Exploring What Makes SORD-Deficiency CMT So Different from Every Other CMT Subtype, and Discussing Why SORD-Deficiency is CMT
"Everyone has high sorbitol. That's part of this disease. We do know that sorbitol level does drive the disease severity. Why is that important? Because, with AT-007 treatment, we're reducing sorbitol levels. So, it's important to know that sorbitol is driving this disease and how high or low your sorbitol levels are makes a difference in terms of how quickly and aggressively the disease will progress." --Shoshana Shendelman, PhD, Founder, Applied Therapeutics
Charcot-Marie-Tooth disease, or what is CMT, is an inheritable peripheral nervous system disease with no current treatment or cure. The peripheral nervous system comprises all the nerves that lie outside of the brain and spinal cord except the optic nerves, and CMT can affect all of them (including the optic nerves for some). CMT is not an easy disease to describe. CMT is a heterogeneous multisystem disease (heterogeneous (het-eh-row-jeh-nay-us) = many different causes and the presentation can be different for everybody). CMT is a peripheral neuropathy (neuro- = nerve, -pathy = disease) that is actually a peripheral polyneuropathy because CMT affects more than one peripheral nerve at a time rather than just one nerve (poly- = many/more than one, mono- = one (polyneuropathy vs. mononeuropathy)). CMT is also a neuromuscular disease because the disease of the peripheral nerves causes symptoms to present in muscles (neuro- = nerve, -muscular = affects skeletal muscle). CMT, however, is not a muscle disease. If this isn’t confusing enough, the name doesn’t help. It gets easier, though, when we know the name’s origin.
CMT gets its name from the three doctors who first described it in 1886: Jean-Martin Charcot (1825-1893), Pierre Marie (1853-1940), both from France, and Howard Henry Tooth (1856-1925) from England. Today, CMT as a disease name has evolved into an umbrella term that refers to many different sensory and/or motor neuropathies, axonopathies, myelinopathies, and neuronopathies (Pisciotta & Shy, 2018) (Bansagi, et al., 2017). In its infancy, however, CMT described a disease that causes only lower leg muscle weakness and atrophy, or what is aptly called, “peroneal muscle atrophy.” Over time, however, CMT has revealed itself to be profoundly more diverse with reaches far beyond the lower legs (multisystem).
The Age of Discovery
First described in 1886, the cause for CMT wasn’t discovered until more than one-hundred years later. In 1991, researchers announced and published the first cause of CMT, a duplication of a tiny segment of chromosome 17 (17p11.2 – 17p12), which they concluded is responsible for causing CMT1A (Raeymaekers, et al., 1991). A year later, this discovery was narrowed down to the exact gene—an extra copy of the PMP22 gene that’s present when the tiny chromosome 17p11.2-p12 segment is duplicated (Patel, et al., 1992). At the time, researchers believed there might only be a small handful of additional causes to find and this thing would be figured out. CMT, however, has proven itself to be, perhaps, the most complicated disease there is.
Scientists have now discovered CMT-causing mutations in more than 120 genes. Mutations in these genes cause more than 150 individual CMT subtypes (Raymond, 2022). New discoveries are happening every year, and there’s no signs of slowing down. Scientists estimate that we are only about halfway to finding all genes that have CMT-causing mutations (Shy, 2020). However, some estimate that we might be closer after the recent discovery of SORD-deficiency (Züchner, 2021).
Gracing the May 2020 cover of Nature Genetics, a truly prestigious achievement, researchers announced the discovery of a new CMT subtype caused by autosomal recessive mutations in the SORD gene (Cortese, et al., 2020). The investigators who make CMT subtype genetic discoveries get to name their discovery. The name they choose becomes known as the subtype name. Rather than choosing a conventional CMT name like CMT1K or CMT4M, for example, the investigators who discovered the CMT-causing mutations in the SORD gene chose to call it, simply, “SORD-deficiency.”
Data show this new CMT subtype, SORD-deficiency, is the most common autosomal recessive CMT subtype, affecting approximately 3,000 CMTers in the US, approximately 4,000 CMTers in Europe, and approximately 60,000 worldwide—accounting for 10% of all axonal CMT cases. (Shendelman, 2022). For context, CMT in whole affects approximately 135,000 in the US, approximately 180,000 in Europe, and just over 3 million globally.
Scientists have a firm grasp on the SORD gene and the biochemical function it’s responsible for. The biochemical process the SORD gene is a part of is implicated in diabetes and other diseases, and scientists have been studying this implication for decades. There was already pharmaceutical expertise in this area when scientists made the SORD-deficiency discovery. Because of this, researchers feel this might be the first truly treatable CMT subtype (CMTA, 2021).
What is SORD-Deficiency?
Also known as SORD-deficiency CMT, or SORD-CMT, or just SORD, whichever we call it, SORD-deficiency is a CMT subtype (Shendelman, 2022). Specifically, SORD-CMT is an axonal CMT subtype, and as an axonal subtype, it fits within the CMT2 nerve conduction and symptom profile. SORD-CMT is mostly a motor neuropathy (primarily affects the motor nerves), but there can be sensory nerve involvement. A likely description on a nerve conduction study (NCS) report would be along the lines of length-dependent axonal motor polyneuropathy (or sensorimotor polyneuropathy if there is also sensory nerve involvement). What is CMT2?
CMT is clinically divided into two main groups according to nerve conduction study results (NCS): CMT1, classified as demyelinating, and CMT2, classified as axonal. These are differentiated by their respective nerve conduction profiles. Clinically, CMT1 has nerve conduction velocities (speeds) that are slower than 38 meters/second (and usually slower than 25 meters/sec) and amplitudes (signal strength) that are somewhat reduced; and CMT2 has velocities that are faster than 38 meters/second with significantly reduced amplitudes (Dyck, Lambert, & Mulder, 1963) (El-Abassi, 2014) (Stojkovic, 2016). Although these are basic and general rules-of-thumb, how CMT is clinically diagnosed without the benefit of a genetic confirmation is typically based on these criteria. Then, once the underlying genetic cause is identified, the diagnosis transitions to the subtype associated with the identified gene mutation. The genetic diagnosis, however, might not remain a CMT1 or a CMT2 classified subtype, such as CMT1B or CMT2D, for example.
