scientific discoveries to improve the lives of your loved ones. I look forward to hearing your thoughts and hope to continue this conversation in the weeks and months to come.

Hi Dr. Carpenter, thank you for taking the time to field and answer questions. Could you please discuss the various applications of gene therapy/gene editing in terms of Rett? Reading through the gene therapy consortium discussion on RSRT's website (and understanding these are summaries of much larger work efforts), it looks like the research is focusing on delivering a healthy copy of the MECP2 gene (or possibly a chunk of the important part of the gene) and mRNA editing. Do you think direct DNA editing to correct the mutation will be a possibility for Rett? Thank you. - Lena D.

DNA editing has taken the science world by storm with hundreds of labs around the world working in this area. I am very excited about the possibility of correcting MECP2 mutations as this strategy should eliminate risks associated with overexpression that could come from gene therapy and/or protein replacement. DNA editing, however, has not yet advanced sufficiently to be applied to neurological diseases such as Rett Syndrome. Simply put DNA editing involves two steps 1) facilitating a break in the patient’s DNA where the mutation exists 2) fixing the break with the proper nucleotide sequences. For now step 1 is doable but the cells that can be fixed is still small, especially in cells that are not rapidly dividing like brain cells. Although neurological diseases are not yet low hanging fruits for DNA editing, numerous scientific teams are focused on overcoming these challenges and progress in this field is moving at lightening speed so stay tuned.

Our daughter was clinically diagnosed (due to symptoms of regression, loss of speech, behavior stages, handwringing, seizures, reflux, breathing, eating, and constipation issues, etc. ) with Rett syndrome at the age of 4 (now 24 yrs old) but tested negative for the Rett sites that were available to test her for way back when. Is there a list of sites that are known to cause Rett to now see if she should be tested for a positive diagnosis? Thank you for all your help. - Valmai M.

I would recommend that you daughter have MECP2 testing. There is additional testing that has become available since your daughter was analyzed. Does she have a neurologist that you can discuss testing with? If you need help with this please contact Monica Coenraads at


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