Project 1, BME 365R 2022
Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare autosomal dominant
disorder that results in premature aging. Within the first years of life, affected children develop several pathologies, which are commonly observed in aging, including alopecia, osteoporosis, atherosclerosis and vascular calcifications. Cardiovascular failure and stroke are the most common causes of death and the median survival is 14.6 years.
Many years of study have revealed that this disorder results from a defect in a protein called lamin A (LMNA), a type of intermediate filament that is found in the nuclear membrane. Lamin A undergoes a post-translational modification that adds a lipid farnesyl group to the protein. In the mutated version, this lipid modification cannot be cleaved for removal and the protein aggregates at the nuclear membrane.
A major breakthrough came in 2021 when the FDA approved a new therapeutic option for patients with progeria resulting from mutated LMNA. See the references from Cell below for an overview of the milestones that led to this point. While promising, treatment with this drug, lonafarib is not a cure; trials show that it extends patients survival by a median of 2.5 years.
In this assignment, we ask you to investigate other therapeutic strategies to improve quality and length of life for these patients.
As a starting point, you may find these references useful:
Benedicto, et al (2022). Progeria: a perspective on potential drug targets and treatment strategies. Expert Opinion on Therapeutic Targets, 26:5, 393-399.
Gordon L, et al. (2018). Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome. JAMA. 2018;319(16):1687- 1695.
Misteli T. (2021). Farnesyltransferase inhibition in HGPS, Cell 10.1016/j.cell.2020.12.029.
YOUR ASSIGNMENT
Carry out a literature search on this topic. Use what you learn to propose and describe two studies (Study 1 and 2) that address one or more of these open questions about HGPS. You wont be able to actually answer the question in this assignment! You will propose well-designed studies that could address the question. Describe these in a 2-page proposal that includes the following sections:
Significance (~1/3 page) describing the question you are addressing, key prior work, and the barriers that have so far prevented progress. All prior work must be properly cited.
Innovation (~1/3 page) describing how your proposed studies are innovative and improve on previous work. Your proposed work should be realistic within 2-5 years. Of course, you may not be able to completely understand any biological question within that time frame. Therefore, choose milestones that are reasonable within that period.
Proposal Plan (~1 1/3 page) describing the 2 technical studies that you will perform. For each, explain what you will measure and how. Include any important controls or comparisons. Include at least one quantitative plot to show your expected results (this is one case where you can make up imaginary data!) How will you interpret the results and measure success of the study? Describe the limitations of your proposed work. All discussions of prior work should be properly cited.
Evaluation Rubric for Project 1
A. Significance
1. Does the Significance section explain the pathophysiology (the disordered physiology (function) process associated with the disease) of the target health problem?
2. Does this section explain prior work to address this health problem?
3. Does this section describe the critical barriers to progress in the field?
B. Innovation
4. Does this section describe, in precise terms, the proposed solution?
5. Does this section describe how the proposed solution improves on previous work?
6. Is the proposed solution realistic, within a time frame of 2-5 years?
C. Proposal Plan
7. Are 2 technical studies described in appropriate detail?
8. Do the milestones explain what will be measured? Are controls or comparisons included?
9. Is there at least one quantitative plot or figure to show the expected results?
10. Does the plan describe the limitations of the suggested approach?
D. Written Proposal
11. Are there sufficient references to prior scientific literature and is the work attributed correctly?
12. Are the page limits followed (the Figure and citations can extend beyond the 2 page limit)?
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