In recent years, major progress has been made in the development of gene therapies for rare diseases. However, research for some rare conditions, such as those due to inborn errors of metabolism, is stagnating due to logistical issues.
The inborn errors of metabolism is a group of rare genetic disorders in which the body is unable to correctly metabolise food, typically due to some enzyme defects. Despite the genetic nature of the diseases, the choice of vectors for gene therapies and the risk-benefit analysis compared to simpler conventional interventions influence the ideal research strategy for these conditions.
Treatment regimens for the inborn errors of metabolism disorders often rely primarily on dietary restrictions. For example, a common treatment option for patients with phenylketonuria, which causes an increase in phenylalanine levels, is an avoidance of high-protein foods. Phenylketonuria affects one in 25,000 newborns, as per data from Medline. Gene therapies are still not ready for a near possibility for several diseases within the group of conditions, says Dr. Hans Andersson, the director of the Hayward Genetics Center in Louisiana. For example, AvroBio, now Tectonic Therapeutic, ceased its Fabry disease gene therapy program for AVR-RD-01 in 2022 after variable responses were seen in a Phase I/II trial.
Nonetheless, there is potential for gene therapies to make a difference in this area. Current treatments mostly help manage symptoms and improve patient quality of life, but gene therapies offer hope for the reversal of disease progression, says Dr. Berna Seker Yilmaz, a research fellow at University College London. Yilmaz is working on development programs for gene therapies for inborn errors of metabolism like ornithine transcarbamylase (OTC) deficiency, a urea cycle disorder, and Niemann-Pick disease type C (NPC).
Barriers to access
Pharmaceutical companies are interested in developing gene therapies for rare diseases. However, researchers and companies face difficulties with funding, and there are post-approval challenges with reimbursement due to the high price required to make such gene therapies profitable, says Yilmaz. There is also a particularly poor understanding of the inborn errors of metabolism due to their complex nature, she adds.
There are a lack of natural history studies on these disorders, which makes it difficult to find suitable targets for gene therapies, highlights Yilmaz. The brain needs to be targeted for some inborn errors of metabolism, and that is much more difficult to reach because of the blood-brain barrier, which prevents vector access, says Yilmaz.
For other conditions like phenylketonuria, therapies need to target the liver. However, adeno-associated virus (AAV) vectors are very toxic to the liver, says Dr. Harvey Levy, a senior physician in medicine at the Boston Children’s Hospital in Massachusetts. As such, patients need to be on high doses of the steroid prednisone to counteract the liver problems, he adds. However, prednisone treatment has been associated with a higher risk for diabetes and causes weight gain, says Levy.
Due to newborn screening, patients as young as one month old can begin treatment for phenylketonuria, says Dr. Arlindo Guimas, a specialist in internal medicine from the Hospital de Santo António in Porto, Portugal. However, the administration of gene therapies in newborns can raise several safety concerns, he explains.
Alongside typical challenges with rare disease therapy access, there are unique factors that influence the therapeutic development for inborn errors of metabolism. As typical treatment for inborn errors of metabolism involves formula and dietary changes, the introduction of gene therapies would introduce a steep increase in safety risks, says Guimas. “The long-term effects that gene therapy has on inborn error of metabolism patients should also be considered, says Guimas. Since phenylketonuria patients have several therapeutic options that alleviate symptoms, a gene therapy would have to be truly impressive for patients to be receptive to receiving gene therapy, he adds.
Future direction
The main treatment option for OTC deficiency is liver transplantation, which is challenging due to a reliance on organ donation, lifelong immunosuppression, and a steep price tag. As such, pharmaceutical companies have been steadily showing interest in filling this gap with gene therapies, says Yilmaz.
According to GlobalData, there are four clinical-stage gene therapy candidates in development for OTC deficiency, including biologics from Ultragenyx Pharmaceutical, Arcturus Therapeutics, Blue Bell, Pennsylvania-based iEcure, and London, UK-based Bloomsbury Genetic Therapies. There are nine candidates in development for phenylketonuria that are not gene therapies compared to two that are gene therapies, and six non-gene therapies in clinical development for Niemann-Pick disease type C compared to no gene therapies.
For some inborn errors of metabolism like Niemann-Pick disease type C, the first priority is to raise awareness surrounding the disease, says Yilmaz. The late onset of symptoms associated with the disease can lead to late diagnosis, leading to patient deterioration in the interim, she explains.
For disorders like phenylketonuria, therapy types other than gene therapies will continue fulfilling treatment needs, says Andersson. Currently, patients are commonly treated with Biomarin Pharmaceuticals’ Kuvan (sapropterin dihydrochloride), an enzyme cofactor therapy, or Palynziq (pegvaliase), an enzyme replacement therapy. Next Generation Gene Therapeutics is currently investigating an AAV gene therapy, NGGT-002, in a Phase I/II study (NCT06332807), while Shanghai, China-based CommBio Therapeutics (CBT102-A) is assessing its bacterial vector gene therapy CBT102-A in a Phase I clinical trial. Still, Andersson is cautious and says that gene therapies may not be available for diseases like phenylketonuria that have established alternatives for a decade or more.
