Seattle researchers fast-track cell and gene therapies for young patients

James Olson, a paediatric oncologist at Seattle Children’s, routinely relies on ‘hand-me-down’ adult cancer therapies that were not specifically developed for children. For other diseases, the reliance on adult drugs is often even more pronounced, and the results can be problematic.

“In some cases, it's because the diseases are different in kids,” says Olson. “In others, the pathophysiology of the disease may be the same, but the toxicity over decades of treatment is different.” And for many rare genetic diseases, effective treatments simply don’t exist.

Seattle Children’s Research Institute is taking a multipronged approach as it works to deliver lifelong and potentially curative therapies to young patients. It is investing in developing cutting-edge cell and gene therapies, and laying groundwork to fast-track these and other innovations for commercial development and clinical deployment.

Rewiring the immune system

Some of the most pernicious childhood diseases involve the immune system. These may stem from genetic abnormalities that either weaken the immune system or give rise to damaging auto-immune responses against healthy tissues.

The good news is that scientists have made steady progress in untangling the roots of these disorders. “Over the past couple of decades, we've gone from having a genetic understanding of maybe 20 or so of these diseases to more than 400,” says paediatric immunologist David Rawlings. As director of the Seattle Children’s Program for Cell and Gene Therapy, Rawlings oversees efforts to leverage these genetic insights into targeted therapies that fundamentally alter the trajectory of childhood diseases.

The most advanced projects are focused on gene therapies for reprogramming haematopoietic stem cells (HSCs), the progenitors for every blood and immune cell in the body. Many patients with severe immune disorders receive bone marrow transplants, which provide a fresh supply of healthy HSCs. But since these treatments are derived from other individuals, they require careful screening and medical management to prevent host rejection.

As an alternative, Seattle Children’s researchers are looking to repair patients’ own HSCs using lentivirus, a non-pathogenic virus that can insert its genetic content into the genomes of cells it infects. This makes it possible to directly deliver functional replacements for mutated, disease-causing genes into HSCs. The team has made considerable headway in this area, with a clinical trial underway for X-linked severe combined immunodeficiency and two other trials based on lentivirally modified HSCs also in the works.

Early work on mature cells

Two other Seattle Children’s research programmes focus on modifying subsets of mature immune cells. The first hinges on regulatory T cells, which act as immunosuppressive watchdogs that prevent inflammation and other immunological responses from spiraling out of control. These cells could be a powerful tool for minimizing the damage from autoimmune diseases, but they are scarce, and difficult to isolate and cultivate.

Seattle Children’s researchers have found a way to take other, more abundant subtypes of T cells and reprogram them to become regulatory T cells. These cells can then be further modified to express engineered immune receptors that could, for example, help preserve the function of pancreatic islet cells in type 1 diabetes. Rawlings says the early stages of this disease offer a window to intercept the autoimmune response before it can cause irreversible damage. “We really think this could be a curative therapy,” he says.

A parallel effort is pursuing the other arm of the adaptive immune system: B cells. Rawlings notes that plasma cells – B cells that churn out antibodies in response to a threat – can essentially survive as long as their human hosts. Through genetic rewiring, it should be feasible to generate durable plasma cells that continuously secrete useful proteins rather than antibodies – for example, essential enzymes that are deficient in rare metabolic disorders.

This work is at an earlier stage, but steadily advancing. “B cells are one of the hardest cells to manipulate,” says Mridu Acharya, a principal investigator at Seattle Children’s Research Institute who studies fundamental mechanisms of B-cell biology and is working on B-cell therapeutics. “Work from Richard James’s lab at Seattle Children’s has led to great progress in being able to edit genes in B cells,” she says. “In addition, we are able to make the B cells survive, differentiate in culture and then engraft in vivo much better than we could before.”

A springboard from lab to clinic

Academic and clinical researchers regularly generate biomedical insights that could yield promising new medicines. But these discoveries require funding, support and oversight to transition into large-scale clinical trials, and countless potential breakthroughs litter the so-called ‘valley of death’ that exists between discovery and clinical use.

Seattle Children’s fosters an entrepreneurial, biotech-oriented approach to team science. Seattle Children’s Research Institute works closely with industry partners and has spun off numerous commercial startups itself. For example, Rawlings is a scientific co-founder of GentiBio and Be Biopharma – new companies now pursuing clinical development of Seattle Children’s regulatory T- and B-cell therapy programmes, respectively. Olson says he was drawn to Seattle Children’s by its methodical and determined approach to the clinical development of protein, cell and gene therapies for paediatric diseases. “No other paediatric research institute in the world has strengths in all three,” he says. “And it’s not just strength in terms of getting a few publications a year. We’ve launched human clinical trials in all of these areas.”

Olson is also enthusiastic about the opportunity to train a new generation of translational researchers and biomedical entrepreneurs through the Invent at Seattle Children’s Postdoctoral Scholars Program. Armed with US$45 million in initial funding, and led by Olson, this programme aims to train 50 junior scientists over the next five years. In addition to conducting standard laboratory research, each scholar is paired with biotech and clinical mentors, and has access to training on intellectual property management, regulatory affairs and other essential industry skills. The programme also offers grants of up to US$1 million to support commercialization of technologies developed during the training.

Perhaps most importantly, the Invent programme aims to recruit talent from communities that have historically been underrepresented in biotech, including people of colour and members of the LGBTQ community. “We’re trying to do it through grassroots network-building,” says Olson. This includes in-person recruiting sessions, outreach on social media, and close collaborations with similarly aligned initiatives such as the Howard Hughes Medical Institute’s Gilliam Fellowship programme. Invent recently enrolled its first scholar, and given the enthusiastic response the programme has received from the biotech community, Olson is hopeful that other institutions will follow its lead. “If more people copied this and adjusted it to be their own, the whole world would be a better place.”