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Genetic Therapies for Brain Diseases Feature NATURE KIM RAFF FOR Evie Lewis with her parents, Elliot and Janell. Evie receives a dose of a genetic therapy every few months to treat spinal muscular atrophy. GENETIC THERAPIES FOR BRAIN DISEASES Hopes are high for a class of drug that could treat neurodegenerative conditions — but a recent clinical trial has brought the field up short. By Diana Kwon 180 | Nature | Vol 592 | 8 April 2021 ©2021 Spri nger Nature Li mited. All ri ghts reserved. ©2021 Spri nger Nature Li mited. All ri ghts reserved. focused. As it progresses, people develop approved the first ASO for a neurological dementia and an inability to speak or move. disease in 2016, and there has since been an Susan, who requested that her last name explosion of activity in this area. The field has be withheld to protect her privacy, vividly gone from just a handful of clinical trials run remembers the day she learnt that her mother over the past two decades to around a dozen had the disease. It was the spring of 1982, and currently under way for various neurodegen- her mother had been admitted to a hospital erative diseases — and a few have reached their because of her extreme exhaustion, frequent final stages. falls and irregular movements. There was no Other ASO researchers are moving beyond genetic test for the condition at the time, so diseases defined by a single mutation to look at she underwent a series of assessments. Her conditions with more-complex genetic under- neurologist gathered the entire family into a pinnings. This recent progress has made many room to break the news. “He told us that our in the area optimistic about the future of the mother had Huntington’s disease,” recalls technology. Don Cleveland, a neuroscientist at Susan. “And that there’s no treatment and it the University of California, San Diego (UCSD), can be wiped out in a generation if you just and one of the first scientists to investigate the don’t breed.” use of ASOs for neurological diseases, sees this Those blunt words had a profound impact on the lives of Susan and her siblings: her brother decided never to get married, and her sister chose to be sterilized. For Susan, how- ever, those options were out of reach: she was pregnant when she received the news. Susan says that she and her husband THERE’S A WHOLE “couldn’t decide what was the right thing to LIST OF THINGS THAT do”. One thought, in particular, was that “if we have the child, then that child will have this HAVE TO BE DONE same decision when they grow up”, she says. “And it seemed so cruel.” Ultimately, the couple BEFORE WE GET TOO made the heart-wrenching choice to terminate the pregnancy. TRIUMPHALIST.” The gene involved in Huntington’s, called HTT, codes for a protein called huntingtin. The as just the beginning. “There’s much, much faulty version of the gene repeats a short piece more coming,” he says. of its sequence — the nucleotide combination But progress in the field has not been com- CAG — too many times. Unlike some genetic pletely smooth. At the end of last month, a conditions, in which a person will develop a large phase III trial was abruptly halted because disease only if they have two faulty copies of the benefit of the drug to patients did not out- a gene, just one copy of the HTT mutation is weigh the risks. And some researchers have enough to lead to Huntington’s, and carriers long urged caution around ASOs, owing to the of the mutation have a 50% chance of passing it fact that their efficacy in many conditions is on to their children. Years after Susan’s mother unknown and that the way they are delivered passed away, the three siblings discovered that — often by spinal injection — is invasive. they had all inherited the disease. Although the outcome of this trial was There are no treatments available to stop disappointing, “I don’t think this is a reason or slow the progression of Huntington’s, even for despair,” says Chris Boshoff, a scien- Evie Lewis with her parents, Elliot and Janell. Evie receives a dose of a genetic therapy every few months to treat spinal muscular atrophy. though its genetic cause has been clear since tific-project manager overseeing genetic 1993. Most other neurodegenerative diseases therapies at the US National Institute of Neu- usan was still a child when she also lack effective therapies and, although rological Disorders and Stroke in Bethesda, first suspected something might their genetic roots are less clear-cut than for Maryland. “There’s still reason to be positive be wrong with her mother. A cup Huntington’s, many of the genes associated and enthusiastic about what this modality can or plate would often crash to the with conditions such as motor neuron dis- accomplish.” floor by accident when her mother ease (amyotrophic lateral sclerosis, or ALS), was serving