CMT1 is a group of ten demyelinating subtypes as determined by nerve conduction. However, there are twenty-eight demyelinating subtypes. CMT2 is a group of thirty-six CMT subtypes, but there are 114 axonal subtypes (Experts in CMT, 2022). Of these 114, there are twenty-three subtypes that have a dHMN name— eighteen dHMN subtypes plus five dSMA subtypes (dHMN and dSMA are synonymous (Inherited Neuropathies Consortium (INC), 2021)). dHMN is the acronym for Distal Hereditary Motor Neuropathy and dSMA is the acronym for Distal Spinal Muscular Atrophy. Despite the names, the CMT experts consider these to be CMT (Bird, 1998, Updated 2022) (Bansagi, et al., 2017). What is dHMN?
The subtypes of dHMN are a length-dependent motor neuronopathy, meaning the issue originates within the motor neuron of the peripheral nerves and affects the longest peripheral motor nerves first and more severally than the shorter ones (the nerves that control the muscles of the feet and lower legs vs. the nerves that control the muscles of the hands, for example). The motor nerves are the nerves that control muscles and movement. Sometimes truncated to just HMN (Hereditary Motor Neuropathy), there is little to no sensory nerve involvement, and these subtypes exhibit an axonal CMT nerve conduction profile. As such, the dHMN subtypes are classified as axonal CMT and are therefore often clinically diagnosed as CMT2. Sometimes, however, dHMN (aka HMN, aka dSMA) is the clinical diagnosis when NCS results show a length-dependent axonal CMT and when there is only motor nerve involvement. This will be important in a moment.
As a general rule-of-thumb, symptoms associated with CMT2 are typically length-dependent, again, meaning the longer nerves are often affected before the shorter ones, and often more severely. Typically, the lower legs and feet are more severely affected than the hands. Symptom onset can occur at any point in life. Nerve conduction can be quite variable from nerve to nerve and even side to side. How does SORD-CMT fit within this CMT2/axonal CMT classification?
SORD-CMT symptom onset is usually in the second decade, typically by about 17 years old (CMTA, 2022). Symptoms are basically that of a motor-predominant CMT2 and/or dHMN, affecting only the motor nerves, in a length-dependent manner, with little to no sensory nerve involvement, and include difficulty with walking, frequent tripping, lower leg weakness, foot deformities, progressing to the need for mobility aids (leg bracing); and later on, hand weakness, for example. However, some can have upper limb sensory and motor involvement early on in their disease course.
Although SORD-CMT is classified as an axonal CMT, some SORD-CMTers have nerve conduction that is more consistent with intermediate CMT (Record, et al., 2022). Intermediate CMT is a group of CMT subtypes as determined by NCS results. Intermediate CMT nerve conduction doesn’t necessarily comport with demyelinating CMT or with axonal CMT, it is somewhere in between, it is intermediate (El-Abassi, 2014). Intermediate CMT does not denote disease severity and refers only to nerve conduction. Regardless of the nerve conduction profile a CMTer who has SORD-CMT might have, SORD-CMT is classified as an axonal CMT subtype.
CMTers who have SORD-CMT are often clinically diagnosed with either CMT2 or with dHMN (or HMN, and some possibly dSMA) based on symptoms and especially on NCS results. Past genetic testing for these CMTers failed to identify a conclusive genetic cause for their CMT. SORD-CMT and its cause were discovered and published only in 2020. Prior to this, the SORD gene was not part of any CMT genetic test. Nobody knew about this gene’s connection to CMT.
Several commercial genetic testing companies moved quickly to offer SORD testing within a year of the initial discovery of its role in CMT. However, SORD genetic testing is not yet a part of the neuromuscular or neuropathy gene panels that are used in CMT genetic testing. So, physicians need to specifically order the SORD genetic test if they suspect a patient might have SORD-CMT (SORD genetic testing resources are discussed in Diagnosing SORD-CMT). Why this name, “SORD,” and why the caps lock?
This Gene has a Name, and Its Name is “SORD” (for short)
Genes have both a long-form name and a short-form called a symbol. The symbol is an abbreviation of the long-form gene name. The HUGO Gene Nomenclature Committee is the entity who manages these names and symbols. The "SORD" in SORD-deficiency is short for SORBITOL DEHYDROGENASE. Where SORBITOL DEHYDROGENASE is the gene name, SORD is the gene symbol (HGNC, 2022). It’s customary to write the gene name in all caps but is not required in literature. The gene symbol, however, is always written in all caps.
The SORD gene codes for an enzyme aptly called sorbitol dehydrogenase (the gene provides the genetic code that makes the enzyme and provides the genetic instructions for how the enzyme functions). An enzyme is a biological catalyst (causes a biochemical change). SORD belongs to a group of enzymes called dehydrogenases. Dehydrogenases are a group of enzymes that each catalyze (change/convert) a compound to another by removing hydrogen atoms (de-hydrogen-ates, ergo de-hydro-gen-ace). Specific to the SORD gene, sorbitol dehydrogenase is the enzyme that converts sorbitol to fructose by removing a hydrogen atom from sorbitol. This action converts (changes) sorbitol to fructose. This is the important part in the context of SORD-CMT, and it all starts with glucose.
The Less Traveled Path[way] of SORD-CMT
Glucose is one of many different simple sugars. When we talk about blood sugar, we're talking about glucose. In biochemistry, anything ending in "ose" is a simple sugar. The body metabolizes (converts to energy) these simple sugars through various biochemical processes. Glucose is metabolized in many ways, and each is referred to as a pathway. Each of these pathways convert glucose to other sugars which are then, eventually, used by the cell for energy.
