The Integration of Gene Therapy for Rare Disease


There’s still much to be understood about gene therapy and its application to rare diseases like sickle cell, but at the progressive pace it’s moving at, gene therapy is likely to be integrated further into standard practice.

Gene therapy was initiated in the 1960s, but it has been within the last decade that the field’s development and research began to rapidly expand into real applications. Once a faraway prospect of medicine, the effects of the treatment approach are currently being investigated on a clinical level across a multitude of disease designations.

The success garnered by preclinical studies has provided hope for the future of genetic disease treatment that coincides with a large proportion of the rare disease population. The potential to correct or replace mutated genes could lead to novel therapy options, and even cures, for rare conditions that previously had limited to no treatment options.

The impact of this approach is not only evident in the scientific and clinical spectrum, but in the biotech and pharmaceutical markets as well. According to the National Institutes of Health (NIH), the US Food and Drug Administration (FDA) and 15 private organizations partnered with the intention of accelerating the development of gene therapies for rare diseases in October 2021, signifying an opportunity to streamline the process from clinical development to pharmaceutical application for promising agents.

The investigative reach extends even further with over 50 companies currently involved in cell and gene therapy research. The global gene therapy market is expected to increase from $5.77 billion in 2021 to $7.37 billion this year, marking a compound annual growth rate of 27.8%, according to the “Gene Therapy Global Market Report 2022.”

Addressing Rare Disease with Gene Therapy

In rare disease, investigators who were involved with genetic-based disease research are particularly confident in the benefit that gene therapies will provide in the future. A recent cross-sectional global survey evaluated the opinions of authors who had published peer-reviewed articles related to rare genetic diseases, showing that investigators primarily believed genetic therapies would serve as the standard of care for rare genetic diseases before 2036, and subsequently result in cures.

Within the next 15 years, CRISPR-Cas9 is believed to be the leading approach for fixing or replacing defective genes.

The approach to gene therapy development for rare diseases appears to be driven by multifarious collaborative efforts. Ashley Winslow, PhD, President and Chief Scientific Officer (CSO) of Odylia, discussed how the biotech company overcomes the obstacles associated with conducting rare disease research in an interview with HCPLive.

“Partnerships with advocacy or patient group foundations are really important, and key, to every one of our programs,” she said. “For each of our pipeline programs, we do have different forms of patient group partnerships.”

Odylia is a nonprofit biotech organization that focuses on advancing gene therapies for rare disease. Unlike mainstream biotech and pharmaceutical companies, the nonprofit Odylia utilizes its profits as an investment for furthering its mission: changing lives one rare disease at a time.

“We are very focused, as a nonprofit, on the treatments we're trying to develop, or how we're helping other groups, so everything comes back to the mission,” Winslow said.

When focusing on a rare disease, the science and technology often support the need for development, but it’s not always recognized in the commercial world. “We have the science and technology to develop these gene therapies, and it feels like a moral obligation to therefore go out and do that,” she explained.

Winslow believes that approaching these problems from a different perspective becomes much less complex.

“At the end of the day it’s a financial argument, it's a commercial argument,” she said. “So, for rare diseases, the problem is fairly simple.”

The organization's resources can come with more constraints, and while the research methods function in the same way, budgeting looks very different, Winslow said. Advocacy and awareness are not only necessary, but serve as a tool for fundraising efforts.

“We have to speak to it in order to really attract people to our mission,” she said. “And that's what we're trying to do through fundraising efforts is speak to what we've accomplished, what we're seeking to accomplish, where we are pushing boundaries.”

Education is crucial for rare disease, and paired with the transparency of working with a nonprofit offers opportunities that the industry doesn’t.

“I really love that aspect of my job,” Winslow shared, “because having worked in industry before, you don't get the opportunity to talk every day about what you do. As a nonprofit, we have to talk about it. I mean, it's not only inspiring, it's easy to get up every day and do what we do.”

Curing Sickle Cell Disease

Specific to one of the most well-known rare diseases, gene therapy as a treatment for sickle cell disease (SCD) has warranted significant attention recently as the potential of a cure comes closer to reality. Currently, individuals with severe cases of sickle cell may be eligible for a bone marrow transplant, though the procedure comes with various limitations and risks.

