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Progress in Treating Genetic Disease: Dwarfism, Inborn Errors, Immune Deficiencies, and a Clotting Disorder

It’s been nearly a decade since my book The Forever Fix: Gene Therapy and the Boy Who Saved It, was published. The field hasn’t come as far as I’d hoped, with FDA approvals for only two conditions – the retinal blindness at the heart of my book and spinal muscular atrophy.

The dance of two-steps-forward one-step-back continues. Several treatments near FDA approval while another, for myotubular myopathy, has claimed the lives of four young children in a clinical trial and the brain degeneration of adrenoleukodystrophy (ALD, of Lorenzo’s Oil fame), continues in three of four boys given gene therapy in 2009. Earlier intervention and/or a different delivery system may be necessary; timing and dose are critical.

Still, gene therapy efforts are alive and well. On October 21, 2021, the FDA, NIH, 10 pharmaceutical companies and 5 non-profits announced joining forces “to accelerate development of gene therapies for the 30 million Americans who suffer from a rare disease.”

NIH’s new Bespoke Gene Therapy Consortium tailors treatments to a patient’s personal mutation. The media are promoting it as a new idea, but it isn’t; a child featured in my gene therapy book had her unique mutation written into the clinical trial protocol years ago. “Bespoke” means “made for a particular user,” and, like “woke,” is in my opinion an unnecessary bit of buzzword blather. “Individualized” works fine.

And so here’s a look at recent progress in treating a few rare genetic diseases (not all technically gene therapy; some intervene to provide what a functioning gene should do).


On November 19, FDA approved Voxzogo (vosoritide), the first treatment for people with achondroplasia. The Endocrine Society calls the condition “a genetic bone growth disorder” and the drug manufacturer BioMarin Pharmaceuticals “disproportionate short stature.” It’s a form of dwarfism that shortens the limbs, with eventual height under four feet, ten inches.

Achondroplasia affects 1 in 25,000 newborns, and in about 80 percent, the condition arises from a new mutation – the parents are of normal height.

In healthy bone growth, cartilage “models” are gradually replaced with bone, a process that completes between ages 16 and 18. In achondroplasia, that doesn’t happen due to a mutation in a gene, FGFR3 (fibroblast growth factor receptor 3), which blocks a signal. The drug is a small protein that mimics the one that the gene should encode, turning the signal back on at a different point. More bone fills in, and kids grow a little more.

In the clinical trial, 121 children aged 5 to almost 15 received the drug or placebo. At the one-year mark, the placebo kids started on the drug, which is a daily injection. The findings appear in Science Progress.

The participants grew about six-tenths of an inch beyond what was expected without treatment. That doesn’t sound like much, but it’s a change in the right direction.

Over more time, the drug might prevent or lessen other symptoms, like sleep apnea, spinal stenosis, and compression in the area where the brain meets the spinal cord, which can cause pain, incontinence, and halt breathing. Even small changes in body proportions might help with daily activities, such as self-care and reaching.

Two Immune Deficiencies: ADA-SCID and CGD

“The very first gene therapy for an inherited disease happened on September 14, 1990,” I wrote in The Forever Fix, describing a 4-year-old receiving her own T cells bolstered with the gene that in every cell of her body bore a mutation that devastated her immune system. She was being treated for adenosine deaminase (ADA) deficiency. An article in the May 21, 2021 issue of The New England Journal of Medicine updates progress in the gene therapy.

Why the 31-year delay?

Changes in the viral vector used to deliver the genes, as well as drugs given to clear out the bone marrow to make room for altered T cells, took years to develop, for a more lasting effect. In the recent paper, Donald Kohn of UCLA and Claire Booth of Great Ormond Street Hospital and their teams update outcomes for kids who received the needed gene between 2012 and 2017 at those institutions and the NIH.

“Fifty patients were treated, and the overall results were very encouraging. All the patients are alive and well, and in more than 95% of them, the therapy appears to have corrected their underlying immune system problems,” said Kohn. The gene therapy is a one-and-done, compared to lifelong enzyme treatment.

Kohn’s group is also part of an international team developing a stem cell gene therapy to treat nine people for X-linked chronic granulomatous disease (X-CGD). The condition impairs the ability to fight off bacterial and fungal infections of skin, bones, and major organs. Although two of the patients died within three months due to pre-existing infections, six are in remission, and able to stop other treatments such as antibiotics to stay ahead of the infections. The patients no longer need donor marrow, because their own, with corrected genes, works fine, without risk of rejection.

Hurler Syndrome

Gene therapy is working for Hurler syndrome, in which an enzyme deficiency causes coarse facial features, heart disease, skeletal abnormalities, respiratory problems, and enlarged liver and spleen. Children rarely live to see their teens.

Technically called mucopolysaccharidosis type I (MPS I), Hurler’s is a severe, rare type of lysosomal storage disease, one of about 50. Lysosomes are tiny sacs inside cells that contain enzymes that dismantle specific substances. Alpha-L-iduronidase (IDUA) is missing in Hurler’s, causing a complex sugar to build up, which causes the symptoms.