The majority of glucose is converted to other substances that are used by the cell for energy via the hexokinase pathway. The hexokinase pathway is the biochemical chain reaction that converts hexoses to energy. As complicated as this might sound, you don’t have to be a biologist to know what all this is and how it works in the context of SORD-CMT
"Medicine makes sense once we understand what the words are saying." --Medicosis Perfectionalis
Hexokinase (hex-oh-kye-nace) is an enzyme that phosphorylates hexoses. Phosphorylates means "to add a phosphate group to a substance." A hexose is any sugar that contains six carbon atoms (hex- = six, -ose = sugar). These are referred to as six-carbon sugars. In biochemistry, "kinase" means "to phosphorylate." Put these together and hexokinase is an enzyme that converts into other substances sugars that contain six carbon atoms, and this is accomplished by adding a group of phosphates to the sugars. Glucose just happens to be a six-carbon sugar—a hexose. Adding a phosphate group to glucose converts it to a different sugar, and further down the complicated hexokinase pathway, after several additional biochemical conversions, the end result is fructose, which is then used by the cell for energy (Chaudhry & Varacallo, 2021).
Another pathway in which glucose is converted to energy is the polyol pathway. The polyol pathway is a two-step biochemical conversion that converts monosaccharides to their corresponding polyol in the first step and then converts the polyol to fructose in the second step. Fructose is then used for energy by the cell. The polyol pathway is the important one for SORD-CMT. What does all this mean and why is this pathway important?
A polyol is an alcohol sugar, of which there are many (poly- = many, -ol = alcohol sugar). The term, "alcohol sugar," is misleading though. Alcohol sugars are neither alcohol nor sugar. They are, however, a compound chemically similar to sugars (BiologyOnline, 2022). A monosaccharide (mono-sack-ah-ride) is any sugar that cannot be further reduced into a simpler sugar. A monosaccharide (mono- = one, -saccharide = sugar) is a sugar in its simplest form. The polyol pathway converts these simple sugars into their corresponding polyol sugar. Hence, polyol pathway. The first step in the two-step polyol pathway is aldose reductase.
Aldose reductase is an enzyme that reduces aldoses to their corresponding polyol. Aldoses are a large family of monosaccharides. Biochemically, an aldose is a simple sugar that contains an aldehyde group (ald- = aldehyde, -ose = simple sugar) (BiologyOnline, 2022). Reductase (re-duck-tace) is any enzyme that reduces a substance to another substance. In biochemistry, metabolism (substance conversion) occurs in terms of electrons: if electrons are lost during the chemical conversion, the process is called oxidation—something is oxidized; and if electrons are gained, it’s a reduction—something is reduced. (The University of Hawaiʻi, 2022).
Glucose, as you might have guessed, just so happens to be a member of the aldose family of simple sugars. The corresponding polyol for glucose is glucitol (gluc- = glucose derivative, -ol = alcohol sugar). Glucitol (gloose-eh-tall) is more commonly known as sorbitol. In the first step of the polyol pathway, aldose reductase converts glucose to sorbitol. Sorbitol cannot cross the cell wall and becomes trapped within the cell. To manage sorbitol levels within the cell, sorbitol must be converted to another substance.
The second step of the polyol pathway, sorbitol dehydrogenase, converts sorbitol to fructose. Fructose is then used by the cell for energy. This solves the issue of sorbitol being trapped within the cell and reaching toxic levels as more glucose is converted by aldose reductase. It’s a simple, quick, and easy two-step (two-enzyme) process for managing glucose levels and acute (short-term) cell energy demands, especially when compared to the more complex hexokinase pathway.
The hexokinase pathway handles the bulk of metabolizing glucose to energy. Under normal conditions, the polyol pathway is barely used, if at all. The polyol pathway, however, becomes activated when hyperglycemic conditions are present within the cell (elevated levels of glucose) or when the cell needs extra energy.
Under normal conditions, sorbitol levels are very low. As sorbitol is produced by the polyol pathway, it’s converted to fructose and sorbitol levels are kept in check. If this pathway is inactive, glucose isn’t being converted to sorbitol within the cell. When the polyol pathway is active, the amount of glucose being converted is minimal compared to the hexokinase pathway, and the sorbitol that is produced is converted to fructose by sorbitol dehydrogenase (Shendelman, 2022). Normally low sorbitol levels are maintained by sorbitol dehydrogenase. So, what happens if sorbitol dehydrogenase can’t perform its job?
Enter SORD-Deficiency CMT
SORD-deficiency CMT is caused by autosomal recessive mutations in the SORD gene (autosomal = gene lives on a numbered chromosome (the SORD gene lives on chromosome 15), recessive = gene must have two mutations in order to cause the disease). Researchers have identified many different CMT-causing mutations within this gene since the initial discovery. Each of these can either cause the SORD enzyme to not be produced at all or they can cause the enzyme to completely shut off and stop working. Because the SORD enzyme no longer functions in this CMT subtype, SORD is deficient - the biochemical conversion performed by the SORD enzyme is deficient. Hence, SORD-deficiency as this CMT subtype name. The subtype name describes the biochemical impairment that causes CMT.
When everything is running well, the polyol pathway, also called the aldose reductase pathway, runs smoothly. When activated in times of need, aldose reductase converts glucose to sorbitol and the SORD enzyme converts sorbitol to fructose. The cellular machinery is happy, and everything moves along nicely. However, the mutations that shut off the SORD enzyme throw a big boulder into this finely tuned machine, as you can imagine.