Expert hematologist and sickle cell doctor Titilope Fasipe, MD, PhD, Texas Children’s Cancer & Hematology Centers, explained gene therapy as a type of transplant. When a patient undergoes a bone marrow transplant, they need new bone marrow because theirs has been affected by their disease. The objective of the transplant is to fix that disease.

"In today's world," she said, "the way we do that is by using somebody else's bone marrow–so you need a donor."

One of the barriers that comes with a transplant is finding a suitable donor who matches the patient. And even with that match, the patient’s safety and the success of the procedure is still not guaranteed, Fasipe said. The majority of people do not have a donor match.

"Gene therapy is trying to find a way to cure you without having to rely on another person that may not match you," she said.

Fasipe explained that 1 in 10 patients have a match in their own family, meaning transplant is an unfeasible option for the majority of patients with sickle cell disease.

She described gene therapy as an "auto-transplant" or a "self-transplant." A transplant physician takes the patient's cells, performs the gene therapy technique that corrects the defective genes before the genes are reintroduced to the body.

By using the patient’s own corrected cells, gene therapy alleviates the need for a matching donor.

"It is still a transplant," Fasipe said, "but instead of getting cells from somebody else, they're using your own cells that they have now fixed through that gene therapy step."

Sickle Cell Disease Treatment has Options

Fasipe explained that one of the ways gene therapy can help patients with sickle cell disease is by using it to introduce a healthy hemoglobin gene to a patient's body in order for them to begin making their own "good hemoglobin."

"The reason why we know this can work is because we know that people who are born with a healthy hemoglobin—they have a mutation that helps them make more fetal hemoglobin [hemoglobin F (HgbF)]—they essentially don't have sickle cell disease, even if they inherit it with sickle cell (so, hemoglobin S plus hemoglobin F)."

Another method incorporates creating a genetic structure similar to sickle cell trait (1 copy of hemoglobin S, HgbS and 1 copy of hemoglobin A, HgbA) in patients with the disease.

Fasipe explained it as an attempt to mimic the effect where a patient ends up having more of a trait phenotype instead of a disease type. "Giving a healthy hemoglobin or gene addition is one type of gene therapy," she said.

Increasing fetal hemoglobin by correcting the gene signal is an additional option provided by gene therapy. Fasipe articulated this as "correction," which has to do with fetal hemoglobin or hemoglobin F. As she mentioned earlier, after birth infants no longer produce hemoglobin F like they did in the womb.

"Another group of scientists is looking at 'How do we turn that instruction back on, how do we press play again and help us make hemoglobin F?'" she continued, "To do this, you take away the thing that's blocking the signal, and you can approach this in multiple different ways."

This is where techniques with CRISPR and RNA silencing come into play.

"That allows you to make hemoglobin F, and again gives you hopefully, not a disease phenotype, but a healthier, almost like a trait phenotype," Fasipe explained.

Then, there’s the option to remove the old hemoglobin and bring in the new. This method implements the addition of healthy hemoglobin, or the correction of hemoglobin F, but also aims to remove the "bad gene,” or hemoglobin S.

"Many of the other steps keep the hemoglobin S there, they just use the healthy hemoglobin to make you healthier, but with this last step, they're trying to also take away the S while giving you a healthy hemoglobin,” she said. “So that one, you can imagine it’s more complicated, but there are scientists working on that as well."

Many data have been published on the subject, some based on clinical use in humans while some are still in the laboratory beginning to approach use in humans.

From her perspective as a pediatric hematologist and a professor, Fasipe is step outside the world of transplant care. Nonetheless, the various techniques being explored within the field of sickle cell care leave her excited to see what the future brings.

"Time will tell which type of gene therapy makes sense for what type of sickle cell patient," Fasipe explained, "There might be some that work better for one person and another that might work better for another."

There’s still much to be understood about gene therapy and its application to rare diseases like sickle cell, but at the progressive pace it’s moving at, gene therapy is likely to be integrated further into standard practice.

"What I say is, a complicated disease like sickle cell does require complicated therapy and definitely requires a complicated cure. So, these are not easy things and the gene therapy trials have been exciting," Fasipe said.

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