SPG47: When rare disease research gets a push from parents

SPG47 citizen science
Robbie’s parents are spurring scientific research into her ultra-rare neurodegenerative disorder.

Spastic Paraplegia 47 doesn’t roll off the tongue. The name is complicated and challenging, much like SPG47 itself. When I tell healthcare providers my 3-year-old daughter’s diagnosis, I take a deep breath and wait for the inevitable question: What, exactly, is that?

More than 70 types of Hereditary Spastic Paraplegia (HSP) have been identified to date; almost all are neurodegenerative. At best, HSP causes distress and disruption; at worst, it has devastating, potentially life-threatening consequences. Its “pure” form impairs the lower extremities, causing extreme spasticity and weakness. Its “complicated” form — like our daughter Robbie’s — also impacts systemic and/or neurologic function. Many HSP sub-types have been diagnosed in only a handful of people worldwide, leaving affected families feeling lost and disconnected.

And that is how we felt when Robbie was first diagnosed. Our journey to that point began when Robbie was 18 months old and had failed to meet essential milestones. She was labeled as globally developmentally delayed (lacking in speech, cognition and fine and gross motor skills). Because of her adorable but disconcertingly microcephalic head, she was scheduled to have an MRI at Boston Children’s Hospital in August 2015. But in July, Robbie had a seizure.

Diagnosis, despair and a new purpose

cortical neurons SPG47

Modeling SPG47 in patients’ own neurons
Led by Darius Ebrahimi-Fakhari, MD, PhD, and Robin Kleiman, PhD, scientists at Boston Children’s Hospital hope to model SPG47 in neurons created in the lab from patients like Robbie.
They already have some leads. In mice, if you knock out the gene that’s mutated in SPG47, AP4B1, something strange happens to their neurons. Receptors for the neurotransmitter AMPA show up in a different place – in axons rather than dendrites, “like a letter that ends up at the wrong address,” says Ebrahimi-Fakhari.
The change could affect communications between neurons, and seems to have something to do with autophagy — a system cells have for disposing of their waste. The protein affected by the mutation, AP-4, is known to be involved in trafficking other proteins within cells. But beyond that, the details are fuzzy.
That’s where stem cell technology comes in. Scientists at the Harvard Stem Cell Institute can transform skin cells from patients with SPG47 into induced pluripotent stem cells. Boston Children’s Translational Neuroscience Center can then differentiate these cells into excitatory cortical neurons bearing the disease mutation (above image).
These neurons have AMPA receptors, and the researchers believe they will provide a fairly faithful model of SPG47 at the cellular level. “We know that neurons of the corticospinal tract are the ones that degenerate first in spastic paraplegia,” says Ebrahimi-Fakhari.
For comparison, the researchers plan to create “control” neurons — made from the same patients, but with the mutation corrected through CRISPR gene-editing technology. They can then compare protein transport, autophagy and other parameters.
Once they establish SPG47’s cellular biology, the next step would be drug testing to see if any existing compounds can reverse the mutation’s effects. To pull this off on a mass scale, they hope to find a change that’s easy to detect with automated technology — for example, tagging an AMPA receptor to see where it goes in the cell.
Autophagy is of particular interest to Ebrahimi-Fakhari, who recently found that defects in autophagy may play a role in tuberous sclerosis and autism. Dysfunctional autophagy has also been implicated in neurodegenerative disorders like Parkinson’s and Alzheimer’s disease. “In the case of SPG47, we think autophagy happens but is getting blocked at a late stage,” he says. “We will be the first to look at autophagy in patient-derived neurons.”
SPG47 research could pay dividends in other hereditary spastic paraplegias (HSPs) and even adult neurodegenerative disorders, he adds. “If it wasn’t for parents advocating and donating cells, not many people would take on this challenge.” — Nancy Fliesler

The preliminary MRI results suggested that Robbie has brain damage resembling periventricular leukomalacia (PVL). Also noted was a thin corpus callosum, with too few nerve fibers connecting her left and right brain. While this was difficult to hear, we took comfort in learning that Robbie would keep the milestones she worked resolutely to attain. And Robbie had started making gains more notably and more often.

