Current and innovative emerging therapies for porphyrias with hepatic involvement

Abstract

Porphyrias are rare inherited disorders caused by specific enzyme dysfunctions in the haem synthesis pathway, which result in abnormal accumulation of specific pathway intermediates. The symptoms depend upon the chemical characteristics of these substances. Porphyrins are photoreactive and cause photocutaneous lesions on sunlight-exposed areas, whereas accumulation of porphyrin precursors is related to acute neurovisceral attacks. Current therapies are suboptimal and mostly address symptoms rather than underlying disease mechanisms. Advances in the understanding of the molecular bases and pathogenesis of porphyrias have paved the way for the development of new therapeutic strategies. In this Clinical Trial Watch we summarise the basic principles of these emerging approaches and what is currently known about their application to porphyrias of hepatic origin or with hepatic involvement.

Therapeutic strategies for acute intermittent porphyria

“…Mice with AIP that received hPBGD mRNA (0.05 or 0.1 mg/kg) had partial protection against PBG accumulation and pain. In contrast, doses of hPBGD mRNA (0.2 or 0.5 mg/kg) provided full protection against PBG accumulation and pain (102,117).…”

“…However, this technology has many unresolved problems. First, there are no biochemical indicators of the effectiveness of gene therapy (102,105). Second, repeated administration is required.…”

“…Second, repeated administration is required. However, initial exposure to the viral vector will lead to the development of neutralizing antibodies (17,102). Therefore, rAAV-hPBGD gene therapy requires a balance between sufficient transgene expression and destructive immune responses, and this may be affected by the serotype of the rAAV vector.…”

“…In addition, patients with AIP should refrain from using nephrotoxic drugs and drink more water (16). The angiotensin-converting enzyme inhibitor losartan may delay the development of renal impairment (10,102). If the patient has already developed renal impairment, blood purification or kidney transplantation is often helpful.…”

“…If the patient has already developed renal impairment, blood purification or kidney transplantation is often helpful. For patients with AIP and kidney failure, renal transplantation or combined liver-kidney transplantation can have a good curative effect (16,102). Liver impairment is common in patients with AIP.…”