Things do happen for a reason. The editors of PLOS asked me weeks ago to post today, Rare Disease Day, about Huntington’s disease (HD). I wondered why, because although HD is a rare disease, it’s a fairly well recognized one, thanks mostly to folksinger Woody Guthrie. But yesterday I received a stream-of-consciousness update from Jacey Mukka, and I knew why I’d been asked.
Jacey, 23, has juvenile Huntington’s disease (JHD). DNA Science has followed her family’s story and efforts to raise awareness that HD is not a solely adult-onset condition. Jacey lost her little sister Karli to HD and her father, and she and another sister face the same fate. Here’s her update (sic):
“They say my swallow is off and when i get too weak i can’t tolerate food or liquid it does choke or throw up back out, progressively it will get worse until i probably die of starvation.. jello apple sauce milkshake ravioli it hurts watching me die.. all of these tests that i used to wait in the waiting room for karli to be done with, except it’s me this time.
i look for movies i can relate to lorenzos oil glass house good mother winters tale my sisters keeper youd be surprised how hard it is to find one i can relate to that doesnt have adult hd in it and miraculous recoveries.”
This post updates one from May, “Can We Cure Huntington’s Disease?, and is dedicated to the amazing Jacey.
A rare disease is one that affects fewer than 200,000 people in the US at any given time; HD affects about 30,000 people, ten percent of whom have the juvenile form. HD in any form remains one of the most difficult diseases to treat, for several reasons.
The disease often begins with subtle shifts in behavior – flashes of anger, irritability, movements that at first seem innocuous. Lisa Genova, MD, in her excellent fictional account of a family coming to grips with HD, “Inside the O’Briens,” captures a possible beginning in her protagonist Joe:
“His frequent toe-tapping, shoulder-shifting, and eyebrow lifting; and his inability to sequence the events that are part of the daily routine.”
Joe’s outbursts intensify as the initial fidgeting expands frighteningly, uncontrollable except during sleep. A trained clinician or family member who has grown up with affected relatives might see an early sign of impending HD in a mere facial expression, so distinctive is the phenotype.
The mutation behind HD is an “expanding repeat,” known in only a dozen or so diseases, most of them neurological. The gene (HTT) that encodes huntingtin (Htt) protein protein starts with a repeat that encodes the RNA triplet CAG, which specifies the amino acid glutamine.
Normal is 35 or fewer CAG repeats; more than 40 spells HD, with 36-39 a gray zone. Aberrant huntingtin protein from the CAG expansion (the polyglutamine) clogs brain parts that control movement and aspects of personality, behavior, and cognition. But the pathology is much more complicated than the expansion.
The gene is a weird one. It’s about 10 times the size of the average gene. It is 800 million years old, deduced from its presence in such ancient creatures as sea urchins and cellular slime molds, yet just last year Rockefeller University’s Ali Brianlou, PhD and his colleagues discovered a hominid-specific exon. The gene’s home at the tip of the short arm of chromosome 4 is why it took a full decade to go from linked genetic marker to the actual gene, circa 1983-1993, using the indirect techniques of the time.
Yet we still don’t know precisely what the normal protein does, other than involvement in such basic processes as transcription regulation, mitochondrial function, and vesicular transport in axons. But the normal gene is vital. Snip wild type HTT out of a mouse and it doesn’t develop beyond an early embryo.
It’s easier to describe HD by what it isn’t.
• HD isn’t due to a deficient enzyme that can be replaced or its substrate reduced
• HD isn’t due to a misfolded protein that can be re-folded like the CFTR protein in cystic fibrosis.
• HD isn’t due to a protein factor that can be supplied, like a clotting factor for hemophilia.
• HD affects hard-to-target brain parts, making gene or stem cell therapies difficult to deliver.
• HD differs from other triplet repeat disorders, such as fragile X syndrome, in which mangled proteins don’t function. Instead, mutant Htt introduces a new, “toxic gain of function.”
HD has nearly complete penetrance: inherit the mutation, and if something else doesn’t get you first, you develop the symptoms. A person who has inherited the mutation but has not yet recognized symptoms is “at-risk” or “premanifest.” (The commonly-used term “carrier” is very confusing because that usually denotes a recessive condition.) As long as that toxic allele is there, adding a working copy of the gene won’t help. It’s there anyway.
Below is an update of strategies to tackle this most daunting of inherited diseases.
GENE SILENCING Ionis (formerly ISIS) Pharmaceuticals and Roche launched a phase 1/2 clinical trial of an antisense oligonucleotide-based drug, ISIS-HTTR, introduced into the spinal cord in early-stage patients, the first treated in London in October, 2015. FDA granted the antisense treatment Orphan Drug Designation on January 5, 2016. For details see the excellent Cure HD blog, by the pseudonymous Gene Veritas.
