In 1902’s Just So Stories, Rudyard Kipling famously explained how the leopard got his spots in what would today be deemed an…
When results of a clinical trial of a treatment for a rare disease are disappointing, feelings of despair among hopeful affected families resurface – especially if the only options are repurposed drugs. That’s the case for Huntington’s disease, an inherited neurological condition that affects about 30,000 people in the US, 16 percent of them children.
The HD community is reeling from two such setbacks. But a new approach to halting the runaway expansion of the HD gene (called HTT) that lies behind the illness may reignite hope. The strategy focuses not on the HTT gene itself, but on another with which it interacts – a gene that takes part in repairing damaged DNA. Results appear in Cell Reports.
An “Expanding Repeat” Disease
“Horse-and-buggy doctor” George Sumner Huntington first described HD in 1872. He’d accompanied his father and grandfather on house calls in East Hampton, Long Island, where a few local families had a mysterious movement disorder. Huntington described two very thin women gripped by constant contortions, several men who staggered about as if intoxicated, and symptoms intensifying “until the hapless sufferer is but a quivering wreck of his former self.”
Dr. Huntington deduced the autosomal dominant inheritance pattern of HD. It affects both sexes, and each child of an affected individual faces a 50:50 risk of inheriting the condition. An affected person has a normal and a mutant copy of the gene.
In HD, loss of motor control typically begins in the late thirties, but behavioral and cognitive signs are often present years earlier: anger, irritability, confusion, loss of impulse control, and aggression. Folksinger Woody Guthrie lost a long battle with HD in 1967.
HD was one of the first identified “expanding repeat” disorders, caused by a mutation that copies a short DNA sequence at the start of the gene.
The HTT gene encodes a protein called huntingtin. A normal HTT gene begins with 36 or fewer copies of the DNA triplet GTC, which are transcribed into the same number of copies of the corresponding RNA codon CAG. In HD, the repeats are unstable and increase in number, like a typo typo typo. The more copies, the sooner symptoms begin, the more severe the movements, and the faster the physical and mental deterioration. The normal function of huntingtin protein isn’t understood
The tagalong CAGs are translated into copies of the amino acid glutamine, and the excess disrupts the folding of huntingtin, making it stick to itself and to other proteins. In the brain’s movement center, the striatum, the gummy proteins block axons of “medium spiny” neurons, preventing distribution of essential growth factors. The white matter of the brain shrinks.
Bad News in March
On March 22, Roche ceased treating new patients in its phase 3 clinical trial of tominersen, following recommendation from an independent data monitoring committee at FDA. The drug is an antisense molecule, designed to bind the extra repeats of the huntingtin gene.
Overall, tominersen didn’t harm anyone, but it also didn’t help. But ongoing analysis of clinical trial findings may reveal whether certain patients did improve or decline more slowly, their responses lost in the compiled data. And it’s possible that the drug indeed lowers levels of abnormal huntingtin protein, but not enough to affect symptoms – meaning the research may be on the right track.
Then on March 29, Wave Life Sciences nixed further development of two drug candidates. The small, synthetic RNA-like molecules bind and silence the mRNA transcribed from the mutant gene. In one trial of 88 participants, the drug didn’t change levels of abnormal huntingtin, and in another trial of 28 people, levels diminished, but “effects were inconsistent.” Analysis of the level of huntingtin in the fluid surrounding the brain and spinal cord indicated that doses high enough to work might not be safe enough to administer.
Fortunately, preclinical research has been ongoing – in new directions.
Commandeering DNA Repair to Brake the Gene Expansion
A team at the UK Dementia Research Institute looked to genes that interact with HTT, focusing on certain DNA repair genes known to modify the time of symptom onset and rate of progression of HD. One gene in particular emerged as a target to circuitously get to the HTT gene: FAN1. With a trio of other genes, it controls “mismatch” DNA repair.
In mismatch repair, enzymes detect small loops emanating from the DNA double helix where the base pair is incorrect – that is, anything other than C with G or A with T. The enzymes snip off the error loops, restoring the sleekness of the helix and gene function. Mispairing happens where the DNA is riddled with repeats – like in the HTT gene.
In Huntington’s disease, mismatch repair works too well, and the gene grows. But the protein that the FAN1 gene encodes interacts with the other mismatch repair genes in a way that stops the expansion.
The researchers showed that FAN1 acts like a brake on the gene expansion in a variety of cell types: in induced pluripotent stem cells from a child with juvenile HD whose genes have 125 repeats, in human white blood cells and bone cells with expanded HTT genes used to study HD, and in mouse models of HD that have 120 or 175 repeats.
Said senior author Sarah Tabrizi, “Our next step is to determine how important this interaction is in more physiological models and examine if it is therapeutically tractable.” The team is now working with biotechnology company Adrestia Therapeutics to develop drugs that could mimic or boost FAN1 inhibition of mismatch repair to treat HD. And the strategy of countering a natural process gone awry may ultimately provide treatments for some of the other 50+ CAG repeat expansion disorders.
Added co-lead authors Rob Goold and Joseph Hamilton, “Evidence for DNA repair genes modifying Huntington’s disease has been mounting for years. We show that new mechanisms are still waiting to be discovered, which is good news for patients.”