10. Gene therapy for adrenoleukodystrophy (ALD)

N. L., J.-P. A., K. P.

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1/2 A. les mots-clés sont faibles. Si des synonymes à ALD ont été trouvés, il n'en va pas de même pour considérer les types d'antiviraux employés.

0/2 B. La grammaire des équations correspondant aux mots-clés n'est pas maîtrisée. Les synonmes de ALD n'ont pas été utilisés (!) dans les équations en association avec d'autres mots-clés pouvant restreindre le nombre de résultats. L'utilisation des mots-clés a certainement contribué à trouver des références intéressantes, mais les équations données dans le wiki ne permettent de faire de la recherche d'information

1/2 C. Outils: plusieurs outils ont été explorés, mais on ne peut pas reproduire les recherches à partir des 2 équations suggérées, car elles ne fonctionnent pas. On en déduit que les références ont été trouvées à partir de mots-clés, et que ensuite, il y a eu des tentatives de reconstitution d'équations...

2/2 D. Les références bibliographiques sont correctes

2/2 E. Les citations dans le texte des réponses à la question sont correctes

1/2 F. La restitution de la démarche documentaire ou méthodologie de recherche d'information est difficile à suivre. Il y a beaucoup d'imprécision, il est difficile pour le lecteur de comprendre vraiment quels équations ont été testées.

Pour information, on peut utiliser des textes intégraux avec guillemets et source, ou des idées empruntées avec paraphrase et source (droit d'auteur). Mais la reproduction par copié collé d'image, de tableau, de dessin, de graphique, de statistiques, n'est pas possible, même en citant la source! Pour une reproduction, il faut demander aux auteurs et à l'éditeur la permission de reproduction (droit de diffusiont). Parfois, il faut payer pour obtenir ce droit. Autrement dit, le droit d'utilisation des "images" n'est pas le même que les idées sous forme écrite!

7 pts

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10.1 What is ALD, from the "National Institute of Neurological Discorders and Stroke"

Synonym

Krabbe's disease, Leukodystrophy (NOS, globoid cell, metachromatic, sudanophilic, Pelizaeus-Merzbacher disease, Sulfatide lipidosis)

What is Adrenoleukodystrophy?
Adrenoleukodystrophy (ALD) is one of a group of genetic disorders called the leukodystrophies that cause damage to the myelin sheath, an insulating membrane that surrounds nerve cells in the brain and leads to a progressive dysfunction of the adrenal gland. People with ALD accumulate high levels of saturated, very long chain fatty acids (VLCFA) in the brain and adrenal cortex because they do not produce the enzyme that breaks down these fatty acids in the normal manner.

Myelin loss in X-ALD (represented here in absence of white matter in right hemisphere) is due to two causes, chemical imbalance and inflammation.

Available on <http://www.neuropathologyweb.org/chapter10> (accessed 9/11/2008)

The most common is the X-linked form (X-ALD), which is caused by the mutated gene ABCD1 located on the X-chromosome. Since men only have one X-chromosome, they are more severely affected. Onset of X-ALD can occur in childhood or in adulthood. The childhood form is the most severe, with onset between ages 4 and 10. The most common symptoms are usually behavioral changes such as abnormal withdrawal or aggression, poor memory, and poor school performance. Other symptoms include visual loss, learning disabilities, seizures, poorly articulated speech, difficulty swallowing, deafness, disturbances of gait and coordination, fatigue, intermittent vomiting, increased skin pigmentation, and progressive dementia. In the milder adult-onset form, which typically begins between ages 21 and 35, symptoms may include progressive stiffness, weakness or paralysis of the lower limbs, and ataxia. Although adult-onset ALD progresses more slowly than the classic childhood form, it can also result in deterioration of brain function. A mild form of ALD is occasionally seen in women who are carriers of the disorder. Symptoms include progressive stiffness, weakness or paralysis of the lower limbs, ataxia, excessive muscle tone, mild peripheral neuropathy, and urinary problems.

HORS-SUJET!

Is there any treatment?
Adrenal function must be tested periodically in all patients with ALD. Treatment with adrenal hormones can be lifesaving. Symptomatic and supportive treatments for ALD include physical therapy, psychological support, and special education. Recent evidence suggests that a mixture of oleic acid and erucic acid, known as "Lorenzo's Oil," administered to boys with X-ALD can reduce or delay the appearance of symptoms. Bone marrow transplants can provide long-term benefit to boys who have early evidence of X-ALD, but the procedure carries risk of mortality and morbidity and is not recommended for those whose symptoms are already severe or who have the adult-onset or neonatal forms. Oral administration of docosahexanoic acid (DHA) may help infants and children with neonatal ALD.

What is the prognosis?
Prognosis for patients with ALD is generally poor due to progressive neurological deterioration. Death usually occurs within 1 to 10 years after the onset of symptoms.

HORS-SUJET!

What research is being done?
The NINDS supports research on genetic disorders such as ALD. The aim of this research is to find ways to prevent, treat, and cure these disorders. Intensive basic research has proposed two new approaches, 4-phenylbutyrate and lovastatin, which could potentially lower levels of VLCFA in the brain. Therapeutic trials for both agents are planned. ¹

10.2 Preliminary considerations

Question addressed

What is the status of treating ALD by gene therapy with lentiviruses?