Our optimism was short-lived. Closer scrutiny of Robbie’s MRI indicated that her brain damage was likely genetic. In May 2016, at age 2½, Robbie was diagnosed with SPG47, an autosomal recessive, neurodegenerative form of HSP that is caused by a mutation in the AP4B1 gene. The only other SPG47 cases then known were nine non-verbal, paraplegic, severely intellectually impaired children and young adults from four Middle Eastern families.

Our grief and despair shifted to purpose when we learned of — and finally met — the Duffy family, whose daughter Molly had the same diagnosis. Since there were no research or clinical trials for SPG47, we knew we would need to initiate research ourselves.

Gathering experts

We founded Cure SPG47, and my husband Chris and I spent countless hours analyzing articles on PubMed and Medscape, targeting authors and using internet sleuthing skills to obtain their contact information. Chris sought out scientists researching any treatments that could feasibly be applied to SPG47. Through the Duffys and other friends, we solicited advice, information and referrals from top executives and lead researchers at biotech companies. This allowed us to gather input about possible treatment options.

We needed HSP experts. Two names came up in online support groups: Craig Blackstone, MD, a prominent HSP researcher at the National Institutes of Health, and John Fink, MD, at the University of Michigan, a foremost investigator of upper motor neuron disorders with the largest HSP clinic in the U.S.

Based on previous leads, we also sought out gene therapy experts with knowledge of neurologic disorders. Published articles led Chris to Steven Gray, PhD, at the UNC School of Medicine Gene Therapy Center, and Jun Li, PhD, at Vanderbilt University School of Medicine.

Coincidentally, I had worked with Basil Darras, MD, director of Boston Children’s Hospital’s Neuromuscular Clinic, years ago when I was a health care service coordinator for the Muscular Dystrophy Association.

Chris convinced these powerhouses to be our scientific advisors, while Kira Dies, a good friend, brilliant genetic counselor and co-director of clinical research and regulatory affairs at Boston Children’s Translational Neuroscience Center, joined our board of directors. She and her boss, Mustafa Sahin, MD, PhD, quickly and generously offered to host a scientific meeting. Jennifer Hirst, PhD, a cell biologist studying HSP, made contact with Chris and agreed to travel from Cambridge University to speak.

Starting up SPG47 science

In March, an international dream team of medical professionals converged at Boston Children’s to consider the most promising treatment avenues for SPG47. The AP4B1 mutation is known to disrupt the intracellular transport of proteins integral to brain development and function. Two possible approaches came out of the meeting: gene therapy research, proposed by Mimoun Azzouz, PhD, Director of Research and Innovation at the University of Sheffield, England, and research using induced pluripotent stem cells, proposed by Robin Kleiman, PhD, head of preclinical research at the Translational Neuroscience Center, and Darius Ebrahimi-Fakhari, MD, in the Sahin lab (see sidebar).

SPG547 Darius Ebrahimi-Fakhari
Darius Ebrahimi-Fakhari presents his proposed research at the March meeting.

With a minimum of $2 million needed to fund these studies, we’ve now turned our efforts toward getting donations and research grants. Since December, three more children have been diagnosed with SPG47, and several more parents have joined our endeavor. Meanwhile, as her disease progresses, Robbie’s leg muscles have begun stiffening and tightening, restricting her movement, and the language she’s defied the odds in mastering is in danger of being lost. This makes research urgent for us. Robbie’s smile and joy in life are blessedly unwavering, but our confidence in her future is faltering.

We know so little about this disease. It is complicated. It is challenging. It is devastating. But is it insurmountable? Every day I take a deep breath, pause when necessary, and bet against that.

Meet Robbie and Molly in this video:

Learn more about the Translational Neuroscience Center at Boston Children’s.