{"id":17778,"date":"2017-02-02T15:17:23","date_gmt":"2017-02-02T23:17:23","guid":{"rendered":"https:\/\/mr66givry2.onrocket.site\/?p=17778"},"modified":"2026-01-20T16:24:18","modified_gmt":"2026-01-21T00:24:18","slug":"improving-clinical-trials-myotonic-dystrophy-thurman-wheeler-md","status":"publish","type":"post","link":"https:\/\/myotonic.org\/es\/improving-clinical-trials-myotonic-dystrophy-thurman-wheeler-md\/","title":{"rendered":"Improving Clinical Trials in Myotonic Dystrophy: Thurman Wheeler, M.D."},"content":{"rendered":"
\n
\n
\n
\n
\n

When Dr. Thurman Wheeler was a resident in neurology, he remembers a senior physician telling him that myotonic dystrophy would probably be one of the most difficult diseases to treat because it involves so many body systems. But thanks to unprecedented advances in laboratory and clinical research since then, \u201cit looks like it might turn out to be fairly straightforward,\u201d Dr. Wheeler says. Now an assistant professor of neurology at Harvard Medical School and a clinical neurologist at Massachusetts General Hospital, Wheeler has spent more than a decade caring for patients with myotonic dystrophy (DM) and conducting lab-based DM studies using mouse models.<\/p>\n

Dr. Wheeler recently received a one-year grant through MDF to develop new serum-based biomarkers in adults and children with type 1 and 2 myotonic dystrophy (DM1 and DM2) for use in therapeutic trials. (For more about MDF grants, see\u00a0Fellows<\/a>\u00a0&\u00a0Grant Recipients<\/a>. Additionally, information about the Wyck Foundation and its related grantees\u00a0is available<\/a>).<\/p>\n

Searching for DM Biomarkers in Body Fluids<\/h2>\n

Dr. Wheeler\u2019s grant, which runs from November 2016 through October 2017, will allow him and his team to begin initial exploration of the viability of developing DM biomarkers that can be measured in blood and urine, reducing or avoiding the need for muscle biopsies \u2013 which are invasive and risky \u2013 to support data collection in clinical studies and trials.<\/p>\n

Dr. Wheeler will examine differences in extracellular RNA that are associated with DM1 and DM2 compared with healthy controls, and look for possible changes in these RNA forms and levels that correlate with disease activity or treatment response.<\/p>\n

\u00abWe\u2019re looking for extracellular RNA in blood and urine,\u00bb Wheeler says. \u00abA few years ago, a colleague here found that blood has extracellular RNAs that can serve as biomarkers for brain tumors,\u00bb Wheeler says. \u00abWe\u2019re going to be adapting the approach of the study that looked for markers of brain tumors and use that for myotonic dystrophy. We\u2019re examining gene expression, splicing, microRNAs, and things like that.\u00bb<\/p>\n

Dr. Wheeler and colleagues will be studying extracellular RNA in adults and children with DM1 and DM2, in collaboration with neurologist Basil Darras at Boston Children\u2019s Hospital.<\/p>\n

The collaboration with Dr. Darras, who sees more pediatric patients than does Dr. Wheeler, is important, Wheeler says, \u201cbecause this enables us to expand the study in children. Muscle biopsies in children require general anesthesia, he notes, \u201cand that\u2019s something you want to avoid in myotonic dystrophy, because patients can have a difficult time coming out of it. So, if we\u2019re successful, we may be able to include children [in clinical trials] much earlier than originally thought.\u201d<\/p>\n

Early Years in the Clinic and Lab<\/h2>\n

Wheeler, who graduated from the University of Washington School of Medicine in 1995 and then completed a neurology residency at that institution, first became interested in muscular dystrophy research during a fellowship in neuromuscular medicine at Johns Hopkins University.<\/p>\n

He then moved to Stanford University to work with Tom Rando, M.D., Ph.D., on developing nonviral gene therapy for Duchenne muscular dystrophy. Then, as now, the potential for unwanted effects associated with using viral vectors as gene delivery vehicles was well understood, and the Rando lab was looking to reduce this downside.<\/p>\n

\u00abWe were doing plasmid and oligo work,\u00bb Wheeler recalls. \u00ab[Dr. Rando] was using a type of non-viral gene therapy called antisense for gene correction of point mutations in a mouse model of Duchenne muscular dystrophy. \u00a0It involves using an oligo that\u2019s complementary to the region across the point mutation except it has the correct base.\u00bb<\/p>\n

