*8.9. Red Blood Cell Therapy*

Recently, the lab grown red blood cells were genetically engineered to produce the enzyme PAL. Researchers at Rubius Therapeutics (https://www.rubiustx.com/) developed RTX-134, a Red Cell Therapeutic™ (RCT) product candidate, by inserting the gene encoding PAL enzyme into the blood cells to degrade toxic levels of Phe in the bloodstream. RTX-134 entered the clinical trials; however, it was recently reported that RTX-134 failed to generate any meaningful signals of efficacy.

The current and ongoing treatment and research are summarized in the Tables 1 and 2. No optimal treatment for PKU and HT1 has ye<sup>t</sup> been developed, and thus novel strategies need to be explored. It is necessary to consider each step involved—folding, assembly, refolding, and degradation—in the cellular handling of mutant PAH and FAH proteins.



### **9. Molecular and Chemical Chaperones as Current Therapeutics for PKU and HT1**

Di fferent technologies have been exploited to discover strategies for treating the most common inborn errors of metabolism, PKU and HT1. For PKU, pharmacological chaperones are currently being studied to functionally and structurally rescue misfolded proteins. Among all the compounds discovered to date, only sapropterin dihydrochloride, a synthetic form of BH4, and dietary restriction are approved and used together for tetrahydrobiopterin-responsive PKU [42]. Side e ffects associated with sapropterin include rhinorrhea, pharyngolaryngeal pain, diarrhea, and lower than normal Phe levels in patients younger than 6 years [127]. Enzyme replacement therapy is another strategy for treating PKU. PEG-PAL (pegvaliase) can metabolize Phe and is approved for the treatment of patients with uncontrolled blood Phe levels. However, participants in the clinical trials had adverse events, and discontinuation of the drug is recommended during pregnancy and breastfeeding [128].

For HT1, only NTBC (Nitisinone) in conjunction with a low tyrosine and phenylalanine diet has been widely used. NTBC inhibits HPPD, an enzyme upstream of FAH, but it only partially protects against liver dysfunction [105].