All the sorbitol created by aldose reductase in the polyol pathway stays trapped within the cell from the very outset. This is normal with sorbitol. Sorbitol is unable to cross the cell wall. Essentially, all sorbitol created by the polyol pathway remains within the cell until SORD converts it to fructose. Since the mutations in the SORD gene that cause SORD-CMT cause the sorbitol dehydrogenase enzyme to completely stop working, sorbitol is not converted. The sorbitol, instead, remains within the cell, trapped. The more glucose that’s converted to sorbitol by aldose reductase, the higher the sorbitol levels climb, and they keep climbing, over time, until they reach levels that become toxic to peripheral nerves and their neurons, leading to neuronal and peripheral nerve impairment, or as we like to call it, CMT. And then, they keep climbing, unabated, as aldose reductase continues to do its job.
The body does process sorbitol in other ways, albeit minimally. Certain enzymes called, “scavenger enzymes,” whose job it is to basically perform cellular housekeeping duties, is one way sorbitol is processed. The kidney’s also play a role in managing sorbitol. In the absence of a functioning SORD enzyme, while these methods do remove some sorbitol, they are quite inefficient and pale in comparison to the amount of sorbitol the SORD enzyme can handle (Shendelman, 2022). For the amount of sorbitol the body is able to process in the absence of a functioning SORD enzyme, aldose reductase keeps adding sorbitol back into the mix, and at a rate greater than what non-SORD sorbitol processing can handle. The result is chronically high sorbitol levels that become toxic to especially motor neurons thereby causing CMT symptom onset, and these things only worsen over time.
The Toxicity of Our [Sorbitol]
When SORD is deficient, the sorbitol created by the polyol pathway cannot be converted to fructose. This sorbitol ends up just sitting there, in the cells, trapped, accumulating over time because sorbitol cannot exit the cell. Eventually, sorbitol accumulates to levels high enough, toxic enough, to cause CMT symptoms to start. As sorbitol levels continue to accumulate, symptoms worsen. These elevated levels of sorbitol are quite toxic especially for motor neurons. Hence, SORD-CMT symptoms. Research has shown that overall symptom severity in SORD-CMT correlates with sorbitol levels in the blood (Shendelman, 2022). The higher the sorbitol levels, the worse the CMT. Because sorbitol continues to accumulate and causes damage over time, the older the CMTer who has SORD-CMT gets, the more severe their CMT becomes.
It's well understood that high sorbitol levels via the polyol pathway in diabetes are a contributing factor to diabetes-induced peripheral neuropathy, or what is referred to as diabetic neuropathy. When glucose is high, such as what is commonly seen in diabetes, there’s more to convert. Elevated glucose activates the polyol pathway causing sorbitol levels to become higher as aldose reductase is converting more glucose. The higher sorbitol levels contribute to the acquired neuropathy often seen in diabetes. Because this is well described and understood in medical science, it makes sense that SORD-deficiency could cause CMT. The difference between diabetic sorbitol levels and SORD-CMT sorbitol levels is staggering though.
Published literature suggests normal sorbitol levels are around 215ng/ml, with levels in diabetes around 400ng/ml (Preston & Calle, 2010). While there is some conflicting data in published literature regarding normal sorbitol levels and that which is seen in diabetes, regardless of the source reviewed for this publication, reported levels of normal vs. diabetes consistently show levels in diabetes are about twice that which is reported as normal by the respective source. By comparison, sorbitol levels in SORD-CMT are in excess of 10,000ng/ml and have been seen as high as 47,000ng/ml in some patients (one-hundred times normal, or higher) (Shendelman, 2022). SORD-CMT sorbitol levels far exceed anything diabetes can cause and far exceed anything obtainable through dietary intake. In the context of CMT, this is unique to only SORD-CMT. And these toxic levels, which continue to climb over time, cause CMT symptom onset and drive overall disease severity.
Leveraging Inhibition
SORD-CMT discovering scientist, Stephan Züchner MD, PhD, professor of human genetics and neurology, chair of the Dr. John T. Macdonald Foundation, Department of Human Genetics at the University of Miami Miller School of Medicine, co-founder and CEO of Genesis Project Foundation, believes SORD-CMT could quite possibly be the first truly treatable CMT subtype (CMTA, 2021). Dr. Züchner might not be too far off. The SORD-CMT discovery was published in May 2020. Today, November 2022, only two and a half years later, there is already a Phase III trial of a potentially disease-modifying treatment (DMT) for this subtype. The speed at which science has moved into a Phase III trial for SORD-CMT is unheard of. This has happened in part because of how well scientists understand the polyol pathway and its implication in diabetes as well as in other conditions, but even more so because the right pieces and the right expertise were already in place.
In 2016, a small pharmaceutical company named Applied Therapeutics was founded by Shoshana Shendelman, PhD. The company quickly developed several experimental drugs in a class of drugs called Aldose Reductase Inhibitors (ARI). An ARI is a drug that blocks (inhibits) aldose reductase from doing its job. On one hand, this is a good thing because this shuts off the first step in the polyol pathway—converting glucose to sorbitol. This means controlling sorbitol levels. On the other hand, however, completely shutting off the actions of aldose reductase leads to unintended “off-target” consequences.
Aldose reductase is most known for catalyzing the first step of the polyol pathway: converting glucose to sorbitol. Aldose reductase also converts other compounds. Aldose reductase converts compounds called aldehydes. Aldehydes are complex compounds that occur in the environment and are also naturally produced by the body’s metabolic activity. Glucose happens to be one of these many aldehydes. Yes, glucose is a simple sugar, but this simple sugar is also an aldehyde, and is an overall complex compound.
If aldehydes are not adequately converted and metabolized to other compounds through biochemical processes, they can accumulate to toxic levels. Aldose reductase’s primary role, therefore, is to convert aldehydes to less harmful compounds which then get converted to even less harmful compounds, etc. Sometimes, the aldose reductase enzyme is but one step of a biochemical chain in a complex metabolic pathway. Where SORD-CMT is concerned, the aldose reductase enzyme is the first step in a simpler two-step enzymatic pathway.