Enzyme replacement therapy, introduced in 2003, alleviates some symptoms, but the enzyme can’t cross the blood-brain barrier and so doesn’t affect cognition. Since 1981, bone marrow transplant (aka hematopoietic stem cell transplant) has been used to stop progression of the disease, but it’s risky. Because of the inheritance pattern, a patient’s parents are carriers and so aren’t ideal bone marrow donors because they only make half the normal amount of the enzyme. Siblings might be carriers too. But a transplant from a donor requires finding one, and even if that happens, the drugs used to clear out the patient’s bone marrow beforehand are toxic.

Now the MPS1 Study Group reports The New England Journal of Medicine what seems, so far, to be successful gene therapy.

The researchers delivered corrected IDUA genes aboard lentiviruses (disabled HIV) to eight two-year-olds. The procedure is as safe as a conventional bone marrow transplant and the children began making the enzyme within a month. Motor development, cognition, and joint stiffness improved and growth normalized. Plus, the enzyme that the children couldn’t make before treatment appeared in their cerebrospinal fluid. The study will continue for another 3 years.

Harnessing DNA Repair to Treat Methylmalonic Acidemia

Two children are showing signs that one-time “in vivo genome editing” corrects the metabolic glitch behind their methylmalonic acidemia (MMA). Researchers at LogicBio are using the body’s own DNA repair system to introduce working copies of a mutant gene into the bloodstream.

MMA affects about 1 in 50,000 newborns. A mutation disrupts the MMUT gene (for methylmalonyl-CoA mutase), which in severe cases abolishes the ability to dismantle certain fats and proteins. Toxins accumulate in the liver, muscles, and brain, with death usually in infancy. In the US newborn screening catches these cases, but even a dietary treatment delivered in a feeding tube is often not able to prevent hospitalizations, brain damage, and early death.

Genome editing delivers the normal version of the gene aboard intravenous adeno-associated virus (AAV) vectors to liver cells – hepatocytes – where a natural DNA repair process, homologous recombination, inserts the cargo into the albumin gene. Albumin is a highly abundant protein normally made in the liver, otherwise known as egg white. Two of 8 children treated showed that the gene arrived and inserted, a little like tracking an Amazon package.

MMA has an interesting historical aside. In 1991, a woman named Patricia Stallings was sentenced to life in prison for killing her baby boy with antifreeze. While in prison she gave birth to another boy, who died in the same manner. Newborn screening picked up the toxic metabolite that indicates MMA in the second child – it has a structure very similar to that of ethylene glycol, aka antifreeze.

Steroids Extend Effects of Hemophilia A Gene Therapy

Gene therapies that make sense before clinical trials sometimes don’t work, or effects aren’t sustained long enough to help after. That’s the case for the clotting condition hemophilia. Even though gene therapy worked, in some patients the immune response released T cells that attacked the viruses used to deliver the clotting factor genes.

Researchers have been developing gene therapy to treat hemophilia A at Children’s Hospital of Philadelphia for decades. This most common inherited bleeding disorder affects 1 in 5,000 males worldwide. A deficiency of clotting factor VIII leads to uncontrolled bleeding episodes, extreme pain from joint bleeds, and risk of death. Infusion of the clotting factor and a monoclonal-antibody based drug can prevent episodes, but doesn’t abolish the joint pain or risk of death.

The effects of earlier attempts to deliver the clotting factor aboard AAV, intended to be a one-and-done, began to diminish after a year. But findings of an international clinical trial recently published in The New England Journal of Medicine are more promising. Eighteen men adult men who received the AAV vector (from Spark Therapeutics) were followed for up to four years, most also receiving steroids to dampen the immune response. Sixteen men maintained expression of the needed gene, with most having a greater than 90% reduction in bleeding episodes, and 12 past the two-year mark. Investigators are now looking at other ways of blocking an immune response to the gene therapy.

CODA: Recipe for a Gene Therapy

The idea for gene therapy arose in the early 1960s, when Francis Crick and others figured out how DNA instructions tell cells how to make specific proteins. Can we augment or even replace faulty or missing genetic instructions?

Looking back over gene therapy attempts over the past 30 years, here’s the strategy that has emerged:

1. Identify how specific mutations in specific genes impair health (the genotype behind the phenotype)

2. Find a way to deliver a specific gene to where and when it is needed. This usually requires a virus to do the delivery.

3. Conduct clinical trials to see if what should work actually does work.

4. Figure out what went wrong and why, then invent a workaround.

Most medical breakthroughs reflect the slow evolution of observations and ideas into treatments. The pace of gene therapy has at times been maddeningly slow, but with the first two approvals, and several more edging closer to the finish line, the time for the technology may finally be near.

  1. Great blog post!! Interesting updates — I am sharing with my IMSA genetics STEM league students!! Thanks, Dr. Lewis!!

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