Tiny orthotics to fit Michael Pirovolakis’s chubby, 18-month-old legs arrived at his family’s home in early July.
It was a hard day for Michael’s father, Terry, because they were a reminder that his smiley, inquisitive baby’s rare degenerative disorder will see him lose function in his legs, arms and eventually his brain as he grows up. The disorder, SPG50, is a rare form of hereditary spastic paraplegia, marked by the absence of a protein in the AP4M1 gene, and Michael is the only Canadian known to have it.
When a child has a disease this rare, there is little incentive for drug companies or government funding agencies to finance initial research into a treatment. So Michael’s parents have remortgaged their home, liquidated their retirement savings and partnered with researchers from the United States to run a clinical trial for a gene therapy that could help him. “If there’s a cure, how could I just sit back and watch my child wither before my eyes?” said his mother, Georgia Kumaritakis.
Michael – who has two older siblings, sister Zoe, 8, and brother Zach, 5 – was diagnosed in early April, after full genome sequencing revealed the reason behind his low muscle tone and small head for his age. He’s one of fewer than 60 people worldwide with SPG50. Most patients are young, since full genome sequencing for a diagnosis came into use only recently.
“Childhood neurology consists of several thousand single gene defect disorders,” said Berge Minassian, chief of the division of child neurology at the University of Texas Southwestern Medical Center. “We used to lump them together based on symptoms. Like seizures, we’d put it under epilepsy. Or social inadequacy was put under autism. And so on. But now we are able to diagnose these patients.”
Dr. Minassian used to work at Toronto’s Hospital for Sick Children but moved to the U.S., where he uses gene therapy to replace defective copies of genes with functional ones. He and his colleague Steven Gray have a template for a gene therapy they think could work for Michael. It has already been used to help children with other genetic disorders.
It would harness the adeno-associated virus (AAV) to insert working copies of the AP4M1 gene into Michael’s brain cells. Like all viruses, AAV infects cells and releases its DNA. Normally, it would replicate in the cell to make more of itself. But in this case, its DNA is replaced with DNA containing the patient’s missing gene, so the virus acts as a delivery mechanism.
The delivered gene is a circular plasmid, Dr. Minassian explained, which doesn’t integrate into the human genome and therefore doesn’t cause problems. The plasmid stays in a brain cell’s nucleus, and the cell can use it to produce the encoded protein. The host cell would normally down a viral plasmid, but since AAV is so benign, host cells tend to leave it alone. As such, the code for the missing gene remains available for the life of the patient.
Dr. Gray, who has developed treatments using the same virus for diseases such as Tay-Sachs and Batten, said it would be “fairly straightforward” to use the same approach with Michael. He has already been working on a gene therapy for another type of spastic paraplegia, SPG47, but even though the symptoms are similar, the two cases would need differently formulated viruses. Each problem gene needs a unique treatment – and its own clinical trial.
That’s why the Pirovolakis family has launched an online fundraiser to raise $3-million and bring the gene therapy that could help Michael to the U.S. Food and Drug Administration for approval.
The Canadian Institutes of Health Research and the U.S. National Institutes of Health are government agencies that provide research grants to look into treatments for various illnesses. But the grant approval process takes time and money isn’t guaranteed.
“It’s not easy to get money for rare diseases. You submit a grant [application], and it comes back saying: This is a study of low impact,” said Guy Rouleau, director of the Montreal Neurological Institute and Hospital and an expert in hereditary spastic paraplegia.
In his 34-year career working with the disorder, Dr. Rouleau has received government funding just once.
And the rarity of such diseases certainly does not simplify the process for developing a treatment.
First, the virus would need to be formulated with Michael’s gene, then tested on mice in a lab. If that proves effective, the trial would move forward to evaluate whether the treatment is harmful. If it is deemed safe, human trials could start, potentially with Michael as one of the first test subjects.
“If the mouse improves, we’re quite confident,” Dr. Minassian said. “Of course, it depends … there have been occasions where it doesn’t work in the mouse.”
Although Michael’s parents often refer to gene therapy as a cure, they’re aware there’s no guarantee it will work. The virus could replace many of his brain cells with working copies of the gene, but there’s no way it can penetrate every neuron. “It’s a sliding scale,” Mr. Pirovolakis said.
Michael’s parents hope the gene therapy can be ready before his third birthday, when doctors say his decline could become more pronounced.
“If I have to be an Uber driver at night and work during the day, I’ll do it,” Mr. Pirovolakis said.
“As a parent, you have to try,” Ms. Kumaritakis added.
The couple suspects there are many more children with SPG50 that haven’t been diagnosed, simply because they haven’t undergone full genome sequencing like Michael has.
“It’s not just for him,” Ms. Kumaritakis said. “Because when we started thinking, what about all the other kids that will be born in the future?”
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