The well-known polyol pathway is just one of the ways aldose reductase carries out its function. Aldose reductase plays a role elsewhere and in other pathways, reducing harmful aldehydes to other less harmful compounds. When an ARI is introduced and aldose reductase is completely shut off, it can no longer convert any aldehyde. These aldehydes can then build to toxic levels, leading to unintended outcomes. This has been a major hurdle to developing successful ARI drugs for diabetic neuropathy and other conditions in which aldose reductase is implicated. Applied Therapeutics could very well have the solution, and this potential solution, in large part, is why and how there is already a Phase III clinical trial for SORD-CMT.
Applied Therapeutics’ ARI development predates the SORD-CMT discovery. When the SORD-CMT discovery was published, the company already had specific expertise in managing the polyol pathway—they already had expertise in sorbitol dehydrogenase. One of Applied Therapeutics’ investigational novel (new) drugs, called AT-007, is an ARI that selectively inhibits (blocks) aldose reductase from converting glucose to sorbitol. The drug is designed to do this without causing “off-target” toxic effects associated with older ARI drugs that shut off aldose reductase completely. AT-007 targets the polyol pathway essentially shutting off aldose reductase at this location which then blocks glucose from converting to sorbitol. The result is a reduction in sorbitol levels without disrupting other critical biochemical conversion processes.
When the SORD-CMT discovery was published, describing SORD-deficiency as the culprit, Applied Therapeutics recognized this unique CMT situation and was able to quickly leverage their aldose reductase expertise to translate their AT-007 ARI to the investigational needs of SORD-CMT. Applied Therapeutics partnered with Dr. Stephan Züchner and colleagues (the Nature Genetics publication team) to jump right into SORD-CMT and study the effect of one of their ARIs on cells from SORD-CMT patients and a fruit-fly model of SORD-CMT (yes, the fruit-flies lose their walking ability too, just like humans with SORD-CMT). Fortunately, this drug, AT-007, was already in a Phase III study for another rare disease that involves the aldose reductase pathway, so there was already a lot of information available on safety and the right dose to use, which allowed researchers to move very quickly (less than one year after the discovery of SORD-CMT) into a pilot study in SORD-CMT patients, and now into a Phase III study.
A Pilot is Born
Researchers in Miami developed a fruit-fly model of SORD-deficiency by “knocking out” the SORD enzyme (referred to as a drosophila SORD-deficiency model (drosophila = scientific name (genus) for fruit-flies), and in 2021, demonstrated that high sorbitol levels caused by a non-functional SORD enzyme led to motor neuron degeneration thereby mimicking the toxic effects of high sorbitol levels that lead to the same motor neuron degeneration in CMTers who have SORD-CMT. The investigative team then treated the fruit-flies with Applied Therapeutics’ investigational AT-007 drug.
Working with the SORD-deficiency drosophila model, AT-007 demonstrated a significant reduction in sorbitol levels (Shendelman, 2022). This reduction resulted in a recovery of degenerated motor neurons, returning the neurons back to a healthy state. As part of this investigation, researchers cultured cells from CMTers who have SORD-CMT. After measuring sorbitol levels in these cells to be as high as one hundred times higher than cells cultured from healthy controls, the cells were treated with AT-007. AT-007 demonstrated that sorbitol levels in these cultured human cells could be reduced to levels that are comparable to the cultured cells from the healthy controls. This breakthrough set the stage for the first trial of AT-007 in SORD-CMT.
On the heels of AT-007 demonstrating success reducing sorbitol levels in the lab, and still in 2021, Applied Therapeutics formed partnerships with CMT patient organizations. Collaborating with these partners, SORD-CMT study candidates were identified. Then, having also forged genetic testing partnerships, candidates underwent genetic testing for SORD-CMT. Of the volunteer CMTers who were confirmed to have SORD-CMT, eight were enrolled into an initial pilot study. Sorbitol levels of these eight CMTers ranged from 25,000ng/ml to as high as 47,000ng/ml (38,000ng/ml mean sorbitol level).
The pilot study lasted thirty days and was an open-label study, meaning each participant knew of the drug that was being administered. Given once daily for thirty days, AT-007 demonstrated a significant reduction in sorbitol levels of between 54% and 75% (66% mean sorbitol reduction). While there was variability in the percentage of overall sorbitol reduction, every participant showed more than a 50% reduction. These reductions were achieved with no adverse increase in glucose levels, demonstrating that AT-007 can inhibit aldose reductase’s involvement in glucose conversion without causing an unwanted and potentially harmful increase in overall glucose levels. Another important finding was disease severity correlation.
Although the pilot study consisted of just eight SORD-CMTers, important disease severity data were learned in addition to AT-007 sorbitol level reduction outcomes. Investigators learned that the higher the sorbitol levels were for an individual, the worse their overall disease severity. Participants with the highest sorbitol levels had a more severe symptom presentation—a more severe phenotype, such as needing leg braces from an early age, upper limb involvement (hand weakness, tremor, sensory nerve involvement (i.e., numbness, tingling) etc.), for example, and a greater overall disability compared to those who had a lower sorbitol level. Researchers learned that, while all SORD-CMTers have very high sorbitol levels, overall SORD-CMT disease severity correlates with sorbitol levels—the higher the sorbitol, the more severe the disease progression (Shendelman, 2022).
After demonstrating AT-007 could safely and rapidly lower sorbitol levels and could sustain this trend with no reported severe adverse effects (SAEs), Applied Therapeutics designed the next step, a Phase III trial of AT-007 for SORD-CMT. If you’re thinking this is moving extremely fast, you’re not wrong. Applied Therapeutics just so happened to be in a unique position to facilitate this.
AT-007 is a drug whose development predates SORD-CMT’s discovery. Applied Therapeutics has been developing AT-007 for use in other diseases in which the aldose reductase pathway is implicated, with the drug already in a Phase III trial for one of these diseases. Having a current Phase III trial with AT-007 positioned the company with unique expertise and an extensive knowledgebase that includes critical dosage data. Drawing on this expertise and knowledgebase, Applied Therapeutics, working with their forged SORD-CMT partnerships, moved with expedience to design a Phase III trial for AT-007 in SORD-CMT.
