The Changing Face of Adrenoleukodystrophy

Abstract

Adrenoleukodystrophy (ALD) is a rare X-linked disorder of peroxisomal oxidation due to mutations in ABCD1. It is a progressive condition with a variable clinical spectrum that includes primary adrenal insufficiency, myelopathy, and cerebral ALD. Adrenal insufficiency affects over 80% of ALD patients. Cerebral ALD affects one-third of boys under the age of 12 and progresses to total disability and death without treatment. Hematopoietic stem cell transplantation (HSCT) remains the only disease-modifying therapy if completed in the early stages of cerebral ALD, but it does not affect the course of adrenal insufficiency. It has significant associated morbidity and mortality. A recent gene therapy clinical trial for ALD reported short-term MRI and neurological outcomes comparable to historical patients treated with HSCT without the associated adverse side effects. In addition, over a dozen states have started newborn screening (NBS) for ALD, with the number of states expecting to double in 2020. Genetic testing of NBS-positive neonates has identified novel variants of unknown significance, providing further opportunity for genetic characterization but also uncertainty in the monitoring and therapy of subclinical and/or mild adrenal insufficiency or cerebral involvement. As more individuals with ALD are identified at birth, it remains uncertain if availability of matched donors, transplant (and, potentially, gene therapy) centers, and specialists may affect the timely treatment of these individuals. As these promising gene therapy trials and NBS transform the clinical management and outcomes of ALD, there will be an increasing need for the endocrine management of presymptomatic and subclinical adrenal insufficiency. (Endocrine Reviews 41: 1 - 17, 2020).

Keywords: adrenoleukodystrophy; gene therapy; hematopoietic stem cell transplant; newborn screening.

Graphical Abstract

Figure 1.

Recommended endocrine surveillance for presymptomatic infants and children with ALD. Infants identified through NBS should have an early morning ACTH and cortisol level at the time of diagnosis to screen for glucocorticoid deficiency, which usually precedes mineralocorticoid deficiency (10, 53). Any ACTH level of > 100 pg/mL and/or any morning cortisol level < 5 ug/dL is considered abnormal and warrants further diagnostic evaluation (53). *In the case of a stimulated peak cortisol level of < 18 μg/dL, stress dose steroids should be started, but daily glucocorticoid replacement can be considered as clinically indicated. Abbreviation: PRA, plasma renin activity.

Figure 2.

Key milestones and developments in BMT/HSCT and gene therapy that led to their use to treat CCALD. General milestones are highlighted in blue, and those specific for the treatment of ALD are highlighted in red. Abbreviations: ADA, adenosine deaminase; ALL, acute lymphoblastic leukemia; BLA, biologics license application; BMT, bone marrow transplant; SCID, severe combined immunodeficiency; other abbreviations noted in the text.

Figure 3.

Lenti-D LV encoding ALD protein used in the Bluebird Starbeam ALD-102 study. Lenti-D LVV is a replication defective, SIN, third-generation HIV-1 based LVV pseudotyped with glycoprotein (G) of the vesicular stomatitis virus (VSV-G), carrying human ABCD1 cDNA-derived sequences that encode the normal human ALDP. The vector sequences encoding the normal ALDP are under control of the MND promoter, which has been shown to drive expression of the transgene in HSCs. The vector is similar to that used in Cartier et al (CG1711 hALD) (59) in regard to the promotor used and ALDP cDNA but differs in elements of the vector backbone, including removal of the WPRE. Abbreviations: cPPT/FLAP, central polypurine tract; ΔU3, promoter/enhancer-deleted unique 3’; MND, myeloproliferative sarcoma virus enhancer with negative control region deleted, dl587rev primer-binding site substituted; ppt, 3’ poly purine tract; Ψ+, packaging signal; R, repeat; RRE, rev response element; U5, unique 5’ site. (Reproduced with permission from Eichler F, Duncan C, Musolino PL, et al. Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2017;377 (17):1630–8.).

Figure 4.

Treatment protocol for the gene therapy study utilized in the Bluebird Starbeam ALD-102 trial. Abbreviations: ALDP, adrenoleukodystrophy protein; DP, drug product; HSC, hematopoietic stem cell; LTF, long-term follow-up. (Reproduced with permission from Sevin, C. Phase 2/3 trial to assess the safety and efficacy of lenti-D hematopoietic stem cell gene therapy for cerebral adrenoleukodystrophy. Presented at: European Society of Paediatric Neurology, Megaron Athens International Conference Centre, Athens, Greece, September 2019. Oral Abstract Presentation [Abstract OC036]).