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NEWS FROM THE AAN ANNUAL MEETING: HDAC Inhibition Appears Safe in Early Trial on Friedreich's Ataxia

Robinson, Richard

doi: 10.1097/01.NT.0000451003.10471.a7
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In a phase 1 trial, a histone deacetylase inhibitor appears to be safe and to increase expression of the frataxin gene in adult patients with Friedreich's ataxia.

HILADELPHIA—A histone deacetylase inhibitor appears to be safe and to increase expression of the frataxin gene in adult patients with Friedreich's ataxia (FA), according to results of a phase 1 trial presented here at the AAN Annual Meeting.

FA is caused by a trinucleotide repeat expansion in the first intron of the frataxin gene, a mitochondrial protein involved in iron metabolism. The expansion causes gene regulatory machinery in the nucleus to deacetylate the histones around which the gene is wrapped, leading ultimately to formation of heterochromatin and silencing of the gene.

Since the gene itself is unchanged, “gene activation is an attractive therapeutic approach,” explained the study author Massimo Pandolfo, MD, who is chief of the neurology service at the Hospital Erasme of the Université Libre of Bruxelles in Belgium.



Preclinical work has shown that a promising strategy for activation is inhibiting the histone deacetylase (HDAC) enzyme, called HDAC3, acting on the frataxin gene. In both animal and cell models, HDAC inhibitors have been able to increase frataxin gene expression and elevate the level of frataxin protein. Drug discovery work has shown that 2-aminobenzamides, inhibitors of so-called class I HDACs (including HDAC3), are primarily active at the frataxin gene. In neurons derived from patient fibroblasts — via induced pluripotent stem cells (iPS) cells — one such compound, RG2833, being developed by Repligen Corporation, almost doubled protein production over 48 hours.

Those results, combined with the drug's oral availability and good safety profile, led to the first Phase 1 trial, conducted in Turin, Italy, under the direction of Luca Durelli, MD.

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Adults with FA were enrolled in one of four cohorts, five subjects per cohort. The first two cohorts received a single dose of the drug, up to 120 mg, unblinded. Cohorts three and four received treatment or placebo, and then crossed over to the other arm, at either 180 mg (cohort three) as a single dose, or 240 mg (cohort four) in divided doses separated by four hours.

The drug was well tolerated, Dr. Pandolfo reported, with no withdrawals and no serious adverse events. There were three reports of tachycardia possibly related to the study drug.



There was a dose-dependent inhibition of HDAC activity in peripheral blood monocytes, with about a 40 percent reduction of normal activity at the two highest doses. Frataxin messenger RNA levels in cohorts three and four increased in the eight hours after dosing, and then fell to baseline by 48 hours. The degree of mRNA increase varied by patient, but achieved at least 80 percent of normal in several patients at the highest dose.

There was a small increase in frataxin protein as well, “but this was less clear than the change in messenger RNA,” Dr. Pandolfo said. “But this was most likely due to the short duration of exposure to the drug.”

A key safety concern was whether HDAC inhibition would induce widespread changes in expression of non-target genes, including oncogenic or pro-apoptotic ones. “That doesn't seem to be the case,” he said. “At least at these doses, most gene expression changes are toward normalization of changes caused by frataxin deficiency.”

Another concern was whether the increased transcription of the gene would lead to accumulation of the expanded intronic RNA, leading to the RNA foci thought to be responsible for sequestering RNA binding proteins in myotonic dystrophy and other disorders. “We don't see any of those foci,” Dr. Pandolfo said. “We think these data are reassuring.”

“This study provides proof of principle that an orally dosed class I HDAC inhibitor can increase both frataxin mRNA and acetylation of a key residue in the blood of FA patients,” Dr. Pandolfo said. “This is the first, but I think a significant, step for the treatment of this disease.”



The “unexpected news” from the trial was that two drug metabolites persist in the serum for hours after the compound itself is broken down — one of which is a suspected cardiotoxin, and the other, a suspected carcinogen. This has led the research group to begin developing related compounds without this effect, and at the same time improve brain penetration and increase potency.

Dr. Pandolfo also pointed out that the correlation seen between the drug exposure response in the iPS-derived cells and peripheral blood monocytes of treated patients confirms the relevance of these patient-derived cells as a model of FA, and may suggest a general path for drug development in neurologic disorders.

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Tetsuo Ashizawa, MD, chair of neurology at the University of Florida in Gainesville, commented that these results were “exciting,” but there remain important questions and concerns.

Among the most salient, he said, was whether the drug is as safe in children as it is in adults, since FA typically begins in childhood, and beginning treatment in childhood would presumably be the most beneficial form of treatment. He pointed out that knocking out the HDAC3 gene in mice is lethal before birth, due to cardiomyopathy, and restricting the knockout to Purkinje cells causes their degeneration.

“Fortunately,” he said, “heterozygous knock-out mice show no phenotype. Since the drug reduces HDAC3 activity by only 40 percent, this is probably going to be OK.”

He noted that developing technologies, including the use of a “guide RNA” to better target the drug, might help reduce off-target effects.

Concern also remains about RNA foci, despite the results presented, since these foci are more difficult to see in rapidly dividing cells, such as blood cells, than they are in neurons. “While they have not been seen in animal models of Friedreich ataxia” Dr. Ashizawa said, “that may be due to the relatively small size of the repeat used in these models.”

There is also the question of whether the transcribed repeated RNA will be translated into the newly discovered repeat-associated non-ATG (RAN) translation products, unusual peptides that can form when ribosomes attach to the very long RNA repeat, translating it into protein, which then aggregates. RAN translation products have been found in several repeat expansion disorders, including myotonic dystrophy, spinocerebellar ataxia type 8, fragile X tremor ataxia syndrome, and amyotrophic lateral sclerosis due to the C9orf72 (chromosome 9 open reading frame 72) gene. So far, no pathogenic role has been associated with these products, but much research remains to be done to fully understand their significance. They have not been found in FA, presumably because the gene is transcribed at such a low level that very little repeat-containing RNA is formed. But successful treatment will greatly increase the formation of that RNA, Dr. Ashizawa noted, which may lead to production of RAN translation products in treated patients.

Finally, he said, if treatment with an HDAC inhibitor is successful, it will be lifelong, and this single-dose study cannot offer guidance on what to expect from years of HDAC inhibition. Further “de-risking” studies may be needed before moving ahead with larger and longer trials.

Nonetheless, he said, “I am very encouraged with this phase 1 trial. It is a major step toward efficacy trials of this strategy in patients with Friedreich's ataxia.”

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•. Neurology archive on Friedreich's ataxia:
    •. Massimo Pandolfo's papers on Friedreich's ataxia:
      © 2014 American Academy of Neurology