Taming Stem Cell Treatment for Fanconi Anemia

Fanconi anemia is the most common inherited bone marrow failure. The condition depletes all types of blood cells: the red cells that carry oxygen, white blood cells that provide immunity, and platelets, which are cell fragments that break open and initiate the blood clotting cascade. As a result, patients experience symptoms of profound fatigue, poor growth, frequent infections, and bruising and bleeding. By age 12, most patients develop progressive bone marrow failure, which is deadly.

The disease is rare, affecting 1 in 160,000 people worldwide. This site lists support groups for patients with Fanconi anemia from many countries.

Diverse mutations in several genes cause the disease, from single-DNA-base changes, to extra or missing stretches of genetic material, to errors in how a gene’s parts are cut and pasted. The condition can be inherited as an autosomal recessive, autosomal dominant, or X-linked. The mode of inheritance can typically be deduced from the pattern of affected relatives. But whatever the nature of the mutation, it sets into motion a cascade of destruction at the cellular level.

Impaired DNA Repair
In the disease, cells lose the ability to repair errors in DNA replication – which typically happens as DNA copies itself. Chromosomes gradually weaken, until they shatter. At the same time, cells become more sensitive to toxins and radiation. Blood counts plunge, as risk of several cancer types rises, both solid tumors and blood cancers. Ultimately, effects of the profound bone marrow failure reverberate throughout the body’s organ systems.

A test for the telltale fragile chromosomes confirms a suspected diagnosis of Fanconi anemia. Treatment is mostly supportive. However, a bone marrow stem cell transplant from a donor can vanquish the disease, but the protocol is intense and risky. The procedure transfers the hematopoietic stem cells that are the forerunners of all blood cell types.

First, the patient’s own bone marrow must be destroyed to make space for new marrow to take over. That step requires a highly toxic “preconditioning” protocol that uses harsh radiation and chemo, usually the drug busulfan.

Taming the preconditioning would make the option of a life-saving transplant available to more patients. Researchers from Stanford Medicine have done just that – developed a way to prep Fanconi anemia patients for stem cell transplants without the toxic radiation and busulfan. The results of their phase I clinical trial are published in Nature Medicine. The approach may also work for patients with other genetic diseases that require stem cell transplants.

“We were able to treat these really fragile patients with a new, innovative regimen that allowed us to reduce the toxicity of the stem cell transplant protocol. We could eliminate the use of radiation,” said study co-author Agnieszka Czechowicz. The clinical trial is early stage, with only three children treated two years ago. So far, they are doing well enough for the group to have published the findings.

“If they don’t get a transplant in time, Fanconi anemia patients’ bodies eventually will not make blood, so they die of bleeding or infections. It is a novel approach to help these patients, who are very vulnerable,” added co-author Rajni Agarwal.

A Long Time Coming
The three young patients in the clinical trial, instead of toxic chemo and radiation, received injections of antibodies against CD117. This is a protein that traverses the cell membranes of blood-forming (hematopoietic) stem cells, where it serves as a receptor. Binding of specific molecules to the receptor then triggers a signaling cascade inside the cell that can lead to various responses. Divide? Specialize? Survive?

The antibody (briquilimab) destroys the patient’s bone marrow stem cells, without the toxic side effects of radiation and chemo. And that ups the odds of survival.

The strategy has been in the works since 2004, when Czechowicz was an undergraduate in the lab of Irving Weissman, MD, a stem cell guru and former director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. Together they developed an antibody against CD117 that destroyed the stem cells in mice without having to deploy the standard radiation and chemo. That work led to the antibody being tested in the clinical trial.

Solving the Donor Problem
A stem cell transplant is an option for a patient with Fanconi anemia only if a compatible donor is found – and about a third of patients can’t find a close enough match. The new approach may expand the pool of patients by modifying donor bone marrow beforehand.

Bone marrow is a complex mixture of several types of cells. The new strategy removes immune cells called alpha/beta T cells. Their absence enables the CD34+ cells needed to fight Fanconi anemia to proliferate.

Tinkering with the bone marrow also lowers the risk of graft-versus-host disease, in which the immune cells in donated bone marrow attack the recipient. And that makes it possible for a Fanconi patient to safely receive bone marrow from a donor who shares only half of their immune markers, such as a parent or child.

The ultimate goal is for all patients with the disease to be able to have and survive a transplant, Agarwal said.

A Trio of Brave Kids
The three trial participants, all under 10, were of different racial/ethnic backgrounds and had different mutations. Each child received a single intravenous infusion of the antibody 12 days before the infusion of donor stem cells. Although they got some meds to dampen their immune response to up the odds of the transplant taking, they didn’t get radiation or busulfan.

Still, even without radiation and chemo, the experience is grueling. It requires more than a month in the hospital with short-term side effects like severe exhaustion, nausea, and hair loss.

The parents donated the bone marrow. The researchers modified the marrow to decrease the population of alpha/beta T cells and enrich for blood-forming stem cells.

Within two weeks, the donated stem cells quickly settled into their new homes, the patients’ bone marrow. And within a month, the cells had almost completely replaced the young patients’ bone marrow. That was an amazing result – the researchers had set as their goal reaching a mere 1% replacement. Two years on, all three patients had nearly all their bone marrow stem cells from their donors.

One young patient is Ryder Baker, of Seguin, Texas. He was the first treated, in early 2022 – he’s now 11. His mother, Andrea Reiley, reports that before the transplant, “He was so tired, he didn’t have stamina. It’s completely different now.” Today, Fanconi anemia “doesn’t slow him down like it used to.” The boy can even play soccer and pickleball, she adds. Ryder has grown taller, put on weight, and doesn’t get sick as often.

A phase 2 trial is adding children to the study, and the procedure will also be tested in kids with Diamond-Blackfan anemia, another genetic disease that destroys bone marrow.

Not only the young may be able to benefit from the milder stem cell treatment. Another team at Stanford Medicine is testing the antibody in older cancer patients who are too weak to tolerate the radiation or chemo needed to prep for a standard bone marrow transplant, said Agarwal.

The best news? The team’s approach is broadening the applicability of the technology. Said Czechowicz, “Bone marrow or stem cell transplants are most commonly used in blood cancers, in which the bone marrow is full of malignant cells and patients have no other options. But as we’re making these transplants better and safer, we can expand them to more patients, including those with many different diseases.”