PKU future treatment update

NSPKU conference May 2024. Sepiapterin by Dr Anupam Chakrapani, mRNA therapyu and more by Prof Tarek Hiwot
From the NSPKU conference May 2024

The NSPKU conference held from 17-19 May 2024 included an update on possible new treatments for PKU. These are my notes from the sessions on sepiapterin, mRNA, gene therapy, solute carrier 6, and options for PegPal.

Part 1: Sepiapterin

Dr Anupam Chakrapani, Consultant IMD Paediatrician, Great Ormond St Hospital NHS Foundation Trust

The conference opened with a look at a new treatment for PKU, which sounds deceptively similar to sapropterin (Kuvan), but which is likely to work for more people: Sepiapterin. (For a simple explanation of on why sapropterin doesn’t work for everyone, see

Both sepiapterin and sapropterin are protein ‘chaperones’

Many of you will have felt like a ‘protein chaperone’ most of your life, but we are talking about pharmacological chaperones here. These are substances which can occur naturally within the body or administered as a medication. In PKU, both sepiapterin and sapropterin assist the metabolism of phe by increasing the amount of BH4 in the body. BH4 does occur naturally in the body, and sepiapterin adds BH4 if a form similar to the body’s BH4. The BH4 in sapropterin, however, is in a form which needs to be converted before working. This is one of the reasons why it doesn’t work in two thirds of patients.

Sepiapterin in trials in the UK

The team have been undertaking small feeder trials. I reported on these in my January 2023 newsletter when these were reported at only paediatric clinics. I have enquired again about adult participation and will report back when I hear. (Subscribe to the monthly update)

The team found that many of those with blood phe levels over 360 before the trial were able to reduce phe levels below that recommended guideline thanks to the trial. They also found that sepiapterin was especially effective in classical PKU, compared with sapropterin on average. The trial also found that sepiapterin was well tolerated, though there were some side effects (nausea, headaches and other effects similar to those produced by sapropterin).

Part 2: mRNA, gene therapy, & more

Prof Tarekegen Geberhiwot, Consultant Metabolic Physician, University Hospitals Birmingham NHS Trust

Professor Geberhiwot took the stage to update the conference on several possible treatment areas which he has been working on. Please note, all of these treatments are currently only being trialed in mice or in small numbers of humans at present.

Gene therapy

This involves taking a relatively safe virus, adenovirus, and modifying it with the enzyme phenylalanine hydroxylase (PAH). A reminder that PAH is the enzyme which breaks down phe in humans, and which is missing or in low levels in those with PKU.

This modified virus would be administered to the liver in a PKU patient, where it would assist in the metabolism of phe. However, it is important to note that the process may trigger an immune response which would need treatment. Further, this treatment is unlikely to work in children as the liver is still growing, meaning the initial dose is outgrown quickly. Furthermore, it is possible that as the liver regenerates over time, the original dose could be lost in adults too.

Oral administration of PegPal

PegPal is the medical name for the medicine in Palynziq, the injectable PKU treatment currently in use. (In the same way that paracetamol is the medicine in the brand name Panadol.) PegPal is a plant enzyme called phenylalanine ammonia lyase, which we will call PAL. This enzyme performs the same job in plants, metabolising phe, that PAH performs in humans.

PegPal is therefore a plant enzyme which is injected into humans to try to process phe. PAL is likely to trigger the immune system, so it is coated with a substance (the PEG) to try to hide it from the body.

Professor Geberhiwot reported on trials where PegPal is taken as a tablet form rather than as an injection. This might appeal to many, but the trial showed only a small fall in phe levels. However, it was found to be safe, so expect to hear more about this in future.

Solute carrier family

This was an entirely new one for me, and I found my notes were thin as I was attempting to follow the presentation. If anyone has a better understanding, then please get in touch! This is a treatment which lowers blood phe by encouraging the kidneys to expel more phe in the urine. As I understood it, the treatment method is similar to that used in some diabetic treatments, and has been shown to be safe in humans. But it has only been shown to work in PKU in mice so far. I will update if I hear more.

mRNA therapy

You may be familiar with the term mRNA, as this is a therapy method which is used in vaccines for Covid. There is a quick breakdown of the location and role which mRNA plays in our cells below.

The professor pointed out that the mRNA used here was still very unstable. There were other drawbacks too. Notably, the treatment was currently by drip only, and reductions were only for a few days.

In conclusion, there are numerous studies going on. PKU is an exciting field of active research.

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