Emerging therapies for acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disease caused by hepatic deficiency of hydroxymethylbilane synthase (HMBS), the third enzyme of the heme synthesis pathway. The dominant clinical feature is acute neurovisceral attack associated with high production of potentially neurotoxic porphyrin precursors due to increased hepatic heme consumption. Current Standard of Care is based on a down-regulation of hepatic heme synthesis using heme therapy. Recurrent hyper-activation of the hepatic heme synthesis pathway affects about 5% of patients and can be associated with neurological and metabolic manifestations and long-term complications including chronic kidney disease and increased risk of hepatocellular carcinoma. Prophylactic heme infusion is an effective strategy in some of these patients, but it induces tolerance and its frequent application may be associated with thromboembolic disease and hepatic siderosis. Orthotopic liver transplantation is the only curative treatment in patients with recurrent acute attacks. Emerging therapies including replacement enzyme therapy or gene therapies (HMBS-gene transfer and ALAS1-gene expression inhibition) are being developed to improve quality of life, reduce the significant morbidity associated with current therapies and prevent late complications such as hepatocellular cancer or kidney failure in HMBS mutation carriers with long-standing high production of noxious heme precursors. Herein, we provide a critical digest of the recent literature on the topic and a summary of recently developed approaches to AIP treatment and their clinical implications.

RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice.

The acute hepatic porphyrias are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks. Factors that induce the expression of hepatic 5-aminolevulinic acid synthase 1 (ALAS1) result in the accumulation of the neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which recent studies indicate are primarily responsible for the acute attacks. Current treatment of these attacks involves i.v. administration of hemin, but a faster-acting, more effective, and safer therapy is needed. Here, we describe preclinical studies of liver-directed small interfering RNAs (siRNAs) targeting Alas1 (Alas1-siRNAs) in a mouse model of acute intermittent porphyria, the most common acute hepatic porphyria. A single i.v. dose of Alas1-siRNA prevented the phenobarbital-induced biochemical acute attacks for approximately 2 wk. Injection of Alas1-siRNA during an induced acute attack significantly decreased plasma ALA and PBG levels within 8 h, more rapidly and effectively than a single hemin infusion. Alas1-siRNA was well tolerated and a therapeutic dose did not cause hepatic heme deficiency. These studies provide proof-of-concept for the clinical development of RNA interference therapy for the prevention and treatment of the acute attacks of the acute hepatic porphyrias.

Helper-dependent adenoviral liver gene therapy protects against induced attacks and corrects protein folding stress in acute intermittent porphyria mice.

Acute intermittent porphyria (AIP) is a hepatic metabolic disease that results from haplo-insufficient activity of porphobilinogen deaminase (PBGD). The dominant clinical feature is acute intermittent attacks when hepatic heme synthesis is activated by endocrine or exogenous factors. Gene therapy vectors over-expressing PBGD protein in the liver offers potential as a cure for AIP. Here, we developed a helper-dependent adenovirus (HDA) encoding human PBGD (hPBGD) and assessed its therapeutic efficacy in a murine model of AIP. Intravenous or intrahepatic administration of HDA-hPBGD to AIP mice resulted in a sustained hepatic hPBGD expression in a dose-dependent manner. Intrahepatic administration conveyed full protection against induced porphyria attacks at a significantly lower viral dose than intravenous injection. Transgenic hPBGD accumulated only in the cytosol of hepatocytes as the endogenous protein. Characterization of PBGD-deficient mouse strains revealed that a strong PBGD deficiency causes the chronic disturbance of cytosolic and endoplasmic reticulum folding machineries. This disturbance was completely restored over time by the over-expression of hPBGD. HDA-hPBGD is a promising vector that protects against porphyria attacks and resolves the chronic folding stress associated with low levels of PBGD activity.

Open-label study of hemin for acute porphyria: clinical practice implications.

BACKGROUND: The acute porphyrias are rare inherited diseases characterized by acute episodes of life-threatening symptoms. Hemin was approved for treating these disorders in 1983. This open-label study of hemin therapy, conducted to demonstrate the safety of hemin manufactured in a new facility, is the largest to date and provides an overview of the use of hemin in clinical practice in the United States. METHODS: During 8 months when hemin was available only through study participation, 130 patients with a clinical diagnosis of acute porphyria received hemin as regularly prescribed by their doctor. Laboratory information and data on use of hemin for acute and prophylactic treatment were analyzed from case report forms. RESULTS: Hemin was administered to 111 patients for treatment of 305 acute attacks and to 40 patients for prophylaxis (usually by weekly or biweekly infusions). Diagnostic laboratory findings reported for 69 patients were confirmatory in only 26. Hemin was regarded as effective for all attacks in 73% of patients. Doses for acute attacks were less than the recommended 3-4 mg/kg/day in 20% of patients. Among 31 patients who received hemin prophylaxis for >1 month, 68% did not require subsequent hemin treatment for acute attacks. Most adverse events were attributed to porphyria and not treatment, and were more common in patients treated for acute attacks rather than prophylaxis. CONCLUSIONS: Safety and perceived efficacy of hemin were consistent with previous studies. Physician education is needed regarding use of diagnostic tests and recommended dosing. Preventive regimens are common and deserve further study.

Recommendations for the diagnosis and treatment of the acute porphyrias.