Information to gather

Scientific articles, reviews, updates on clinical trials, congresses, symposiums, foundations.

Keywords

adrenoleukodystrophy, ALD, x-linked, gene therapy, lentivirus, HIV, review, clinical trial(s)

[Remark: Alternative names for the disease or its forms exist (adrenomyeloneuropathy, addison disease, childhood cerebral adrenoleukodystrophy, schilder-addison complex) but searches with adrenoleukodystrophy and ALD generated already countless hits so that we did not consider these.]

NON!  par l'équation (ALD OR adrenoleukodystrophy OR "addison disease" OR "schilder-addison complex" OR X-linked adrenoleukodystrophy ) AND lentivir* dans Web of science donne 8 résultats pertinents! La formation s'est évertuée à montrer l'importance des synonymes en recherche documentaire dans des moteurs de recherche aussi bien que dans les BDB!

Equations

1) "Aubourg P"[auth] gene therapy

2) "ALD" AND "lentivirus" AND "gene therapy" or "ALD" AND "HIV" AND "gene therapy"

- dans l'équation, les guillements de "ALD" ne servent à rien.

10.3 Keywords and equations tested in the different search engines

Electronic internet tools

Google: "adrenoleukodystrophy gene therapy lentivirus", "ALD lentivirus gene therapy", "ALD HIV gene therapy", "clinical trial ALD gene therapy" -> dig further for interesting hits ("principal site", further links)

Google images: "ALD lentivirus gene therapy", "adrenoleukodystrophy"

Google scholar: "ALD review"

Electronic library tools

Wikipedia: "ALD" -> references

Pubmed: "adrenoleukodystrophy lentivirus", "gene therapy adrenoleukodystrophy", equation 1 -> related articles, sort by pubdate, references of review

WOS: "adrenoleukodystrophy lentivirus", "gene therapy adrenoleukodystrophy", equation 1 -> related articles, sort by pubdate, references of review

Scopus: "ALD" AND "gene therapy", equation 2

ISI Web of knolwedge: equation 2, "adrenoleukodystrophy" AND "lentivirus", "adrenoleukodystrophy"

NEBIS: "gene therapy lentivirus", "adrenoleukodystrophy",  "gene therapy adrenoleukodystrophy"

E-books: "gene therapy adrenoleukodystrophy", "gene therapy ALD", "lentivirus ALD", "lentivirus adrenoleukodystrophy": no results

Catalogue vaudois: "ALD", "adrenoleukodystrophy": no results

[Remark: Some articles could not be accessed freely but we could ask the librarians for help in these cases.]

10.4 Suggested bibliography

1. National Institute of Neurological Disorders and Stroke. NINDS Adrenoleukodystrophy Information page [online] http://www.ninds.nih.gov/disorders/adrenoleukodystrophy/adrenoleukodystrophy.htm (accessed 31/10/08) (found in the bibliography of wikipedia)

2. The Stop ALD foundation [online] http://www.stopald.org/ (accessed 31/10/08) (found with Google)

3. The myelin project [online] http://www.myelin.org/ (accessed 31/10/08) (found in the bibliography of Wikipedia)

4. American Society of Gene Therapy. Presentation on challenges in advancing the field of gene therapy [online]. Available on <http://www.asgt.org/archived_course_materials//stakeholders/rsalzman.pdf> (accessed 31/10/08) (found with Google)

5. BENHAMIDA S, PFLUMIO F, DUBART-KUPPERSCHMITT A, ZHAO-EMENET JC, CAVAZZANO-CALVO M, ROCCHICCIOLI F, FICHELSON F, AUBOURG P, CHARNEAU P, CARTIER N.  Transduced CD34+ Cells from Adrenoleukodystrophy Patients with HIV-Derived Vector Mediate Long-Term Engraftment of NOD/SCID Mice. Molecular Therapy, 2003 7(3):317-324 (found with Pubmed, Scopus, Google, Google scholar, ISI)

6. BUTLER D. Gene therapy sees early success for neurodegenerative disease. Nature News, 30 Oct 2007 (found with WOS)

7. CARLIER N, AUBOURG P. Hematopoietic stem cell gene therapy in Hurler syndrome, globoid cell leukodystrophy, metachromatic leukodystrophy and X-adrenoleukodystrophy. Current Opinion in Molecular Therapeutics 2008 10(5):471-478 (found with ISI Web of Knowledge)

8. MOSER HW. Therapy of X-Linked Adrenoleukodystrophy, NeuroRX 2006 3(2):246-253 (found with PUBMED)

9. UNIVERSITY OF MINNESOTA. Doctors Uncover Treatment For Advanced ALD Patients. ScienceDaily [online] 2007, February 27. Available on <http://www.sciencedaily.com/releases/2007/02/070220182857.htm> (accessed 10/11/2008) (found on Science Daily)

10. BOESE, VERA. Molekulargenetische Untersuchungen zur Adrenoleukodystrophie. Bonn: Diss. Univ. Bonn, 2005

outils?