After three years at Stanford, Wheeler took advantage of an opening at the University of Rochester (N.Y.) to switch gears and study DM. \u201cI knew what myotonic dystrophy was,\u00bb he says, \u201cbut I had never done any research on it. I moved to Rochester, took what I learned about nonviral gene therapy from Tom, and applied it to myotonic dystrophy.\u201d<\/p>\n

\u00abWe ended up getting antisense to work for exon skipping to eliminate myotonia [in a DM mouse model]. The chloride channel RNA is misspliced in myotonic dystrophy. There\u2019s an exon included aberrantly in the disease state. So if you use antisense to induce skipping of that exon, that can potentially rescue the myotonia, because you\u2019d be restoring the normal chloride channel RNA, and that leads to a normal chloride channel protein. We did that in mice, and it worked beautifully.\u201d<\/p>\n

Correction of chloride channel splicing wasn\u2019t taken forward into drug development, Wheeler says, \u00abbecause there\u2019s much more to myotonic dystrophy than myotonia. You\u2019d eliminate the myotonia, but ultimately you\u2019d be doing nothing for the rest of the symptoms.\u00bb<\/p>\n

It did, however, provide evidence that antisense could be an effective therapy, setting the stage for therapy development to target the fundamental DM1 RNA defect \u2013 expanded CUG repeats in the DMPK gene. \u201cIn parallel, we were working on CUG targeting,\u201d Wheeler says of his Rochester work. \u201cWe were doing them both at the same time, and we finished the chloride channel work first. But we knew that the CUG targeting was working in the mice and that that could be a long-term answer.\u201d<\/p>\n

Developing Antisense for DM1 Treatment<\/h2>\n

At first, the Rochester team\u2019s goal was to develop antisense against the CUG repeat expansion in the DMPK gene. \u00abWe originally were using antisense that was targeting the repeat expansion directly,\u00bb Wheeler recalls, \u00aband the concern was that there are other genes that have shorter CUG repeats where that could interfere. We didn\u2019t really find that in mice, but it was a theoretical concern.\u00bb<\/p>\n

Then came involvement with\u00a0Ionis Pharmaceuticals<\/a>, a Carlsbad, CA-based biotechnology company specializing in RNA-targeted drug discovery and development.<\/p>\n

\u00abWe tried some of the Ionis drugs that they developed earlier, but they didn\u2019t really work very well,\u00bb Wheeler says. \u00abThen Ionis suggested we try their gapmer approach, and that worked incredibly well.\u00bb A gapmer, he explains, refers to the design of the antisense. \u201cThe antisense has modified RNA at the 3-prime and 5-prime ends, separated by a central gap of DNA. When the oligo binds to the target RNA, you get a DNA-RNA heteroduplex that is recognized by RNAse H, which cleaves it. When the cleavage happens, the rest of the transcript is degraded by exonucleases.\u00bb Non-gapmer antisense compounds, he explains, \u00abjust bind to the target and kind of sit there.\u00bb<\/p>\n

Unlike earlier antisense approaches for DM1, the Ionis gapmer approach did not directly target the CUG repeat expansion. \u00abIt targets outside the repeats,\u00bb Wheeler says, thus removing the risk of inadvertent binding to CUG repeats in other genes. And, since RNAse H is located in the nucleus, the strategy preferentially targets aberrant DMPK RNA transcripts, which get stuck in that location, while normal DMPK RNA quickly leaves the area. \u00abTranscripts that have a prolonged dwell time in the nucleus appear to be more susceptible,\u201d he notes, although \u201cpotentially, the gapmer still could target the pre-messenger RNA of DMPK alleles with non-expanded repeats [normal alleles], so that is one of the things we\u2019ll be watching in the clinical trials.\u00bb<\/p>\n

A phase 1-2 trial of IONIS-DMPKRx-2.5 in adults with DM1<\/a>, testing the gapmer antisense against DMPK RNA at multiple U.S. centers, opened in 2014. It ended in late 2016, with\u00a0results reported<\/a>\u00a0in January 2017. \u201cI know that Ionis has taken great steps to test the safety ahead of time, and it\u2019s been very effective in mice and other preclinical models of DM1,\u201d Wheeler says. While the Ionis clinical trial did not achieve sufficient drug levels in skeletal muscle, they are exploring two other antisense oligonucleotide molecules that show promise of greater potency.<\/p>\n

