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Therapeutic developments in peroxisome biogenesis disorders
M C McGuinness1, H Wei, K D Smith
1Kennedy Krieger Institute, Room 400A, 707 North Broadway, Baltimore, MD 21205, USA. smithk@welchlink.welch.jhu.edu
Insights
Peroxisome biogenesis disorders (PBDs) are severe genetic diseases. Sodium 4-phenylbutyrate shows promise in improving biochemical functions in milder PBD patient cell lines.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Peroxisome biogenesis disorders (PBDs) encompass a spectrum of severe genetic conditions, including Zellweger syndrome and infantile Refsum disease.
- PBDs are characterized by metabolic dysfunction, affecting peroxide degradation, fatty acid metabolism, and synthesis of vital lipids like plasmalogens and bile acids.
- Current treatments for PBDs are limited to supportive and symptomatic care, with significant challenges in addressing severe congenital neurological alterations.
Purpose of the Study:
- To review current and emerging treatment strategies for peroxisome biogenesis disorders (PBDs).
- To evaluate the potential of dietary interventions and pharmacological approaches for PBD management.
- To explore the efficacy of inducing peroxisome proliferation as a therapeutic avenue for PBD patients.
Main Methods:
- Review of existing literature on PBD treatments, including dietary supplementation and pharmacological induction of peroxisomes.
- Analysis of experimental therapies targeting biochemical abnormalities in PBDs.
- Investigation into the effects of sodium 4-phenylbutyrate on peroxisome function in patient-derived fibroblast cell lines.
Main Results:
- Rodent peroxisomal proliferators were ineffective in inducing human peroxisomes.
- Sodium 4-phenylbutyrate demonstrated the ability to induce peroxisome proliferation in fibroblast cell lines from patients with milder PBD phenotypes.
- This induction led to improved biochemical functions, including enhanced very long chain fatty acid beta-oxidation and normalized very long chain fatty acid and plasmalogen levels.
Conclusions:
- Dietary modification and pharmacological induction of peroxisomes represent promising therapeutic strategies for PBDs.
- Sodium 4-phenylbutyrate shows potential for improving peroxisomal function in milder PBD cases.
- Further research is warranted to translate these findings into clinical benefits for PBD patients.
Abstract:
Clinically, peroxisome biogenesis disorders (PBDs) are a group of lethal diseases with a continuum of severity of clinical symptoms ranging from the most severe form, Zellweger syndrome, to the milder forms, infantile Refsum disease and rhizomelic chondrodysplasia punctata. PBDs are characterised by a number of biochemical abnormalities including impaired degradation of peroxide, very long chain fatty acids, pipecolic acid, phytanic acid and xenobiotics and impaired synthesis of plasmalogens, bile acids, cholesterol and docosahexaenoic acid. Treatment of PBD patients as a group is problematic since a number of patients, especially those with Zellweger syndrome, have significant neocortical alterations in the brain at birth so that full recovery would be impossible even with postnatal therapy. To date, treatment of PBD patients has generally involved only supportive care and symptomatic therapy. However, the fact that some of the milder PBD patients live into the second decade has prompted research into possible treatments for these patients. A number of experimental therapies have been evaluated to determine whether or not correction of biochemical abnormalities through dietary supplementation and/or modification is of clinical benefit to PBD patients. Another approach has been pharmacological induction of peroxisomes in PBD patients to improve overall peroxisomal biochemical function. Well known rodent peroxisomal proliferators were found not to induce human peroxisomes. Recently, our laboratory demonstrated that sodium 4-phenylbutyrate induces peroxisome proliferation and improves biochemical function (very long chain fatty acid beta-oxidation rates and very long chain fatty acid and plasmalogens levels) in fibroblast cell lines from patients with milder PBD phenotypes. Dietary supplementation and/or modification and pharmacological induction of peroxisomes as treatment strategies for PBD patients will be the subject of this review.