Becoming INSPIREd
Applied Therapeutics has named their SORD-CMT AT-007 trial “INSPIRE.” INSPIRE is the acronym for INhibiting Sorbitol Production through Inhibition of the aldose Reductase Enzyme (Applied Therapeutics, 2022). The purpose of the earlier pilot study was to assess AT-007’s ability to safely reduce toxic sorbitol levels. The study achieved this goal. The purpose of the Phase III INSPIRE trial is to continue assessing AT-007 safety and effectiveness, and to also assess therapeutic benefit of AT-007 for SORD-CMT. What does all this mean?
"This trial is designed to investigate the ability of AT-007 versus placebo to reduce toxic sorbitol levels, and to evaluate the effect of AT-007 on improving symptoms of the disease over a longer period of time." --Applied Therapeutics
The SORD-CMT AT-007 pilot study demonstrated the extremely high sorbitol levels seen in SORD-CMT could be safely reduced by the drug, that they could be quickly reduced, and that a continuing reduction in sorbitol levels was possible. This was the intention of the study. The pilot study was not intended to assess AT-007’s ability to slow or to stop disease progression, or the drug’s ability, via lowering toxic sorbitol levels, to improve SORD-CMT symptoms (the study was not designed to assess clinical improvement). To assess what happens when sorbitol levels are brought down, a new study was needed.
Applied Therapeutics, building on the successes of and knowledge gained with the pilot study, designed the INSPIRE Phase III trial to assess not only AT-007’s ability to lower high sorbitol levels over the long-term, but to assess the influence on disease progression lowering sorbitol levels could potentially have— to assess clinical improvement. Designed as a twenty-four month, double-blind, placebo-controlled, international multi-center study to include up to fifty participants, the INSPIRE Phase III trial is intended to assess AT-007’s long-term sorbitol reduction potential along with the potential to slow or to stop disease progression and the potential to improve overall disease severity (clinical improvement).
In a double-blind study, participants don’t know whether they’re getting the drug or a placebo, and the principal investigators don’t know which participants are getting the drug or the placebo. Placebo-controlled means some participants will receive a placebo and others will receive the drug; and, according to Applied Therapeutics, a randomized two-thirds of the study participants will receive the drug while the remaining randomized one-third will receive a placebo (a 2:1 active drug to placebo randomization). An international multi-center study is a trial that includes several different facilities located in more than one country that are enrolling study participants, evaluating study participants, and collecting study data.
Applied Therapeutics is enrolling INSPIRE Phase III trial participants in the US who are ages 18-55 and in the EU who are 16-55 (the age differences are regulatory agency driven). There are six INSPIRE trial sites in the US and three in Europe. These sites evaluate participants according to an interval schedule set by the trial. The first part, at three months, measures sorbitol level reduction for comparison against the participant’s baseline that was established when they entered the study. At regular intervals thereafter, for a period of up to twenty-four months, in addition to routine sorbitol levels, glucose levels, and other related bloodwork, various metrics are evaluated using what’s called the CMT Functional Outcomes Measure (CMT-FOM) and the CMT Health Index (CMT-HI).
The CMT-FOM and the CMT-HI are standardized functional assessments developed by CMT experts as a means by which to accurately measure overall disease progression and severity. The CMT-FOM is a performance-based measure assessing functional ability in adults with CMT (Eichinger, et al., 2018), while the CMT-HI is a disease-specific patient-reported outcome for Charcot-Marie-Tooth disease (Johnson, et al., 2018). In addition to these assessments, and also at regular intervals throughout the trial, leg MRIs are performed to assess what’s called “muscle-fat fraction.”
In 2018, researchers demonstrated that an MRI technique that measures the amount of fat present within calf muscle tissue, developed at Queen Square Centre for Neuromuscular Diseases in London and referred to as the Queens Square calf muscle fat-fraction protocol, can be used as an outcome measure in CMT1A (Morrow, et al., 2018). This MRI technique measures the amount of fat that has replaced healthy calf muscle, and this measurement, researchers have shown, correlates with overall disease progression in CMT1A. Additional research has shown that this same MRI technique can be used to assess therapeutic outcomes by measuring progression, cessation of progression, or regression (improvement) of calf muscle fat-fraction.
Although initially demonstrated only in CMT1A, many additional publications have replicated Morrow, et al. (2018), and the findings have been extrapolated to be reproducible in CMT across the board. Hence, its use in the INSPIRE study. While this has potential to be a particularly valuable tool for doctors to have in their CMT diagnostic and monitoring tool bag, it’s presently used only in experimental therapy outcome measures.
As of this publication, Applied Therapeutics is nearing full enrollment in their INSPIRE Phase III trial. The study is on track to have the aforementioned three-month sorbitol levels reduction data readout by early 2023. The study is hopeful to hit statistical significance in the second half of 2023, at the twelve-month mark (statistical significance is the point at which data show the results are real and not occurring by chance), and to conclude the study in the second half of 2024, at the twenty-four-month mark, with clinical outcomes and final study data available shortly thereafter. SORD-CMT has gone from discovery and no available treatment, through a Phase I trial (drosophila SORD-CMT model outcomes), through a Phase II trial (the pilot study), and now into a Phase III trial with near full enrollment in only about two-and-a-half years. Even though INSPIRE is scheduled to complete in the second half of 2024, which is another two years from now, the speed at which we’ve gotten to this point is unheard of. And it’s happened because of the tireless work of everybody involved.