dinner or washing up Alzheimer’s and Parkinson’s have been known Breakthrough for a rare disease dishes. “She was, she would have for decades. Now, the tide might be turning Elliot and Janell Lewis’s first child, Blakely, was said, ‘clumsy’, but she wasn’t really for treating these kinds of diseases. Many born in 2011 with a rare, inherited neurodegen- Sclumsy,” says Susan. “Her hands had beautiful, researchers are hopeful about drugs known erative disease known as spinal muscle atrophy glamorous movements, which I now recognize as antisense oligonucleotides (ASOs). These (SMA). People with SMA have a mutated form as early HD.” are short strings of DNA or RNA letters that of SMN1, a gene responsible for producing a Huntington’s disease (HD) is an inherited are designed to cling to particular sequences protein called survival motor neuron (SMN). condition that causes widespread deteriora- of RNA made by faulty genes, and to rebalance The resulting lack of SMN prevents the brain tion in the brain and disrupts thinking, behav- the levels of proteins they produce — boosting from being able to communicate effectively iour, emotion and movement. The disease missing proteins or quashing faulty ones (see with the body, leading to muscle weakness and usually begins in midlife, with subtle changes ‘Toggling problem proteins’). wasting that worsens over time. There are four such as mood swings and difficulty in staying The US Food and Drug Administration (FDA) types of SMA; the most common form, SMA1, Nature | Vol 592 | 8 April 2021 | 181 ©2021 Spri nger Nature Li mited. All ri ghts reserved. ©2021 Spri nger Nature Li mited. All ri ghts reserved. Feature TOGGLING PROBLEM PROTEINS were those who received a placebo3. An emerging class of drug called antisense oligonucleotides (ASOs) uses tiny pieces of DNA So far, more than 10,000 people worldwide or messenger RNA matched to disease-causing proteins to suppress or correct them. have received nusinersen (Spinraza), which Ionis licensed to drug maker Biogen, based in Silencing Boosting Diseases such as Huntington’s and ASOs can replace missing proteins. The ASO nusinersen treats spinal Cambridge, Massachusetts, in 2016. The drug motor neuron disease (amyotrophic muscular atrophy (SMA), in which the body lacks a protein called has drastically altered the course of the dis- lateral sclerosis) are caused by a SMN. There are two SMN genes: in healthy people, SMN1 makes a ease: infants with SMA who receive it shortly build-up of mutant proteins. stable protein and SMN2 an unstable version. In people with SMA, ASOs in development aim to SMN1 is disrupted. Nusinersen makes up for this by acting on SMN2 after birth are no longer dying within the first quell their production. to stabilize its normally inactive protein. years of life. Nowadays, “conversations [with Healthy individual families] don’t just end with, ‘We’re going to DNA Mutation Mutation do everything we can, but your baby’s going Disease-causing gene SMN1 SMN2 to die’,” says Russell Butterfield, a paediatric Silencer Transcription protein neurologist at the University of Utah in Salt Pre-mRNA Transcription Lake City (Butterfield has received consulting payments from Biogen). “Instead, that con- Splicing versation switches to, ‘We have this new drug, mRNA it’s absolutely amazing. We need to get it in as soon as possible’.” Translation Translation mRNA shortened Evie Lewis, now four years old, receives a dose of Spinraza by a lumbar puncture every few months, and she recently had her 15th Disease-causing protein Active protein Unstable protein injection. Although she still faces some issues, Drug treatment fixes such as having to eat through a feeding tube, Drug treatment SMA disrupts SMN1 gene mutation in SMN2 she is able to walk, run and climb — things that ASO SMN1 SMN2 Blakely was never able to do, Elliot says. A packed pipeline mRNA tagged for breakdown Following the success of nusinersen, research- ASO prevents ers began to tackle other diseases associated Enzyme silencer protein from binding with clearly defined genetic mutations, such as Huntington’s. That led to the drug tominersen, NATURE No disease-causing No active protein Active protein produced which was developed by Ionis and licensed for protein produced produced from SMN2 mRNA clinical testing to the pharma company Roche in Basel, Switzerland. It is thought to work NIK SPENCER/ is also the most severe. People with SMA1 investigating the mechanisms that led SMN2, by targeting CAG repeats on the RNA strand typically show symptoms shortly after birth, another gene that encodes SMN, to typically produced by both the normal and faulty HTT and many do not survive past the age of two. produce less viable protein than its counter- genes, and tagging them for destruction by Blakely was diagnosed at three months old.
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