Move to Harvard<\/h2>\n

As fruitful and exciting as his time at the University of Rochester was, Wheeler was eager to expand his lab-based research and begin clinical work in DM and other muscular dystrophies. With that in mind, in 2013, he relocated to Massachusetts General Hospital and Harvard Medical School. \u00a0\u201cIt was just a great professional opportunity,\u201d he says. \u201cIt was a natural step. In Rochester, I was doing no clinical work. Here I have a research lab that focuses on developing new biomarkers, including this new clinical project [for biomarker identification], as well as studying the factors that make muscles weaker and identifying new treatments for myotonic dystrophy. I also have an all-ages clinic every week and a pediatric clinic twice a month where I see patients with both types of myotonic dystrophy and all other forms of muscular dystrophy.\u201d<\/p>\n

Improving and Expanding Clinical Trials<\/h2>\n

\u201cI\u2019m optimistic that [antisense oligonucleotide therapies] will be safe and have some therapeutic effects,\u201d Wheeler says. \u201cI guess the question is to what extent the knockdown of the expanded repeat RNA will reverse the symptoms. In someone with mild symptoms, the drug may have a tremendous effect and slow progression. \u00a0But how will it work for patients who have a greater degree of weakness, more muscle atrophy, or problems walking? \u00a0Will the drug be able to improve their function at all? Or will we need to develop second-line therapies, the way the Duchenne dystrophy field is doing?\u201d<\/p>\n

Downstream effects of the expanded CUG repeats that appear to contribute significantly to disease symptoms include functionally low levels of the MBNL proteins and abnormally high levels of the CELF1 protein. Increasing MBNL activity and reducing total CELF1, preferably with small molecules, might add a lot to antisense therapy, Wheeler notes. \u201cA small molecule that you could take by mouth would be ideal,\u201d he says. \u201cUntil we have something that is proven to be highly effective, I think we should continue developing new therapies that target the disease from different angles.\u201d<\/p>\n

Continuing clinical trials of new DM therapies, including those for children, will require reliable biomarkers of disease activity, preferably markers accessible in blood or urine rather than muscle markers that require biopsies.<\/p>\n

\u201cThe plan is to begin the process of identifying biomarkers,\u201d Wheeler says of his new grant. \u201cThat was one of the goals described by MDF. They want to find a project that is working toward biomarkers that will be on track to get qualified by the Food and Drug Administration (FDA).<\/p>\n

\u201cThe goal that I have is to try and reduce the need for muscle biopsies by looking at biofluids, so that there\u2019s no anesthesia, no incision, no scarring, and no bleeding risk. This would allow monitoring during the treatment trial instead of waiting until the end.<\/p>\n

\u201cWe had our first contact with the FDA back when the grant was submitted, which was in June [2016]. I think that no one expects that we\u2019re going to have a biomarker or a group of biomarkers by the end of the year, but we\u2019re going to be working toward that goal.\u201d<\/p>\n

 <\/p>\n

For more about Dr. Wheeler\u2019s MGH-based research, see\u00a0Wheeler Muscular Dystrophy Research Lab<\/a>. For information about muscular dystrophy clinics for adults, call (617) 726-3642; for children, call (617) 643-4645. Recruitment for the biomarker study is being done through the clinics.<\/em><\/p>\n<\/div>\n

\n
    \n
  • <\/li>\n<\/ul>\n<\/div>\n<\/div>\n<\/article>\n<\/div>\n<\/div>\n
    \n
    <\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

    When Dr. Thurman Wheeler was a resident in neurology, he remembers a senior physician telling him that myotonic dystrophy would probably be one of the most difficult diseases to treat because it involves so many body systems. But thanks to unprecedented advances in laboratory and clinical research since then, \u201cit looks like it might turn […]<\/p>\n","protected":false},"author":7,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[72],"tags":[],"class_list":["post-17778","post","type-post","status-publish","format-standard","hentry","category-research"],"_links":{"self":[{"href":"https:\/\/myotonic.org\/es\/wp-json\/wp\/v2\/posts\/17778","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/myotonic.org\/es\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/myotonic.org\/es\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/myotonic.org\/es\/wp-json\/wp\/v2\/users\/7"}],"replies":[{"embeddable":true,"href":"https:\/\/myotonic.org\/es\/wp-json\/wp\/v2\/comments?post=17778"}],"version-history":[{"count":0,"href":"https:\/\/myotonic.org\/es\/wp-json\/wp\/v2\/posts\/17778\/revisions"}],"wp:attachment":[{"href":"https:\/\/myotonic.org\/es\/wp-json\/wp\/v2\/media?parent=17778"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/myotonic.org\/es\/wp-json\/wp\/v2\/categories?post=17778"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/myotonic.org\/es\/wp-json\/wp\/v2\/tags?post=17778"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}