Diagnosing SORD-CMT
There’s a generalized set of guidelines that are used when diagnosing SORD-CMT. Diagnosing SORD-CMT isn’t any different than diagnosing any of the many other CMT subtypes. In order to diagnose CMT, doctors look for the right diagnostic picture—high arched feet (but feet can be flat, too), weakened ankles, lower leg atrophy, numbness or tingling in the feet & hands (although this would be found typically to a lesser extent with SORD-CMT, or to a lesser extent earlier in the disease course), reduced or absent reflexes, symptoms that can’t be explained by treatable conditions such as diabetes, G6PD-deficiency, or Vitamin B12-deficiency, for example. (Raymond, 2021). Then, if NCS results show very slow speeds, the clinical diagnosis is usually CMT1; and if speeds are only somewhat slowed, CMT2 (and sometimes dHMN (or HMN, or possibly dSMA) if there is only motor nerve involvement).
After a doctor has made a clinical CMT diagnosis (the diagnosis that’s based on symptoms and NCS results), they’ll typically order CMT genetic testing. While genetic testing is not needed to definitively diagnose CMT, it is needed to pinpoint the exact subtype. There are many commercial labs that offer CMT genetic testing. Twenty years ago, access to CMT genetic testing was limited and costs were regularly prohibitive. Things have changed drastically and CMT genetic testing is now readily available. Despite the growth in testing accessibility, CMT genetic testing has some limitations.
Scientists have discovered CMT-causing mutations in more than 120 different genes. A review of publicly available lists of genes included in genetic testing panels shows the larger panels include up to 89 of these genes (a genetic testing panel is a genetic test that analyzes more than one gene vs. a single-gene test). The SORD gene is not yet available in panels that are used in CMT genetic testing (GeneDx Charcot-Marie-Tooth Panel Test Code: J778, 2022) (GeneDx Hereditary Neuropathies Panel Test Code: 737, 2022) (Invitae Comprehensive Neuropathies Panel, 2022) (Invitae Charcot-Marie-Tooth Disease Comprehensive Panel, 2022). After exhausting these CMT genetic testing options without finding a cause, if the doctor feels SORD-CMT is a possibility, there are testing options available.
There are at least two commercial labs offering SORD gene testing. Invitae Corp is a popular lab for CMT genetic testing. They offer SORD gene testing but only as part of a large and complex genetic test called Whole Exome Sequencing (WES) (Invitae - Exome, 2022). WES is a type of test that attempts to look at the coding regions of all genes. WES has limitations (Raymond, 2021), so to ensure the test covers the SORD gene, when ordering the test, the doctor would need to specifically request the SORD gene to be included in the analysis. According to Invitae Corp., the doctor can call them for ordering the test or can order the test through their provider portal, and when ordering, can specifically request SORD gene inclusion in the interpretive analysis. The second lab is GeneDx.
GeneDx, like Invitae Corp., is a popular lab for CMT genetic testing. They offer SORD gene testing as a single-gene test. According to GeneDx, to order SORD gene testing, the doctor can call them and request their Exome Slice, Test Code: TG70, and manually add the SORD gene. The doctor can also order the test via GeneDx’s provider portal by searching for Test Code: TG70. The search result opens the Exome Slice Tool, and the doctor can easily add the SORD gene by simply typing “SORD” in the appropriate field (GeneDx - Slice Tool, 2022). Coincidentally, Applied Therapeutics is partnered with GeneDx for SORD genetic testing as part of their INSPIRE study candidate screening.
Reviewing the websites of other labs who are popular with CMT genetic testing yielded no results for SORD gene testing. Testing might be available even though public facing websites don’t show availability. SORD testing costs, insurance coverage for the testing, etc., is highly individualized. Each lab can be contacted to discuss these costs if the doctor feels SORD gene testing should be explored.
Get INSPIREd
Has your doctor diagnosed you with CMT2 or dHMN based on symptoms and on NCS results that show an axonal CMT (or diagnosed you with HMN or dSMA (dSMA is synonymous with dHMN)? Has genetic testing not found your CMT genetic cause, so you are therefore a “CMT2, subtype unknown (or unknown cause)?” Are you between 18 and 55 in the US or 16 and 55 in Europe? Is there no established family history of CMT—you’re the first in the family diagnosed and nobody else in the family seems to have CMT? If yes to these questions, you might be a candidate for Applied Therapeutics’ INSPIRE study for SORD-CMT.
Although almost at full enrollment, as of this publication, Applied Therapeutics is actively enrolling participants in their INSPIRE study. If you meet the above criteria (answered yes to each question), and you’re interested in participating in the INSPIRE study, after contacting Applied Therapeutics, the screening process begins. If they feel you meet study criteria, they will send somebody to you to perform a blood draw. This person is an employee and not a contractor/vendor. The blood draw is to check your sorbitol levels.
When the blood test comes back, typically within a few days, and your sorbitol levels are at or above 10,000ng/ml, you essentially have SORD-CMT and meet the criteria for moving onto the next screening steps which will include genetic testing and an in-person visit to a study center. The sorbitol blood test, which is not available commercially, the SORD genetic testing (if sorbitol levels in the blood meet criteria for SORD-CMT), travel to and from the center (Applied Therapeutics handles all travel arrangements, including ground transportation so that study participants don’t have to stress about it), meals, and lodging are all covered costs. They even assign a concierge to each study participant in case there are any hiccups along the way, such as canceled or missed flights. The study also provides compensation for each participant (Shendelman, 2022). The INSPIRE study truly is unlike any other by every measure.
If you meet study criteria and would like to be considered for inclusion, or you have already obtained SORD-CMT genetic confirmation through commercial genetic testing, you can send an email with all your contact info to sord@appliedtherapeutics.com. You can also visit their INSPIRE website to learn more about the study and to submit an interest form: https://www.appliedtherapeutics.com/inspire/.
The CMT patient community consistently reports a very fast reply from Applied Therapeutics—within a couple of days, and sometimes within hours. After Applied Therapeutics has determined you meet the INSPIRE study criteria, the community consistently reports that the company continues moving very quickly with getting somebody to you for the initial screening, getting the sorbitol level results to you, getting somebody back to your door for going over blood test results, going over study paperwork, etc. The community also consistently reports that through everything, everybody with whom they’ve had contact within the study has treated them with the utmost respect, compassion, and grace; and they’ve wanted for nothing at every step of the way, and this includes concierge assistance with resolving cancelled flights. There isn’t enough praise for the company or for their INSPIRE study.
