On an unseasonably warm day in late February, scientists at Kunming Medical University’s Experimental Animal Center in the far southwestern province of Yunnan injected a female crab-eating macaque with an experimental new drug, code-named Rett001.

The drug’s core component is a specific gene, MECP2, encased in an adeno-associated virus (AAV). If the experiment works, the AAV will take its genetic payload through the monkey’s spinal fluid directly to cells in the brain, where it will replicate and replace the defective copies being produced by the monkey’s body.

Thousands of miles away, neuroscientist Qiu Zilong monitored the experiment from his office at Shanghai Jiao Tong University’s Songjiang Research Institute. Qiu hopes to start clinical trials on human subjects as soon as this fall, provided the drug is proven safe in primates, as he plays catch-up in the race to find new treatments for children affected by Rett syndrome, a severe and very rare genetic neurological disorder that occurs almost exclusively in girls. Once classed as an autism spectrum disorder, Rett affects approximately 1 in 10,000 girls, causing profound impairments that affect nearly every aspect of a child’s life: their ability to speak, walk, eat, and even breathe.

There is currently no known cure, though two new gene therapy treatments have started clinical trials outside China. But Qiu worries about the slow approval process and high prices of foreign drugs in China. If he can steer Rett001 to market, it would not only offer Chinese families a cheaper alternative but also bring closure to Qiu’s nearly 20-year fight against the condition.

1.

Qiu was drawn to autism research as a doctoral student in neurobiology at the Shanghai Institute of Biochemistry and Cell Biology, in part because of the relative clarity of its causes. “Compared to other brain disorders, autism is a relatively clear scientific problem,” Qiu says. “Conditions like Alzheimer’s or depression often have multiple causes, whereas the cause of autism is relatively straightforward, often involving genetic mutations. In fact, we can identify the specific genetic cause of over 50% of autism patients in China.”

Qiu expected to continue that research when he took a postdoctoral research position at the University of California, San Diego in 2003. But his mentor, neuroscientist Anirvan Ghosh, who joined the UCSD faculty the same year as Qiu, pushed him to also consider looking for funding to study syndromes associated with autism. That’s how, in 2006, he met Monica Coenraads, the co-founder and scientific director of the Rett Syndrome Research Foundation.

Coenraads became involved with Rett syndrome research after her 2-year-old daughter was diagnosed with the disorder. In 1999, spurred by physician Huda Zoghbi’s groundbreaking finding that Rett was caused by mutations on the X chromosome within the MECP2 gene, she co-founded the RSRF to ignite scientific interest and stimulate research on the syndrome.

Qiu’s meeting with Coenraads was the first time he’d heard of Rett syndrome — which he calls a “severe subtype of Autism spectrum disorder” — but he took to researching it almost immediately. The condition, with its clear-cut genetic causes but no obvious solution, resonated with his scientific sensibilities, he says, and he applied and received an RSRF research grant the following year.

In 2009, as China ramped up its push to lure overseas academics back to the country, Qiu took a position with the Center for Excellence in Brain Science and Intelligence Technology in Shanghai, where he continued his research into autism and Rett syndrome. In that role, he worked with two of the city’s largest hospitals — Xinhua and the Shanghai Mental Health Center — to build China’s largest autism gene sequencing database.

Qiu’s team has since performed genetic sequencing on over 1,000 families and identified 22 genes related to autism, including nine that were not previously known. Qiu also found that the genetic mutations linked to autism in China differ significantly from those in Europe and the United States, which he tentatively suggested could be due to the country’s relative genetic homogeneity. And in 2016, his team published a paper in Nature that demonstrated the aforementioned effects of an edited MECP2 gene on crab-eating macaques, an advance that allowed scientists to study Rett syndrome in non-human primates.

But Qiu was growing restless with a life of basic research and increasingly interested in the clinical applications of his research. “Sometimes, parents of autistic children would visit my office,” Qiu recalls. “These parents were deeply motivated to help their children. It hurt to explain to them that I was a basic researcher, not a physician.”

2.

Qiu credits his mentor, Ghosh, as his model for how a scientist can successfully transition into pharmaceutical development. In 2011, shortly after Qiu returned to China, Ghosh surprised his colleagues at UCSD by quitting his job and taking a top research position at pharmaceutical firm Roche.

“Anirvan’s decision sent an encouraging message: Be bold in pursuing what interests you,” Qiu says. “He made that decision when he was 45, around the same age I was when I contemplated making a change (in 2017).”

But the real draw was the chance to work with cutting-edge technologies that had drastically shortened the path from basic research to potential treatment.

“Initially, I thought that diseases related to genetics, like autism, had too many question marks,” Qiu says. “There was a lot of debate, and it might take another 20 years to fully understand them. But the emergence of CRISPR gene editing technology began producing miraculous clinical results within a few years,” he adds, referring to new methods that allow genetic modification of living organisms. “So, researchers like me could suddenly start looking at ways to translate our findings into practical solutions for patients.”

Qiu’s interest dovetailed nicely with a push by the Chinese government to prioritize new sources of economic growth, including the pharmaceutical industry. In 2022, the government of Shanghai’s suburban Songjiang District teamed with the Shanghai Jiao Tong University School of Medicine to build a new neurological research institute focused on applied research.

The institute’s director, Duan Shumin, a former colleague of Qiu’s at the Center for Excellence, quickly reached out, and in early 2023, Qiu left the place where he had spent the previous 15 years for a new job and a new purpose: finding a cure for Rett syndrome.

3.

Recent scientific advances have opened up new possibilities for the treatment of a host of neurological conditions, from deep brain stimulation for Parkinson’s disease to brain implants targeting depression.

None of these methods are effective in autism patients, however.

“Autism is a brain-wide condition, not limited to any specific region,” Qiu says. “Currently, gene therapy is the only approach that can effectively treat the entire brain and yield relatively good results.”

In essence, gene therapy involves introducing genes into target cells, often by using adeno-associated viruses as carriers. While this has been proven safe in liver, muscle, and ocular tissue, directly using it to treat brain disorders remains rare. The challenge lies in delivering replacement genes through the protective blood-brain barrier. Substances administered orally or intravenously cannot cross this barrier easily, forcing clinicians to inject gene-carrying adenoviruses directly into the spinal column.

Qiu’s team started by testing genetic therapies targeting the MECP2 and MEF2C genes on mice, with positive results on social interaction and repetitive behavior deficits. Now they’re testing the effectiveness of MECP2 interventions on monkeys, with an eye on proving the treatment’s safety for use in humans.

In the meantime, Qiu is starting to look for potential research participants. “In theory, the younger the patient, the better the effects of gene therapy,” he says. “Ideally, we would treat newborns or children aged 1 or 2, as their brain development is most active. However, for safety reasons, we’re planning to select slightly older children for this trial.”

He’s keen to start — and acutely aware that China still lags in autism and Rett syndrome research. Two drugs have already started human trials outside China: TSHA-102, which was administered to an adult in Canada for the first time last June, and NGN-401, which started pediatric trials in the United States last December. Still, he remains optimistic that his research can have a positive impact.

“Even if foreign countries successfully develop these drugs, they will undoubtedly be prohibitively expensive and beyond the reach of ordinary Chinese families,” Qiu says. From this perspective, having domestically developed drugs in China is crucial. “Besides, who knows, maybe ours will be even better.”

(Header image: Archv/VCG)