This week, a team of researchers mostly from Boston Children’s Hospital and Harvard Medical School reported what seems likely to be the first clinical evidence of a dramatic medical breakthrough for children suffering with a rare and terrible disease. Hutchinson-Gilford Progeria Syndrome (HGPS) afflicts just one child in four to eight million with fearsome and deadly signs and symptoms: thinning bones, muscular and adipose loss, a distinct kind of vascular disease, kidney failure, and failing eyesight, amongst others.(18-21) The course of the disease is moderately rapid, such that victims appear normal at birth but begin to show signs of the disease late in the second year of life, and typically survive for another 1-2 decades; no patient has yet survived her third. Aspects of the children’s appearance (wrinkled skin, bulging scalp veins, and thinning hair), along with the resemblance of some of the disease phenotypes to age-related diseases and the very shortened life expectancy, led the disease to originally be called “progeria,” and to continue to be commonly described as a kind of “premature aging.”
The cause of HGPS is a de novo point mutation in the LMNA gene, which results in abnormal processing of its product: the precursor protein of lamin A, an intermediate filament protein constituent of the nuclear membrane that regulates a wide range of cellular functions.
Typically in progeria, a single silent C to T transition mutation at nucleotide 1824 (Gly608Gly) activates a cryptic splice site, resulting in the deletion of 150 messenger RNA bases in the 3′ portion of exon 11. The aberrant protein, progerin, lacks the cleavage site for removal of its C-terminal farnesylated peptide by Zmpste24 endoprotease, and therefore remains bound to the inner nuclear membrane. Hence, progerin resembles an aberrant form of farnesylated-prelamin A. However, whereas prelamin A is a transient, intermediate protein, which is present at very low levels in the cell, progerin is a nontransient protein whose concentration builds with successive cell divisions.(1)
Unlike the wild-type protein, progerin cannot be properly incorporated into the nuclear lamina, and as a result, the lamina is unable to provide normal structural support to the nuclear membrane, leading to perturbations in the membrane’s structure and function. These abnormalities interfere with a range of cellular functions, including DNA replication, apoptosis, nuclear transport, epigenetic regulation of gene expression, modulation of chromatin structure, and others. Amongst other things, these abnormalities impair mitosis and likely increase apoptosis of stem cells; these effects likely play a key role in most of the characteristic disease phenotypes.(1-5)
In 1998, when extremely little was known about the disease, Drs. Leslie Gordon and Scott Berns — physicians and parents of a child with HGPS — established the Progeria Research Foundation (PRF) to improve medical care for their son and his vanishingly few and geographically dispersed fellow patients, and support research on the disease. They gained enormously from the support of now-National Institutes of Health (NIH) Director Francis Collins, who was then overseeing the International Human Genome Sequencing Consortium, and in 2003 two teams — one supported by PRF and another from NIH — identified the LMNA gene mutation responsible for HGPS.(6,7)
In a scientific serendipity, researchers had already been pursuing small molecules with a mechanism of action that seemed to make them plausible as treatments for the disease: farnesyltransferase inhibitors (FTIs), which were already being synthesized and developed as possible chemotherapy agents. Two FTIs (ABT-100 and tipifarnib) were reported to increase weight and strength, decrease the occurrence of rib fractures, reduce cardiovascular pathology, and slightly improve survival in a mouse model of HGPS.(25,26,27) Subsequently, clinician-parent Dr. Gordon and colleagues affiliated with Boston Children’s Hospital moved to initiate a small (but large, relative to the patient population) clinical trial to test another farnesyltransferase inhibitor (lonafarnib/SCH66336/Sarasar) in patients with the disease. Lonafarnib was chosen for the pre-existing evidence of its good safety profile in children, established during prior early-stage trials in children with a range of brain malignancies; it had previously been abandoned in development for chemotherapy of solid tumors, but is still under investigation for leukaemias. Dr. Mark Kieran, the Director of the Pediatric Neuro-Oncology Center at Dana-Farber Cancer Institute, had done some of the early work with lonafarnib in this setting,(29) and assumed the position of Principal Investigator for the study.
The investigators have now reported preliminary evidence of safety and efficacy similar to that seen in the murine model:
Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes.(5)
As of this writing, a second Phase II trial is being launched, testing a cocktail of lonafarnib, zoledronic acid (Zometa®) and the HMG-CoA reductase inhibitor pravastatin (Pravachol®) in patients with progeria; while the latter drugs are usually mechanistically characterized (respectively) as a bisphosphonate and an HMG-CoA reductase inhibitor, and used for osteoporosis and secondary prevention of cardiovascular disease, they also have additional activity against different points in the protein farnesylation pathway, and thus might have additive or synergistic benefit with an FTI.
All of us at SENS Research Foundation are inspired by the rapid progress that was made against this tragic disease, hopeful for the children that are stricken (and will be stricken) with the disease and their parents, and more than happy to further raise awareness of this latest advance for medical science and human health. In addition to being a powerful example of the ongoing power of biomedical research to continue to improve the human condition, we believe that there are lessons to be learned about the institutional and scientific strategies that were employed to allow HGPS research leap forward in so short a period of time.
However, it is also important not to read too much into this apparent advance in regards to its implications for the development of new medicines against the diseases and disabilities of aging. In particular, the common characterization of HGPS “progeria” as a disease of “premature aging” leads some to expect that this research has direct implications for the development of rejuvenation biotechnologies, targeting the damage and disabilities of aging.
