From time to time the leadership of CMTRF will explore the challenges of finding treatments and a cure for CMT.  To the extent we are able, we will try to overcome these obstacles to accelerate successful CMT research.

Treatment of diseases, especially rare diseases like Charcot-Marie-Tooth (CMT) is very complex due to specific changes in the genetic makeup of individual patients. (Although rare, it should be pointed out that the number of patients with CMT is larger than those with MS or ALS.) Diseases that share the same set of symptoms are often reclassified into different subtypes based on their genetic variants (CMT has nearly 100 genetic variants) however the majority of them fall into CMT1 (diseases affecting the insulating cell) or CMT2 (diseases affecting the nerve cell). Targeting these subtypes has transformed drug discovery into a highly segmented pursuit driven by the fact that every individual is genetically unique and has led to “disease-in-a-dish” drug screening programs.

Because of the inherent biological differences between humans and other mammals, animal models for studying human disease remain inadequate and overwhelmingly untranslatable. Despite attempts to improve animal models, the majority of drugs that pass preclinical research and include “pivotal” animal tests fail in human trials. This figure has increased from the FDA’s 2004 estimate of 92%.Furthermore, it is unclear whether variability within human populations, due to either genetic or environmental factors, can be captured sufficiently within laboratory animal models. For many rare genetic diseases, there simply isn’t an animal model on which to test the efficacy of lead candidates.

Studies have even shown that compounds that produce promising results in animal models sometimes exhibit the opposite effect in humans. Besides issues with efficacy, if you ask any professional in pharmaceutics, they will likely tell you that animal testing for safety, both for toxicology and pharmacokinetics, is not going anywhere anytime soon.

Although animal models can be useful to study drug safety and distribution, more and more researchers are avoiding animal models to assess the efficacy of therapeutic candidates. Instead many groups are now developing “disease-in-a-dish” drug screening programs that harness the promise and power of human inducible pluripotent stem cells (iPS).

This can be relatively easy for many cell types. A researcher can obtain some types of cells from a patient, expand the cells in a petri dish, test the compound of interest on the cultivated cell lines and even introduce specific mutations. But finding volunteers to donate affected cells for a specific disease adds a level of difficulty. This is one area where foundations and the NIH have become increasingly important since they aim to generate some of these biobanks to facilitate drug discovery in specific diseases. These types of cells are important because some cells, such as cardiomyocytes and neurons, cannot be isolated from living humans, making research in diseases that affect these biological systems even more complex. Due to these facts, a combination of iPS cell-derived cells and animal models — in some form or another — will be required to complete modern drug discovery going forward. Importantly, however, this marriage between the disease-in-a-dish and the animal model is being employed by many biotech/biopharma companies and academic groups in an effort to create personalized, centered approaches for drug discovery.

iPS cells derived from an individual patient can be differentiated into a variety of cell types (i.e., skeletal muscle, neurons, cardiomyocytes, etc.) that can be used to evaluate the effects of potential therapeutics on cells from the target organ of the disease. This is beneficial because it demonstrates the direct effect of a potential therapeutic on the organ of interest versus using an animal model to evaluate target engagement.

IPS cell differentiated into a neuron

Additionally, iPS cells from multiple patients with similar genetic changes can be differentiated at the same time, in the same assay dish, providing a means to potentially stratify populations of patients that may respond to a potential therapeutic, completing a “clinical-trial-in-a-dish”. Furthermore, having the ability to differentiate the same iPS cell from a patient into multiple lineages provides an immediate means to assess off-target/cytotoxic effects.

When Shinya Yamanaka discovered inducible pluripotent stem cells in 2006, the most obvious trajectory for their use was in regenerative medicine such as rebuild muscles compromised by CMT. Derived from adult skin cells, pluripotent stem cells can be differentiated into a variety of different cell types and composite tissues. Therefore, they can in principle be employed to replace damaged or diseased patient cells through cellular therapy approaches. To date, however, only one therapeutic treatment has been developed (and subsequently halted) for human trials using the cells. Importantly, other efforts are continuing and it is not unreasonable to expect that in the next 10 years we will see iPS cell–derived cellular therapy (allogenic — coming from a single patient) approved in some rare diseases, like CMT.

However, many concerns still exist with regards to the safety of employing these cells and their potential to undergo unlimited cellular expansion if not appropriately addressed. Although regenerative therapies employing iPS cells have been heralded as the future of medicine, iPS cells have made a quieter revolution in drug discovery. Plagued with the lack of translatability of human diseases in animal models, researchers understand the possibility of iPS cells to create specialized cell lines that previously couldn’t be harvested (such as neurons). With the introduction of CRISPR-cas9 gene-editing technology, the iPS cell field has again been transformed. Researchers can now use iPS cells to build cell lines of previously difficult-to-harvest cell types, and then modify these cells to exhibit a disease.

iPS cell–based approaches to generate neurons and muscle cells can be pharmacologically evaluated by therapeutics that modulate channel function. In order to transform capabilities to the next level of human biology, we need to create complex tissue systems of co-intercommunicating human cells that combine contractile skeletal muscle cells with motor neurons derived from diseased and normal iPS cells to essentially create a functional motor unit. Leveraging this entire human tissue model, disease mechanisms can be studied at the neuromuscular junction at a molecular level never before possible. In addition, therapeutic molecules for neurodegenerative diseases like CMT, can be evaluated.

These types of in vitro–engineered “tissues” are capable of producing some of the greatest breakthroughs in science and could someday lead to the evaluation of drug candidates in complete in vitro human systems. For rare diseases, like CMT, with historically inadequate animal models that lack predictivity, there is a strong case to work with partners to create unique human cell models that will outperform the animal model alternative, leading to the identification and development of new therapeutics.

Although the future holds great potential with these cells, there are still many challenges that need to be overcome. Cell models for CMT are difficult to create because it requires two types of cells to represent the CMT. Both peripheral nerve cells and insulator (Schwann) cells are required to create a model of CMT in the dish. Scientists have been challenged with getting the two cells to interact in ways that they do easily in the body. Thus, more research is required to create this perfect model.

The relevance of the human “disease-in-a-dish” model — and the throughput it enables — is guaranteed to outpace what is possible in any of the leading animal models. We are positioned to be at the forefront of phasing out obsolete and inadequate animal models, in hopes of contributing to the advancement of new methods that will improve safety and efficacy, and shorten the discovery time for new drugs.