The acute porphyrias, 4 inherited disorders of heme biosynthesis, cause life-threatening attacks of neurovisceral symptoms that mimic many other acute medical and psychiatric conditions. Lack of clinical recognition often delays effective treatment, and inappropriate diagnostic tests may lead to misdiagnosis and inappropriate treatment. We review the clinical manifestations, pathophysiology, and genetics of the acute porphyrias and provide recommendations for diagnosis and treatment on the basis of reviews of the literature and clinical experience. An acute porphyria should be considered in many patients with unexplained abdominal pain or other characteristic symptoms. The diagnosis can be rapidly confirmed by demonstration of a markedly increased urinary porphobilinogen level by using a single-void urine specimen. This specimen should also be saved for quantitative measurement of porphobilinogen, 5-aminolevulinic acid, and total porphyrin levels. Intravenous hemin therapy, started as soon as possible, is the most effective treatment. Intravenous glucose alone is appropriate only for mild attacks (mild pain, no paresis or hyponatremia) or until hemin is available. Precipitating factors should be eliminated, and appropriate supportive and symptomatic therapy should be initiated. Prompt diagnosis and treatment greatly improve prognosis and may prevent development of severe or chronic neuropathic symptoms. We recommend identification of at-risk relatives through enzymatic or gene studies.

Use of gonadotropin-releasing hormone analog with tibolone to prevent cyclic attacks of acute intermittent porphyria.

A 25-year-old woman with a 10-year history of recurrent attacks of acute abdominal pain just before menstrual periods had acute intermittent porphyria (AIP) diagnosed when she was 23.5 years old. Many acute attacks required hospitalization. Suppression of the menstrual cycle with a gonadotropin-releasing hormone analog (GnRHa; triptorelin) and tibolone administration as add-back therapy resulted in absence of acute porphyric attacks. The patient had no acute attacks over a 1-year follow-up period. This case suggests that long-term GnRHa therapy with tibolone add-back may be a therapeutic option for patients with AIP.

[Uniform programme in caring for patients with acute hepatic porphyria]. / Ujednolicony program postepowania z chorymi na ostre porfirie watrobowe.

The programme commissioned by the Ministry of Health is presented. Data basis for the years 1996-1998 were created. A booklet on diagnosis, treatment and prophylaxis of porphyrias was edited and distributed in Poland in 5000 copies to all hospitals, major laboratories, medical libraries, regional officers as well as patients. The booklet lists simple diagnostic methods which can be easily introduced to hospital laboratories for early diagnosis of porphyria. It also includes a list of the safe drugs for patients with porphyria. Several lectures for doctors and medical staff were delivered, nine publications appeared and six others were accepted for publication. Results of the work, evaluated after three years are as follows. Early clinical diagnosis of porphyria and its prophylaxis among family members has significantly improved. The frequency of severe attacks and the mortality rate due to porphyria has been reduced to singular cases. The proposed organization of small regional centers (with help of Porphyria Center), oriented at early diagnosis of porphyria appears to be impossible without further financial support.

[Prevention of acute intermittent porphyria is the best solution. Most important are early diagnosis and counseling]. / Bäst förebygga vid akut intermittent porfyri. Tidig diagnos och rådgivning till anlagsbäraren viktigast.

Recent mapping of acute intermittent porphyria (AIP) in Sweden has confirmed its very high prevalence in northern districts, though about fifty per cent of the gene carriers are to be found in the central and southern parts of the country. More than eighteen different AIP mutations are currently recognised in the Swedish kindreds. One mutations, evidently originating in northern Sweden, is predominant. As AIP is a pharmacogenetic disease, more than 200 substances being currently known to precipitate the neuropsychiatric symptoms, the greatest care is required in prescribing drugs to carriers of genetic predisposition to the disease. Guidelines are provided in the booklet. Drugs contraindicated in acute porphyria (Läkemedel farliga vid akut porfyri), jointly issued by the Swedish Porphyria Association and the Corporation of Swedish Pharmacists (Apoteksbolaget). Where doubt exists, specialists should be consulted since there are a number of factors that may contribute to an adverse reaction. Early diagnosis, preferably before puberty, and counselling are the cornerstones of management, and genetic analysis the diagnostic tool of choice, applicable in most families. In the symptomatic phase, glucose or haem arginate is effective in reversing the metabolic processes responsible for the exacerbation. Recently, the hepatic and late renal manifestations of the disease have been recognised, and early detection of the associated conditions is recommended. This includes monitoring for paraneoplastic prodromes of hepatocellular cancer.

Acute intermittent porphyria: mutation analysis and identification of gene carriers in a German kindred by PCR-DGGE analysis.

Acute intermittent porphyria (AIP) is the most frequent acute porphyria. Symptomatic patients and asymptomatic gene carriers are characterized by a reduction of their porphobilinogen-deaminase (PBG-D) activity to 50%, which is sufficient for porphyrin biosynthesis. PBG-D is encoded by two different mRNAs which are expressed in a tissue-specific manner. In classical AIP, the enzyme activity is reduced in erythroblasts and all other heme-forming body cells, whereas in the variant form of AIP, the PBG-D activity in erythroid tissues remains normal. Acute porphyria attacks can occur in gene carriers when the biosynthesis of heme is increased by drugs, low calorie intake, alcohol consumption or infections. Under these conditions, PBG-D cannot convert the precursors adequately so that PBG and delta-aminolevulinate accumulate. This may lead to neurovisceral symptoms and other neurological complications which are potentially life threatening. In patients with AIP, mutation analysis by PCR-DGGE (denaturing gradient gel electrophoresis) is becoming increasingly important since it also permits rapid identification of their presymptomatic relatives. Using this technique, more than 120 mutations have been identified in the PBG-D gene. When identified, the family members are informed about their genetic predisposition and are taught how to prevent porphyric attacks. Here, I illustrate this preventive strategy by describing a German kindred of an affected patient with the variant form of AIP with 17 family members.