Cerebral Adrenoleukodystrophy (cALD)
Cerebral adrenoleukodystrophy (cALD) is an X-chromosome linked, recessively inherited genetic disease that can lead to a vegetative state or death within 2-5 years.
Cerebral adrenoleukodystrophy (cALD) is an X-chromosome linked, recessively inherited genetic disease in which mutations of ABCD1 lead to accumulation of very long chain fatty acids (VLCFA) in the brain and the adrenal gland, resulting in demyelination of nerve fibers that impair information transmission from the brain to the rest of the body. The clinical signs and progression of the disease can vary widely due to individual patient variability, making early diagnosis difficult. More than half of the patients begin showing symptoms such as behavioral problems, psychological instability, poor memory, and among kids, difficulty in reading, writing and comprehension; then progress to different types of disabilities, such as progressive psychomotor disorder, diminution in vision and audition, and adrenocortical dysfunction. Without treatment, cALD progresses rapidly, often leading to a vegetative state or death within 2-5 years.
The prevalence of cALD across the world is about 1 in 100,000 people, among them, 95% are males, 5% are females. Women who carry ABCD1 mutations often do not develop the full cALD condition or develop a milder cALD disease, compared to men.
Current Treatment
Current treatments for cALD are quite limited, and largely symptomatic. Dietary therapy targeting inhibiting endogenous VLCFA synthesis is commonly used to normalize plasma VLCFA level, which might be beneficial for asymptomatic patients. For cALD patients with adrenal deficiency, hormone replacement therapy with steroids is generally effective relieving the adrenal symptoms. However, these treatments do not resolve neurological symptoms nor halt demyelination progress.
Hematopoietic stem cell transplantation (HSCT) is the only effective treatment for cALD, proven to slow or stop the neuroinflammatory demyelinating process, when the procedure is performed at the early stage prior to onset of neurological symptoms and manifestation of extensive demyelination lesions. However, if the neural damages have progressed, HSCT procedure could instead accelerate neurologic decline. Given that early clinical symptoms are generally unspecific for cALD, HSCT is highly limited to young patients with familial history. In addition, allogenic HSCT remain associated with significant risks of severe graft-versus-host disease (GVHD) and prolonged immune deficiency, particularly in adults. Moreover, not all cALD patients have HLA-matched donors.
Genetic therapy, in which the host’s HSCs (hematopoietic stem cells) are genetically corrected with wildtype ABCD1 gene, has been examined for patients for whom a donor is not available. Pilot studies have shown a promising efficacy comparable to HSCT. However, neither treatment improves adrenal functions.
New Avenue for cALD Treatment – T-MSC Therapy
T-MSCs have several advantages over bone marrow derived HSCs (BM-HSCs) as a better therapeutic choice. First, T-MSCs express much lower human leukocyte antigens (HLAs), hence a lower immunogenicity, compared to adult tissue derived stem cells, which enable them to be better tolerated by the host and lower the likelihood of severe adverse effects from graft-versus-host-disease and immunosuppressing medicine for patients. More importantly, there is no need to find a matching donor for T-MSC treatment. These could greatly improve the quality of life of cALD patients.
Second, T-MSCs show stronger immunomodulatory and trophic functions than adult tissue derived stem cells, which indicate a better potential in stopping inflammatory damage to neural sheath and promoting neural repair. Moreover, preclinical studies from ImStem using in-vitro cell models have shown that T-MSCs can cross the blood brain barrier (BBB) and reduce the barrier permeability, supporting a potential for T-MSCs to further suppress neural inflammation by stabilizing BBB structure and consequently preventing activated inflammatory T-cells being recruited to affected areas across BBB.
Lastly, T-MSCs can be expanded ex vivo almost indefinitely while maintaining normal cellular properties, which makes it an ideal target for genetic modification for optimized therapeutic effects.