If I had to name a good disease to tackle with DNA editing, it would be the over-extended gene behind Huntington’s. Jan Nolta, PhD, from UC Davis and colleagues have deployed the genome editing tool TALENS against the mutant allele in fibroblasts from patients. Nicole Déglon, PhD and Nicolas Merienne, PhD, of the University of Lausanne in Switzerland, reported use of CRISPR-Cas9 at the Society for Neuroscience Conference in October to edit out the mutation in mice, who improved in the short term. The researchers are now tweaking the protocol so that it snips out only the mutant allele.
TREATING SYMPTOMS How do drugs commonly used to dampen the symptoms of HD affect the course of the disease? Sarah Tabrizi, PhD, director of the University College London HD Centre and colleagues assessed symptoms among 123 HD patients who take such drugs. They discovered that patients who take neuroleptics have better motor function and affect (display of emotions) but poorer cognition compared to patients who do not take these drugs. SSRI anti-depressants were associated with less apathy and diminished affect, but better overall behavioral scores. Therefore, taking the common drugs shouldn’t hamper evaluation of new treatments, the researchers conclude. Results are published in PLOS CURRENTS HUNTINGTON DISEASE.
ALTERED SLEEP A team from the University of Cambridge found that 38 premanifest individuals experienced “fragmented sleep profiles” and shortened REM periods compared to 36 controls. The results, publishing in the Annals of Neurology, suggest that disrupted sleep patterns may be an early sign of disease onset.
THE DISEASE TRAJECTORY HD ranges widely in age of onset and rate of worsening, and knowing when symptoms may start might be helpful. Kristina Becanovi, PhD, from the Karolinska Institute and colleagues identified a single nucleotide polymorphism (SNP) in the promoter of the HTT gene that tracks with delayed onset if it is part of the mutant gene, but with an earlier onset if it is in the wild type allele on the other chromosome 4, published in Nature Neuroscience. And Jong-Min Lee, PhD, of Massachusetts General Hospital and co-workers discovered a gene on chromosome 15 that alters age of onset by up to six years, depending upon which variant a person has inherited. The number of CAG repeats also predicts age at death, although not disease duration, according to a recent study published in the American Journal of Human Genetics from Marcy MacDonald, PhD and James Gusella, PhD from Massachusetts General Hospital and colleagues.
A CLOSER LOOK AT HUNTINGTIN Patrick C.A. van der Wel, Ph.D., assistant professor of structural biology at the Pittsburgh School of Medicine and colleagues used NMR spectroscopy to glimpse the centers of the polyglutamine clumps, published in PNAS. They found that exon 1-encoded fibrils form “intramolecular B-hairpins tied together via interdigitating extended side chains.” And Ed Wild, PhD, at University College London and colleagues found that the closer premanifest patients got to symptom onset, the higher the level of Htt in their cerebrospinal fluid.
DRUG UPDATE Raptor Pharmaceuticals’ CYST-HD trial is testing cysteamine to delay symptoms. The drug appeared to slightly slow worsening of motor symptoms in 78 patients, especially if begun early. However, despite soaring headlines, results were “not statistically significant,” but are “regarded by clinical leaders in the field as clinically meaningful,” according to a press release from the company. This post at HD Buzz puts the findings into perspective — not good enough, yet, for marketing approval.
A potential treatment approach that has made it into the media, but not yet clinical trials, concerns raising sheep that have a genetic condition that makes them overproduce GM1 ganglioside. This molecule has had some success in mouse models of HD.
COMPANION OBSERVATIONS Investigators from the Neurobiological Predictors of Huntington’s Disease (PREDICT-HD) project have found that early psychiatric manifestations in HD are more common than had been thought, increase as the disease progresses, and that companions are more aware of these symptoms than the people who have them, suggesting that patients may not notice these symptoms.
DATA SHARING The website HD in High Definition (HDinHD) is a clearinghouse of sorts for all manner of mouse data pertaining to HD.
A STOMACH CONNECTION HD affects the nervous system in the digestive tract. Andrew C. McCourt, from Lund University and colleagues there and in the UK examined the gastric mucosa from 12 patients and noted decreased expression of gastrin, also seen in HD mice. Results are published in PLOS CURRENTS HUNTINGTON DISEASE.
AND FINALLY … NUTS AND BOLTS Researchers from the John van Geest Centre for Brain Repair, Cambridge, UK and Edith Cowan University, Perth, Western Australia, asked 24 premanifest individuals, 27 HD patients, and 32 controls to screw a nut onto a bolt in one direction. The protocol tested use of both hands on three different sized bolts. Impairments appeared with use of the non-dominant hand among the premanifest individuals and the patients, but not among the controls, according to results published in PLOS CURRENTS HUNTINGTON DISEASE. Screwing nuts into bolts could be used to assess motor function in clinical trials.