Why haven’t we fixed this yet?


Fragile X syndrome is the most common inherited form of intellectual disability. Approximately 1/4,000 males
and 1/8,000 of females are impacted by this disorder which causes distinctive physical characteristics including a triangular-shaped face, large
ears, a prominent chin, and broad forehead. Individuals with Fragile X also experience significant developmental delays, varying degrees of intellectual
disability and autistic-like behaviors.

The genetic cause for Fragile X syndrome was identified in 1991, during the early years of the Human Genome Project. The Fragile X syndrome gene,
FMR1, is located on the X chromosome. Females have two copies of the X chromosome, while males have only one. This is why males are
more frequently and severely affected by Fragile X syndrome. When the FMR1 gene is mutated, it is unable to produce a protein that
is vital for healthy brain development.

In the 26 years since the genetic cause was found, rapid progress has been made, including understanding of the pathophysiology of the condition,
the development of animal models, and the identification of drugs that correct the features of Fragile X in mouse models.

This relatively rapid progress caused great excitement among the Fragile X community, and numerous clinical trials have been implemented in the
past decade – nearly all have failed, showing no improvement.

But if we’ve learned so much about Fragile X, why haven’t we made more progress in treating it?

A new study recently published in the Journal of Neurodevelopmental Disorders offers a theory.

Walter Kaufmann, MD,
the senior author of the study, says much of it has to do with how we are measuring the impact of the drugs.

In a review of 22 clinical trials that have been conducted on individuals with Fragile X syndrome, Kaufmann and his coauthors found that the trials
failed in part because of the deficiencies of the outcome measures.

Outcome measures are the ways that researchers evaluate whether or not the study drug is having an effect. They can include self-report measures
such as behavioral questionnaires, performance-based measures such as IQ tests, or even physiological measures such as biomarkers in the blood
that may change with treatment. Outcome measures are compared before, during and after the clinical trial to assess the efficacy or impact
of the drug.

“Part of the problem with these trials is that the tools that are being used to measure the drugs’ effectiveness are of limited or moderate quality,”
said Kaufmann. “Many of the current outcome measures being used to assess cognitive improvement and behavioral changes in response to the drugs
have not been proven to have reliability, validity or sensitivity to treatment.”

“These drugs may have had a benefit to the patient, but if we’re not able to measure that within the context and timeframe of the study, it is
considered a failure,” he said. “And without concrete evidence to show efficacy, the trials are halted or never progress to the next level.”

Another shortcoming of the measures is that many are intended for long-term assessment, rather that the relatively short duration of most clinical

If scientists can’t objectively and consistently show that a drug is having a meaningful impact on function and quality of life, the NIH and FDA
will not move these trials forward toward an effective treatment, Kaufmann said.

“Measures for Fragile X syndrome were evaluated for this study because of the numerous clinical trials already done for this disorder,” said Kaufmann,
“but the same issues exist for other neurodevelopmental disorders, including autism. We must be able to quantitatively demonstrate therapeutic
efficacy for these complex disorders. That is the key to success.”

What are we doing about it?


Since joining GGC in 2015, Kaufmann and his team have been committed to advancing clinical trials for neurodevelopmental disorders, including Fragile
X syndrome, Rett syndrome, and autism. A key goal of GGC’s Center for Translational Research, which is headed by Kaufmann, has been to develop
effective outcome measures for these disorders including scales, questionnaires, and biomarkers.

Dr. Walter Kaufmann is the Ravenel Boykin Curry Chair in Genetic Therapeutics and Director of the Center for Translational Research (CTR) in the Greenwood
Genetic Center. Coauthors on this study include researchers from Johns Hopkins University School of Medicine, Rush University, Cincinnati Children’s
Hospital, Stanford University, University of California Davis, and Novartis Pharmaceuticals


Meet Reggie Roper

Meet Reggie Roper

Reggie has been part of the GGC family for over 18 years. He has short stature, webbing of his hands, pulmonary stenosis, seizures and hydrocephalus along with developmental delay. He carried an initial diagnosis of cardiofaciocutaneous (CFC) syndrome; however, as genetic testing advanced, GGC made the diagnosis of Noon...

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