What possible therapies are there?
Hutchinson-Gilford Progeria Syndrome (HGPS), is a rare genetic disorder characterized by accelerated aging. It is a complex disease that has a great impact on the patient’s quality of life. The current therapies for progeria are limited and not curative. While treatments like lonafarnib (FTI therapy) and experimental gene editing (CRISPR, antisense oligonucleotides) show promise, they primarily slow disease progression rather than completely reversing it.
Farnesyltransferase Inhibitors (FTIs): LONAFARNIB
Lonafarnib is a farnesyltransferase inhibitor initially developed for oncology and later used for the treatment of Progeria. In HGPS, a genetic mutation leads to the production of progerin, a toxic protein that accumulates in the nuclear envelope, altering nuclear morphology and impairing cellular function. Lonafarnib reduces intracellular accumulation and toxicity.
Clinical studies have demonstrated that lonafarnib can extend survival, improve vascular stiffness, bone structure, hearing, and certain laboratory markers in children with HGPS. It represents the first and only FDA-approved therapy for this condition, receiving approval in November 2020 based on the results of open-label clinical trials showing a significant increase in median lifespan.
Lonafarnib is administered orally as capsules or liquid usually twice a day. The administration starts either 21 or 100 days after the birth. While effective, lonafarnib is not a cure and has limitations. Its benefits are very limited, mostly slowing disease progression rather than reversing it. It does not fully prevent progerin production, and some toxic effects persist.
Side effects are generally manageable but include gastrointestinal symptoms (such as diarrhea, vomiting, and weight loss), fatigue, and electrolyte imbalances, which may require supportive care or dose adjustments. Importantly, the drug’s long-term effects beyond current clinical follow-ups are still under investigation. Therefore it is important to take in consideration that there may be side effects not observed in the mouse model but possible in humans. We also need to take into consideration that results from mouse models may not fully replicate in human subjects. There is also a possibility of developing resistance to therapy over extended periods.
Gene editing approches in progeria treatment: CRISPR/Cas-9-based therapy
CRISPR/Cas is a very versatile technique with versatile applications. One of its many applications regards HGPS. Traditional treatments have focused on mitigating the downstream effects of progerin accumulation. However, recent advancements have turned towards gene editing to address the root cause.
The CRISPR/Cas9 approach aims to introduce frameshift mutations in the LMNA gene, disrupting the aberrant splice site responsible for progerin production. This way the production of lamin A and progeria is reduced drastically but lamin C expression remains unaffected, which is crucial since lamin C is essential for normal cellular functions.
The studies focus on this type of therapy using lentiviral vectors (adeno-associated virus serotype 9) to deliver CRISPR/Cas components. These vectors were administered to both HGPS patient-derived cells and a mouse model harboring the human HGPS mutation. The lentiviral system facilitated the integration of the gene-editing machinery into target cells, enabling the desired genetic modifications.
HGPS patient-derived fibroblasts treated with the CRISPR/Cas9 system exhibited a significant reduction in progerin levels in different tissues. This reduction led to improvements in nuclear morphology and a decrease in DNA damage markers, indicating enhanced cellular health.
Treated HGPS mice showed a notable decrease in progerin expression across various tissues. This reduction was associated with improved vascular pathology, enhanced overall health, and an extension of lifespan compared to untreated counterparts.
Potential downsides of this therapy are various. CRISPR/Cas9 technology carries the risk of unintended genetic modifications, which could lead to various effects. While this technique is usually precise with minimal off-target activity, it is necessary to assess all of the possibilities before clinical application of this therapy. The efficiency of gene editing may vary among cells, resulting in a mosaic pattern where not all cells are corrected. This incomplete editing could limit the overall therapeutic efficacy. Furthermore, lentiviral vectors integrate into the host genome, raising concerns about insertional mutagenesis and long-term safety. Alternative delivery methods may need exploration to mitigate these risks. Another factor that needs to be taken into account is immune response. The introduction of bacterial-derived Cas9 protein could elicit an immune response in patients, potentially compromising the treatment’s safety and effectiveness.
Antisense Oligonucleotide therapy that slows progeria
One of the most recent advancements in the treatment of HGPS is the use of antisense oligonucleotides (ASOs). These molecules can effectively reduce mRNA and progerin levels, leading to a lifespan extension in HGPS mouse models. ASOs are short synthetic strands of nucleotides designed to specifically bind to target mRNA sequences, inducing their degradation or modifying their splicing.
In the context of Progeria, they can prevent the production of progerin by modifying the splicing of LMNA mRNA or degrading the mutant transcripts.
ASOs were administered systemically to HGPS mouse models. Systemic administration allows the ASOs to circulate throughout the body and target multiple tissues affected by progerin accumulation. The specific delivery methods and dosing regimens were optimized to maximize tissue penetration and therapeutic efficacy.
Treatment with ASOs led to a significant decrease in both progerin mRNA and protein levels across various tissues. Treated mice exhibited amelioration of disease symptoms, including improved vascular health and increased body weight. Notably, there was a marked extension in the lifespan of ASO-treated HGPS mouse models compared to untreated controls.
Besides these great benefits, there are also downsides and many considerations that need to be examined. For example, achieving efficient and uniform delivery of ASOs to all affected tissues remains a significant challenge. While ASOs are designed for specificity, there is a risk of unintended interactions with non-target mRNAs, which could lead to side effects.
Furthermore, ASOs may have a relatively short half-life in circulation, necessitating frequent administrations to maintain therapeutic levels. Repeated administration of ASOs could potentially elicit immune responses, reducing efficacy or causing adverse effects.The development of ASO-based therapies offers a promising way to directly target the genetic underpinnings of HGPS. By reducing progerin production, these therapies have demonstrated significant benefits in preclinical models. However, challenges related to delivery, specificity, and long-term safety must be addressed before clinical application can be realized.
For more infromations about actual herapeutic options for treating progeria we advice the reading of the scientifics articles you can find at the following links: