The integration of gene therapy for rare diseases


Gene therapy was pioneered in the 1960s, but it was in the last decade that development and research in the field began to rapidly expand into real-world applications. Once a distant prospect of medicine, the effects of the therapeutic approach are now being studied clinically across a multitude of disease designations.

The success of preclinical studies has given hope for the future of treatment for genetic diseases that coincide with a large portion of the rare disease population. The ability to correct or replace mutated genes could lead to new therapeutic options, and even cures, for rare conditions that previously had few or no treatment options.

The impact of this approach is not only evident in the scientific and clinical spectrum, but also in the biotechnology and pharmaceutical markets. According to the National Institutes of Health (NIH), the United States Food and Drug Administration (FDA) and 15 private organizations have teamed up to accelerate the development of gene therapies for rare diseases in October 2021, which represents an opportunity to streamline the process from clinical development to pharmaceutical application for promising agents.

The scope of investigations extends even further with more than 50 companies currently involved in cell and gene therapy research. The global gene therapy market is expected to grow 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 “.

Treating rare diseases with gene therapy

In the field of rare diseases, researchers who have been involved in genetic disease research are particularly confident in the benefits that gene therapies will bring in the future. A recent global cross-sectional survey assessed the opinions of authors who had published peer-reviewed articles related to rare genetic diseases, showing that researchers primarily believed that genetic therapies would serve as the standard of care for rare genetic diseases before 2036, and would subsequently result in heals.

Over the next 15 years, CRISPR-Cas9 is seen as the main approach to repairing or replacing faulty genes.

The approach to developing gene therapy for rare diseases appears to be driven by multiple collaborative efforts. Ashley Winslow, PhD, President and Chief Scientific Officer (CSO) of Odylia, discussed how the biotech company is overcoming obstacles associated with rare disease research in an interview with HCP Live.

“Partnerships with advocacy foundations or patient groups are really important and essential for each of our programs,” she said. “For each of our pipeline programs, we have different forms of partnerships with patient groups.”

Odylia is a nonprofit biotechnology organization focused on advancing gene therapies for rare diseases. Unlike large biotech and pharmaceutical companies, the nonprofit Odylia uses its profits as an investment to further its mission: changing lives one rare disease at a time.

“We’re very focused, as a nonprofit, on what treatments we’re trying to develop, or how we’re helping other groups, so it all comes down to mission,” Winslow said.

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

Winslow thinks approaching these issues from a different angle becomes much less complex.

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

Organizational resources can come with more constraints, and while research methods work the same way, budgeting is very different, Winslow said. Advocacy and sensitization are not only necessary, but serve as a tool for fundraising efforts.

“We need to talk about 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 to talk about what we’ve achieved, what we’re looking to achieve, where we’re pushing the boundaries.”

Education is crucial for rare diseases and, coupled with the transparency of working with a non-profit organization, provides opportunities that the industry does not.

“I really like that aspect of my job,” Winslow explained, “because having worked in the industry before, you don’t get to talk about what you do every day. As a non-profit organization, we need to talk about it. I mean, it’s not just inspiring, it’s easy to get up every day and do what we do.

Cure sickle cell disease

Specific to one of the best-known rare diseases, gene therapy as a treatment for sickle cell disease (SCD) has recently garnered significant attention as the potential for a cure approaches reality. Currently, people with severe cases of sickle cell disease may be eligible for a bone marrow transplant, although the procedure has various limitations and risks.

Expert hematologist and sickle cell physician 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 cure this disease.

“In today’s world,” she said, “the way we do it is to use someone else’s bone marrow – so you need a donor.”

One of the hurdles that comes with a transplant is finding a matched donor that matches the patient. And even with that match, patient safety and the success of the procedure are still not guaranteed, Fasipe said. Most people don’t have a matched donor.

“Gene therapy tries to find a way to cure you without having to depend on another person who may not be your match,” 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 “auto-grafting” or “auto-grafting.” A transplant doctor takes the cells from the patient, performs the gene therapy technique which corrects the faulty genes before the genes are put back into the body.

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

“It’s still a transplant,” Fasipe said, “but instead of getting cells from someone else, they’re using your own cells that they’ve now fixed through this therapy step. genetic.”

Sickle Cell Treatment Has Options

Fasipe explained that one of the ways gene therapy can help patients with sickle cell disease is to use it to introduce a healthy hemoglobin gene into a patient’s body so they can start making their own. “good hemoglobin”.

“The reason we know it can work is because we know that people born with healthy hemoglobin have a mutation that helps them produce more fetal hemoglobin. [hemoglobin F (HgbF)]- they basically don’t have sickle cell disease, even though they inherit it with sickle cell disease (so, hemoglobin S plus hemoglobin F).”

Another method is to create a genetic structure similar to the 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 than one trait phenotype instead of one disease type. “Giving healthy hemoglobin or gene addition is a type of gene therapy,” she said.

Increasing fetal hemoglobin by correcting the gene signal is an additional option offered by gene therapy. Fasipe referred to this as a “correction”, which has to do with fetal hemoglobin or hemoglobin F. As she mentioned earlier, after birth infants no longer produce hemoglobin F as they used to. in the womb.

“Another group of scientists are studying ‘How do we reactivate this instruction, how do we press play again and help us make hemoglobin F?’ , and you can approach this in a number of different ways.”

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

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

Then there is the possibility of removing the old hemoglobin and bringing 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.

“A lot of other steps keep the hemoglobin S there, they just use the healthy hemoglobin to make you healthier, but with this last step they’re also trying to take the S away and still give you healthy hemoglobin. “, she said. “So this one, you can imagine it’s more complicated, but there are also scientists working on that.”

A lot of data has been published on the subject, some based on clinical use in humans while others are still in the lab and beginning to approach human use.

From her point of view as a pediatric hematologist and professor, Fasipe goes beyond the world of transplant care. Nevertheless, the various techniques explored in the field of sickle cell care leave her eager to see what the future holds.

“Time will tell which type of gene therapy makes sense for which 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.”

Much remains to be understood about gene therapy and its application to rare diseases like sickle cell disease, but at the progressive rate at which it is evolving, gene therapy is likely to be further integrated into mainstream practice.

“What I’m saying is that a complicated disease like sickle cell disease requires complicated therapy and certainly requires complicated treatment. So these are not easy things and the gene therapy trials have been exciting,” said Fasip.

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