The GENESIS
The SORD-Deficiency discovery would not have been possible if not for the invaluable GENESIS platform. GENESIS is the genomics research and database platform developed by The Genesis Project Foundation. Cofounded and led by Dr. Züchner, The Genesis Project Foundation is a patient and scientist managed (501(c)(3)) (The Genesis Project, 2022).
The Genesis Project Foundation focuses on finding genetic causes for rare diseases and on accelerating new treatments for rare diseases via these genetic discoveries. Since its founding in 2011, The Genesis Project’s genomics research database and platform, GENESIS, which boasts more than 18,000 stored genomes (and counting), has contributed to more than 100 rare disease gene discoveries (The Genesis Project - Gene Discoveries, 2022). These discoveries allow investigators the opportunity to develop first ever treatments for many rare diseases, and SORD-deficiency CMT is just one example.
If not for the foundational work of Dr. Züchner and his team, and if not for the contributions from The Genesis Project’s GENESIS platform, SORD-deficiency CMT might not have been discovered for years to come. The Genesis Project offers researchers a unique opportunity to analyze and query thousands of genomes as they try to identify causes diseases. When a discovery is made, the speed at which researchers can then develop potential therapies is truly remarkable, as Applied Therapeutics’ INSPIRE trial has shown. The contributions of The Genesis Project help lead Cortese et, al. (2020) to the SORD-deficiency discovery. On the heels of this discovery, scientists were able to quickly leverage expertise into a potential treatment for this new CMT subtype. Please visit The Genesis Project Foundation to learn more about their work here.
In Closing
CMT does not cause SORD-deficiency. A CMTer who has CMT2A, for example, will not develop SORD-deficiency, and their CMT will not cause high sorbitol levels. The only CMT subtype that has high sorbitol as part of the disease is SORD-deficiency CMT. While the name “SORD-deficiency” has some inherent confusion, SORD-deficiency is the name of the subtype and is not a second diagnosis. Where some of the confusion might arise, for example, is with Vitamin B12-deficiency.
Vitamin B12-deficiency, or what is pernicious anemia, can mimic CMT in many ways, as can anemia in general. Pernicious anemia is caused when the intestines cannot absorb Vitamin B12. Not absorbing Vitamin B12 in the digestive tract leads to Vitamin B12-deficiency. When Vitamin B12 is deficient, it’s typically easily treatable. For example, getting regular Vitamin B12 injections can keep Vitamin B12 levels in check. SORD-deficiency, however, is not like Vitamin B12-deficiency.
Vitamin B12-deficiency is something a CMTer can have in addition to their CMT. SORD-deficiency is CMT, is the name of the CMT subtype. SORD-deficiency is not something a CMTer who has a different subtype will develop. A CMTer who has SORD-deficiency cannot get a shot to restore their SORD levels. If a CMTer has genetic confirmation—has a genetic diagnosis that is other than autosomal recessive mutations in the SORD gene, such as CMT4C, for example, they do not have SORD-deficiency and cannot develop SORD-deficiency.
The sorbitol levels seen in SORD-CMT are astronomical. Normal sorbitol levels are around 215ng/ml. Due to increased glucose that’s seen in diabetes, sorbitol in diabetes is about double that which is normal, and this is due to aldose reductase having to convert more glucose to sorbitol in the polyol pathway. The difference between diabetes and SORD-CMT is that in diabetes, sorbitol dehydrogenase is functional, and although sorbitol levels are higher, they are only about double that which is normal. They are this way because of aldose reductase handling excess glucose. In contrast, in SORD-CMT, sorbitol dehydrogenase is non-functional or absent and sorbitol, therefore, is not converted and stays trapped within the cell. Levels will climb to well over 10,000ng/ml, regardless of glucose levels. In SORD-CMT, it doesn’t take elevated levels of glucose to cause these astronomically elevated levels of sorbitol. In SORD-CMT, glucose levels are normal.
SORD-CMT is all the rage right now. The biochemistry that causes SORD-CMT is well studied, is well described, is well understood. The many symptoms and presentations of CMT can be treated and managed. There is an absence, however, of DMTs (disease-modifying treatments). Currently, there is a Phase III trial for CMT1A being conducted by a pharmaceutical company named Pharnext. They are trialing their investigational drug called, “PXT-3003” (Pharnext, 2022). This drug is being studied only in 1A. A study end-date was not found for this publication. There’s currently no other Phase III trial in CMT.
Considering how well scientists already understand the enzymatic pathway that is implicated in SORD-CMT, coupled with gains demonstrated with Applied Therapeutics’ investigational selective ARI, AT-007, SORD-CMT could quite well be the first truly treatable CMT subtype. Yes, it is still early in the trial, and nobody knows what the data will reveal or if the drug will be successful. However, many, for the first time in their CMT lives, because of these things, have hope, and that is huge. Knowledge gained from the INSPIRE study might be translatable to other CMT subtypes, and this is the best part. CMT just might get cracked wide open in the very near future.
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About the Author
Kenneth Raymond was first diagnosed clinically with CMT1 in late 2002, at the age of 29. He was genetically confirmed to have CMT1A a year later. Kenneth has since devoted his life to studying, researching, and learning all things CMT, with an emphasis on the genetics of CMT as they relate to everyday CMTers, and with an equal emphasis on CMT-related respiratory impairment. As a member of the Charcot-Marie-Tooth Association’s Advisory Board, Kenneth serves as a CMT genetics expert, a CMT-related respiratory impairment expert, and as a CMT advocate who is committed to raising CMT awareness through fact-based information rooted in the latest understandings of CMT.
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