It is true that the splicing defect responsible for formation of progerin is sporadically active in wild-type cells, and that number of cells in which progerin is present and the level at which it appears do appear to rise with aging.(8-12) However, such cells are rare enough, and their progerin levels low enough, as to seem highly unlikely to meaningfully contribute to tissue dysfunction with aging, at least within the bounds of a currently-normal lifespan. Additionally, there is evidence that progerin can be turned over in the nuclear lamnia,(9) and the causal relationship between the higher prevalence of progerin in aging cells and cellular senescence or disease are not clear, leaving open the possiblity that repair of well-established forms of aging damge may in turn lead to the reversal or obviation of this phenomenon. Notably, the need to remove “senescent” cells as part of a comprehensive panel of rejuvenation biotechnologies is already clear from first principles, and its potential to ameliorate aspects the frailty and disability of aging has been demonstrated in proof-of-concept rejuvenation research, rendering the specific role of progerin in the process moot. That is, removing “senescent” cells is essential whether progerin accumulation is a cause or a consequence of cellular senescence, and will be equally effective as a regenerative medical therapy against age-related disability in either case.
More profoundly, the use of the language of “premature aging” in reference to HGPS and similar disorders in mice (eg. (13-17)) and (wo)men is a petitio principii, simultaneously assuming and being proferred as proof of the very facts that would be required to so designate a syndrome.(28) The degenerative aging process is caused by the accumulation of multiple forms of cellular and molecular damage in our tissues, and so anything that leads to progressive dysfunction of those tissues may bear some resemblance to the phenotype and pathology of aging. However, a similar phenotype need not have a similar mechanistic basis. The question is exactly whether the cellular and molecular causes of such disorders are the same as those underlying the similar-looking phenotypes in aging, and the progressive rise in disease, disabilty, dependence, dementia, and ultimately death that harrow the aging body. And importantly, the fact that a mutationally-driven increase in the rate of generation of some form of cellular and molecular damage can cause a syndrome that bears a phenotypic resemblance to degenerative processes seen in aging does not imply that reducing the level of such damage to levels well below those present in wild-type animals (or humans) will have biomedical importance, particularly within the bounds of a currently-normal lifespan.(27) This can clearly be seen in the repeated failure of antioxidant supplementation (as, eg, in the prominent case of resveratrol, discussed in two previous posts, and see recently (22)) and/or transgenic increases in antioxidant enzyme expression(23,24) to extend lifespan in otherwise-normal animals, despite their efficacy in models of “accelerated aging.”
As two respected biogerontologists have quipped,
“Until you show me that you can postpone aging, I don’t know that you’ve done anything,” sniffs Michael R. Rose, geneticist at the University of California. “A lot of people can kill things off sooner, by screwing around with various mechanisms, but to me that’s like killing mice with hammers — it doesn’t show that hammers are related to aging.”
This is another instance in which somebody makes a very sick mouse and points out a number of ways the sickness they see reminds them of some aspect of ageing, so they call it premature ageing,” says Richard Miller, a gerontologist at the University of Michigan in Ann Arbor. His point is that it is easy to make mice die young. To convince sceptics that [something] is involved in ageing you need to demonstrate that reducing this damage makes mice live longer.
Of course, children with HGPS are not mice. But the fact that they are human patients makes it even easier to see that the phenotypic resemblance of HGPS to aging is much more limited than media and other accounts often imply. Thus, for instance, the vascular defects of HGPS bear only limited resemblance to atherosclerotic cardiovascular disease:(11,18) patients do not have hyperlipidemia, but the low serum cholesterol levels typical of children,(11,20) and there is only a limited and tenuous involvement of macrophages in the artery wall (as in ‘normal’ aging);(11) the lesions are not the result of cholesterol storage within foam cells, but instead arise primarily because of early thinning of the vasculature, caused by replicative and/or mutational senescence.(11) Similarly, the causes of bone decay in HGPS are very different from those seen in aging humans. And while HGPS patients do exhibit some phenotypes with a superficial resemblance to those associated with ‘normal’ aging (hair loss, thin-looking skin because of a a lack of subcutaneous fat, wrinkling, skeletal abnormalities), many age-related diseases are absent from progeroid patients: they are, happily, not plagued by dementia (except when caused by a stroke), cataracts, age-related macular degeneration, near- or farsightedness, diabetes (although ~50% of patients exhibit some insulin resistance), or cancer, and have only limited renal involvement (18-21). Moreover, while degenerative aging is characterized by progressive thymic involution that contributes to the progressive decline of adaptive immunity with age, the thymus of HGPS patients is of normal size and in some cases exhibits significant hyperplasia, and their hormone levels and immune function appear to be normal for their calendar age.(20)
We are heartened to hear news of this potential breakthrough in the treatment of HGPS, because of the suffering it will relieve in parent and child alike. But we must look elsewhere for guidance in the development of therapies against the diseases and disabilities of aging — to rejuvenation biotechnologies, that remove, repair, replace, or render harmless the cellular and molecular lesions that accumulate in aging tissues and restore them to healthy function. On the other hand, this new study can inspire us with the power of medical research to improve the lives of all of us. Ultimately, all degenerative aging is “premature,” because like HGPS, it robs its victims of health and strength, and brings suffering to their loved ones. It is SENS Research Foundation’s mission to develop, promote, and ensure widespread access to the new medicines that will comprehensively address the damage of aging — postponing, arresting, and ultimately putting an end to the frailty, sickness, and excessive proximity to death that is inflicted on all of us by “garden-variety” aging.
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